Atypical Pyoderma Gangrenosum Mimicking an Infectious Process

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Derek To

2014-01-01

Full Text Available We present a patient with atypical pyoderma gangrenosum (APG, which involved the patient’s arm and hand. Hemorrhagic bullae and progressive ulcerations were initially thought to be secondary to an infectious process, but a biopsy revealed PG. Awareness of APG by infectious disease services may prevent unnecessary use of broad-spectrum antibiotics.

Successful treatment of myelodysplastic syndrome-induced pyoderma gangrenosum.

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Koca, E; Duman, A E; Cetiner, D; Buyukasik, Y; Haznedaroglu, I C; Uner, A; Demirhan, B; Kerimoglu, U; Barista, I; Calguneri, M; Ozcebe, O I

2006-12-01

We report successful treatment of a refractory myelodysplastic syndrome-associated pyoderma gangrenosum with the combination of thalidomide and interferon-alpha2a in a single patient. A non-healing wound developed on a 40-year-old woman's left thumb after minor trauma. Massive ulcerovegetative lesions developed after reconstruction surgery. Histopathological examination of the bone marrow and cytogenetic studies revealed an atypical myeloproliferative/myelodysplastic syndrome. The skin lesions resolved dramatically after two months of thalidomide and interferon-alpha2a combination therapy and the haematological status improved.

Successful Use of Adalimumab for Treating Pyoderma Gangrenosum with Ulcerative Colitis under Corticosteroid-tapering Conditions.

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Sagami, Shintaro; Ueno, Yoshitaka; Tanaka, Shinji; Nagai, Kenta; Hayashi, Ryohei; Chayama, Kazuaki

2015-01-01

A 52-year-old woman with ulcerative colitis was admitted to our hospital for an ulcerative colitis flare-up under salazosulfapyridine therapy. The symptoms improved with high-dose corticosteroids. After prednisolone was tapered to 10 mg, the frequency of diarrhea increased. The diarrhea was accompanied by joint pain and a skin ulcer with abscess formation, which was diagnosed to be pyoderma gangrenosum. The patient was started on adalimumab. A positive response to the adalimumab therapy was observed after 2 weeks, during which time the ulcerative skin lesion healed completely, however, colonic mucosal healing was achieved at 2 months. Therefore, adalimumab appears to be an effective therapeutic option for patients with ulcerative colitis-associated pyoderma gangrenosum.

A pregnancy-associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome.

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Horiuchi, Isao; Fukatsu, Yuko; Ushijima, Junko; Nakamura, Eishin; Samajima, Koki; Kadowaki, Kanako; Takagi, Kenjiro

2016-10-01

Little is known about the influence of pregnancy on pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome. We experienced a rare case of pregnancy complicated with PAPA syndrome. The patient had various histories of skin and joint disorders and experienced subarachnoid hemorrhage during pregnancy; however, her skin lesion was unaffected.

A case of pyoderma gangrenosum involving the prostate gland after radiation therapy for prostate cancer

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Kanno, Toru; Ito, Masaaki; Tsuji, Hiroshi; Kawase, Norio; Taki, Yoji

2002-01-01

A 76-year-old man complained of difficulty in urination and miction pain with abacterial pyuria after radiation therapy for prostate cancer. Transurethral resection of the prostate was performed and histopathologically widespread necrosis was observed in the prostate. Thereafter retention of urine and fever occurred and computed tomography scan revealed an abscess of the penile corpus. The abscess was drained, but the fever continued. He developed an abacterial lung abscess and abacterial necrotic ulcerating lesions on his back, his left leg and his lower abdomen. Macroscopic findings demonstrated typical features of pyoderma gangrenosum. Steroid treatment was initiated and the response to steroid therapy was dramatic. Finally urinary diversion using an ileal conduit was performed. We found few cases of pyoderma gangrenosum involving lesions other than those of the skin in the literature. This is the first report of pyoderma gangrenosum involving the prostate gland after radiation therapy for prostate cancer. (author)

A case of pyoderma gangrenosum involving the prostate gland after radiation therapy for prostate cancer

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Kanno, Toru; Ito, Masaaki; Tsuji, Hiroshi; Kawase, Norio; Taki, Yoji [Toyooka Hospital, Hyogo (Japan)

2002-09-01

A 76-year-old man complained of difficulty in urination and miction pain with abacterial pyuria after radiation therapy for prostate cancer. Transurethral resection of the prostate was performed and histopathologically widespread necrosis was observed in the prostate. Thereafter retention of urine and fever occurred and computed tomography scan revealed an abscess of the penile corpus. The abscess was drained, but the fever continued. He developed an abacterial lung abscess and abacterial necrotic ulcerating lesions on his back, his left leg and his lower abdomen. Macroscopic findings demonstrated typical features of pyoderma gangrenosum. Steroid treatment was initiated and the response to steroid therapy was dramatic. Finally urinary diversion using an ileal conduit was performed. We found few cases of pyoderma gangrenosum involving lesions other than those of the skin in the literature. This is the first report of pyoderma gangrenosum involving the prostate gland after radiation therapy for prostate cancer. (author)

Wall-eyed bilateral internuclear ophthalmoplegia (webino syndrome and myelopathy in pyoderma gangrenosum

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Marco Aurélio Lana

1990-12-01

Full Text Available A 35-year-old female with pyoderma gangrenosum developed paraparesis with a sensory level at L1. Three months later she complained of diplopia and was found to have bilateral internuclear ophthalmoplegia with exotropia and no ocular convergence. The term Webino syndrome has been coined to design this set of neuro-opthalmologic findings. Although it was initially attributed to lesions affecting the medial longitudinal fasciculus and the medial rectus subnuclei of the oculomotor complex in the midbrain the exact location of the lesion is still disputed. In the present case both myelopathy and Webino syndrome were probably due to vascular occlusive disease resulting from central nervous system vasculitis occurring in concomitance to pyoderma gangrenosum.

A novel de novo PSTPIP1 mutation in a boy with pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) syndrome.

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Fathalla, Basil M; Al-Wahadneh, Adel M; Al-Mutawa, Mariam; Kambouris, Marios; El-Shanti, Hatem

2014-01-01

Autoinflammatory disorders are a group of Mendelian disorders characterized by seemingly unprovoked inflammatory bouts without high-titer autoantibodies or antigen-specific T-cells and are probably due to defects in the innate immunity. We here report on a 4-year-old Arabic boy with the clinical presentation of an autoinflammatory disorder, namely Pyogenic Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome. The presentation includes abscess formation after immunization and recurrent mono-articular acute arthritis in various joints that responded favourably to systemic glucocorticosteroids, albeit without acne or pyoderma gangrenosum. The mutation analysis of the boy identified a novel de novo mutation in PSTPIP1, the gene responsible for PAPA syndrome. We recommend that the diagnosis of PAPA syndrome should be entertained in the differential diagnosis of patients with recurrent sterile pyogenic arthritis prior to the development of pyoderma gangrenosum or acne in order to initiate a timely management of the disorder.

Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome.

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Braun-Falco, Markus; Kovnerystyy, Oleksandr; Lohse, Peter; Ruzicka, Thomas

2012-03-01

PAPA syndrome is a recently identified hereditary autoinflammatory syndrome clinically characterized by pyogenic arthritis, severe acne, and pyoderma gangrenosum. It is caused by mutations in the PSTPIP1 gene and may be closely linked to the aseptic abscesses syndrome, which has been shown to be associated with CCTG repeat amplification in the promoter region of PSTPIP1. We describe two unrelated patients with a clinical presentation quite similar to, yet distinct from, PAPA syndrome. Both patients had pyoderma gangrenosum and acute or remittent acne conglobata, but, in contrast to PAPA syndrome, lacked any episodes of pyogenic arthritis. Instead, they had suppurative hidradenitis. Mutations in PSTPIP1 exons 1 to 15 were excluded. In the promoter region, an increased repetition of the CCTG microsatellite motif was present on one allele in both patients. Alterations of the most commonly affected exons of the MEFV, NLRP3, and TNFRSF1A genes also were not detectable. One patient was treated with the interleukin (IL)-1 receptor antagonist anakinra and responded well, although without complete remission. This implies that IL-1ß may be of pathogenetic importance. Small number of patients, no gene mutation identified, and unclear efficacy of therapy are limitations. The clinical triad of pyoderma gangrenosum, acne, and suppurative hidradenitis represents a new disease entity within the spectrum of autoinflammatory syndromes, similar to PAPA and aseptic abscesses syndrome. For this disease, we propose the acronym "PASH" syndrome. PASH syndrome may respond to IL-1ß blockade. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

A Case of Pyoderma Gangrenosum with Ulcerative Colitis Treated with Mesalazine

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Lee, Jae In; Park, Hyun Jeong; Lee, Jun Young; Cho, Baik Kee

2010-01-01

Pyoderma gangrenosum (PG) manifests as recurrent deep ulceration of the skin and PG is associated with a variety of disorders. Approximately 30% of the cases of PG develop in patients with inflammatory bowel disease. A 34-year-old woman presented with a one-week history of recurrent ulcers on the right cheek and back. She was diagnosed with ulcerative colitis (UC) 4 years previously and with PG 1 year previously. The clinical course of the skin lesions followed the status of her UC. The patie...

Simultaneous Onset of Ulcerative Colitis and Disseminated Pyoderma Gangrenosum

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Albrecht Neesse; Patrick Michl; Steffen Kunsch; Volker Ellenrieder; Thomas M. Gress; Martin Steinkamp

2007-01-01

Pyoderma gangrenosum (PG) is an immune-mediated inflammatory skin condition representing one of the most distinct extraintestinal manifestations of inflammatory bowel disease (IBD). PG occurs independently from intestinal disease activity in about 1–2% of patients suffering from ulcerative colitis or Crohn's disease and is characterized by chronic deep skin ulcers whose exact pathogenesis is still unknown. So far, patients with ulcerative colitis have only been reported to develop PG during t...

Intravenous immunoglobulin use in managing severe, perioperative peristomal pyoderma gangrenosum following subtotal colectomy with end ileostomy for medically refractory chronic ulcerative colitis

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Behm, Kevin; Larson, David W.; Colibaseanu, Dorin

2015-01-01

Peristomal pyoderma gangrenosum (PPG) is a rare subtype of pyoderma gangrenosum that is characterized by painful, necrotic ulcerations occurring in the area surrounding an abdominal stoma. PPG is typically seen in younger patients with active inflammatory bowel disease. The etiology and pathogenesis is largely unknown and risk factors are not well defined. Therapy typically involves a combination of aggressive local wound care and systemic medications. Diagnosis and management of PPG can be d...

[A Case of Pyoderma Gangrenosum of the Penis Difficult to Distinguish from Fournier Gangrene].

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Taguchi, Makoto; Inoue, Takaaki; Nishida, Teruhisa; Kawabata, Takashi; Kawakita, Shigenari; Muguruma, Kouei; Murota, Takashi; Kinoshita, Hidefumi; Matsuda, Tadashi

2015-11-01

Here, we report a case of pyoderma gangrenosum of the penis which was difficult to distinguish from Fournier gangrene. The patient was a 54-year-old male who was aware of redness and swelling of the glanspenis for 1 month prior to a consultation at our department. Although he was diagnosed with herpes and treated at a nearby hospital, his symptoms did not improve. Subsequently, the patient visited our department following the onset of pain and fever. During his initial consultation, he had a fever of 39 °C as well as redness and swelling of the glans penis with partial spontaneous purulent discharge. His blood test revealed an elevated white blood cell count (20, 000/μl) and C-reactive protein (19.1 mg/dl). Because Fournier gangrene was suspected, administration of broad-spectrum antimicrobial agents was initiated but proved to be ineffective. An abscess (2 cm in diameter) was also noted in the umbilical region.Enterococcus faecalis was detected by the bacterial culture ; and therefore, Fournier gangrene was diagnosed. A partial penectomy was performed to control the infection. Pathological findings showed only non-specific inflammation ; however, fever persisted postoperatively and blood test results showed no improvement. Furthermore, new abscess lesions emerged on the right heel and back. Because the re-performed abscess bacterial culture test result was negative, pyoderma gangrenosum was suspected, and he was started on oral prednisolone (20 mg/day). On the following day, his fever subsided and his blood test results also showed improvement. A final diagnosis of pyoderma gangrenosum was ultimately made.

Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: identification of Helicobacter bilis by mass spectrometry analysis.

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Murray, Patrick R; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B; Ecker, David J; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L

2010-05-01

Pyoderma gangrenosum-like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient's culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when subcultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum-like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum-like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy.

Pyoderma gangrenosum: A clinician′s nightmare

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Bindhu Bhaskaran

2016-01-01

Full Text Available Pyoderma gangrenosum (PG is a rare disease and that affecting specifically the sole of the foot, is even rarer. Here, we report the case of a 54-year-old female admitted with a painful ulcer on the sole of the right foot which was initially treated with empirical antibiotics and debridement. The disease was found to spread rapidly after each debridement. The culture reports were negative; rheumatology workup and Doppler study were within normal limits. A clinical suspicion of PG was made and was confirmed with tissue biopsy. She was started on oral steroids following which she dramatically improved. Thus, when a patient presents with a rapidly expanding painful ulcer in a vascular limb that is refractory to antibiotic treatment and exacerbating on debridement, it is imperative to consider the possibility of PG.

A rare case of adult scalp pyoderma gangrenosum with cranial osteolysis

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L. Aljohmani; K. Abdul-Jalil; C. deBlacam; G.M. Murphy; J.B. O'Sullivan

2018-01-01

Pyoderma gangrenosum (PG) is a rare and painful idiopathic skin condition that has one or more areas of chronic ulceration with well demarcated and undermined borders. Bone osteolysis (the pathological destruction of bone tissue) secondary to PG is a rare phenomenon with limited cases reported in children only. This is the first case report of scalp PG with cranial osteolysis in an 80-year-old adult, with an initial presentation mimicking skin carcinoma. This case highlights the importance...

Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).

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Demidowich, Andrew P; Freeman, Alexandra F; Kuhns, Douglas B; Aksentijevich, Ivona; Gallin, John I; Turner, Maria L; Kastner, Daniel L; Holland, Steven M

2012-06-01

To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment. This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome. Copyright © 2012 by the American College of Rheumatology.

Intravenous immunoglobulin use in managing severe, perioperative peristomal pyoderma gangrenosum following subtotal colectomy with end ileostomy for medically refractory chronic ulcerative colitis

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Behm, Kevin; Larson, David W.; Colibaseanu, Dorin

2015-01-01

Peristomal pyoderma gangrenosum (PPG) is a rare subtype of pyoderma gangrenosum that is characterized by painful, necrotic ulcerations occurring in the area surrounding an abdominal stoma. PPG is typically seen in younger patients with active inflammatory bowel disease. The etiology and pathogenesis is largely unknown and risk factors are not well defined. Therapy typically involves a combination of aggressive local wound care and systemic medications. Diagnosis and management of PPG can be difficult and data on treatment are limited. We present a case of severe postoperative peristomal recalcitrant to conventional therapy successfully treated with intravenous immune globulin. PMID:25802252

A case of pyoderma gangrenosum with ulcerative colitis treated with mesalazine.

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Lee, Jae In; Park, Hyun Jeong; Lee, Jun Young; Cho, Baik Kee

2010-11-01

Pyoderma gangrenosum (PG) manifests as recurrent deep ulceration of the skin and PG is associated with a variety of disorders. Approximately 30% of the cases of PG develop in patients with inflammatory bowel disease. A 34-year-old woman presented with a one-week history of recurrent ulcers on the right cheek and back. She was diagnosed with ulcerative colitis (UC) 4 years previously and with PG 1 year previously. The clinical course of the skin lesions followed the status of her UC. The patient's skin lesions and bowel symptoms were not improved with prednisolone. After she was started on mesalazine, we observed rapid resolution of skin lesions and bowel symptoms. Herein, we report a case of recurrent PG with UC, and we discuss the possible association between these two conditions, and the efficacy of mesalazine therapy for the treatment of PG combined with UC.

Biological Therapy for Pyoderma Gangrenosum

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Naw Ally Krüger

2013-10-01

Full Text Available Introduction: pyoderma gangrenosum (PG is a rare and severe neutrophilic dermatosis asso- ciated with inflammatory bowel disease (IBD and other systemic diseases such as rheu- matoid arthritis and hematological malignancies. Diagnosis is based on clinical criteria and exclusion of other skin disorders. There is no gold standard for the treatment of PG; traditionally intravenous corticosteroids are used, but recently the use of drugs that in- hibit tumor necrosis factor alpha (TNF-alpha has changed the management of PG, showing great effectiveness.Case report: female patient, 23 years old, diagnosed with severe nonspecific ulcerative colitis (UC three years ago, undergoing treatment with oral mesalamine and azathioprine. She developed PG fourteen days after hospital discharge; hospitalization was due to worsening of intestinal disease symptoms. She was successfully treated using biological therapy after unfavorable evolution with corticosteroid therapy.Conclusion: PG, a rare extraintestinal manifestation of IBD of difficult resolution that has significant impact on patient quality of life. The use of biological therapy for PG has higher efficacy in the treatment of patients decreasing wound healing time and return to daily activities. Resumo: Introdução: pioderma gangrenoso (PG é uma rara e grave dermatose neutrofílica associada a doença inflamatória intestinal (DII e a outras doenças sistêmicas como a artrite reumatoi- de e neoplasias hematológicas. O diagnóstico é baseado em critérios clínicos e exclusão de outras desordens da pele. Ainda não há padrão ouro para o tratamento do PG, tradicional- mente usa-se corticoides endovenosos, porém recentemente o uso de fármacos inibidores do fator de necrose tumoral alfa (TNF-alfa tem mudado o manejo do PG mostrando grande efetividade.Relato do caso: paciente feminina, 23 anos, com diagnóstico de retocolite ulcerativa inespe- cífica (RCUI severa há três anos, em tratamento com

Simultaneous Onset of Ulcerative Colitis and Disseminated Pyoderma Gangrenosum

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Albrecht Neesse

2007-10-01

Full Text Available Pyoderma gangrenosum (PG is an immune-mediated inflammatory skin condition representing one of the most distinct extraintestinal manifestations of inflammatory bowel disease (IBD. PG occurs independently from intestinal disease activity in about 1–2% of patients suffering from ulcerative colitis or Crohn’s disease and is characterized by chronic deep skin ulcers whose exact pathogenesis is still unknown. So far, patients with ulcerative colitis have only been reported to develop PG during the course of IBD but not at the initial manifestation of bowel symptoms. This is the first report demonstrating the simultaneous onset of ulcerative colitis and severe multifocal PG. In addition, we provide first evidence that infliximab may have a particularly powerful effect in early disseminated PG compared to late-onset PG, advocating an early application of this drug.

Pyoderma gangrenosum in association with microscopic colitis, idiopathic hypereosinophilic syndrome, selective IgE deficiency and diabetes mellitus.

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Riyaz, N; Sasidharanpillai, S; Rahima, S; Bindu, V; Shaan, M; Raghavan, N T; Mohan, L; Janardhanan, A K

2015-08-01

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis of unknown aetiology. We report a 27-year-old male patient with diabetes, who presented with a nonhealing ulcer on the left leg, pruritic hyperpigmented papules distributed over the trunk and limbs, and chronic diarrhoea. He had eosinophilia, low haemoglobin and serum IgE levels, and raised erythrocyte sedimentation rate. Histopathology of the leg ulcer was consistent with the diagnosis of PG, while the histology of the hyperpigmented papule revealed tissue eosinophilia. Subsequent evaluation was conclusive of the diagnosis of PG, idiopathic hypereosinophilic syndrome (IHES) and selective IgE deficiency. Dexamethasone pulse therapy achieved resolution of the ulcer and reduction in the eosinophilia. Further evaluation for the persistent diarrhoea led to a diagnosis of lymphocytic colitis (LC), which responded to budesonide. To our knowledge, the association of PG with IHES, selective IgE deficiency or LC has not been previously reported. © 2015 British Association of Dermatologists.

Pyoderma Gangrenosum Masquerading as Necrotizing Fasciitis: Stepping Away from Cognitive Shortcuts

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Rachael Hilton

2017-09-01

Full Text Available A patient with post-Cesarean wound complication was treated for necrotizing fasciitis (NF with sharp debridement and broad-spectrum antibiotics. Several operations and three weeks later, her abdominal skin, subcutaneous fat, right-sided rectus abdominus, and underlying fascia had been removed without any improvement in granulation tissue. Original pathology samples demonstrated sheets of necrosis consistent with NF, but were re-reviewed by a dermatopathologist who diagnosed the patient with pyoderma gangrenosum (PG. She was started on high-dose steroids and dapsone, and her wound quickly showed signs of improvement. Anchor bias delayed the initiation of steroids and diagnosis of PG as the surgical, medical, and consulting teams were hesitant to stray from the diagnosis of NF.

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome: differential diagnosis of septic arthritis by regular detection of exceedingly high synovial cell counts.

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Löffler, W; Lohse, P; Weihmayr, T; Widenmayer, W

2017-08-01

Pyogenic arthritis, pyoderma gangrenosum and acne syndrome was diagnosed in a 42-year-old patient, after an unusual persistency of high synovial cell counts had been noticed. Clinical peculiarities and problems with diagnosing septic versus non-septic arthritis are discussed.

Biologics for the treatment of pyoderma gangrenosum in ulcerative colitis.

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Arivarasan, K; Bhardwaj, Vaishali; Sud, Sukrit; Sachdeva, Sanjeev; Puri, Amarender Singh

2016-10-01

Pyoderma gangrenosum (PG) is an uncommon extra-intestinal manifestation of inflammatory bowel disease (IBD). Despite limited published literature, biologics have caused a paradigm shift in the management of this difficult-to-treat skin condition. The clinical data and outcomes of three patients with active ulcerative colitis and concurrent PG treated with biologics (infliximab two and adalimumab one) are reviewed in this report. Biologics were added because of the sub-optimal response of the colonic symptoms and skin lesions to parenteral hydrocortisone therapy. All three patients showed a dramatic response to the addition of the biologics. In view of the rapid healing of the skin lesions, superior response rate, and the additional benefit of improvement in the underlying colonic disease following treatment, anti-tumor necrosis factor blockers should be considered as a first line therapy in the management of PG with underlying IBD.

Behçet's syndrome with pyoderma-gangrenosum-like lesions treated successfully with dapsone monotherapy.

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Joshi, Arun; Mamta

2004-10-01

Behçet's syndrome (BS) is a rare multisystem disorder belonging to a group of neutrophilic dermatoses. We report a 65-year-old male patient who had suffered from recurrent painful orogenital ulcers for 50 years from the age of 15 and started developing pustular and bullous lesions evolving into non-healing ulcers similar to those seen in pyoderma gangrenosum (PG) two months prior to presenting to us. There was no evidence of systemic disease or malignancy. Routine baseline investigations were within normal limits. The patient was treated successfully with dapsone, antibiotics, and local wound care.

Atypical pyoderma gangrenosum following total knee replacement surgery: first report in dermatologic literature Pioderma gangrenoso atípico após artroplastia total do joelho: primeiro relato na literatura dermatológica

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Shyam B. Verma

2009-12-01

Full Text Available An atypical pyoderma gangrenosum mimicking a post surgical cutaneous and subcutaneous infection is being reported for the first time in international literature after knee replacement surgery with the operation site being the starting point of pyoderma gangrenosum. Orthopedic surgeons and general surgeons should be aware of the existence of this disease and its association with surgical trauma.Um pioderma gangrenoso atípico, similar a uma infecção cutânea e subcutânea pós-operatório, está sendo relatado pela primeira vez na literatura mundial, depois de realização de artroplastia do joelho, tendo como foco inicial o local da cirurgia. Cirurgiões ortopédicos e gerais devem estar cientes da existência dessa doença e de sua associação ao trauma cirúrgico.

Pyoderma gangrenosum: an exceptional complication of venous access device.

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La Marca, Sophie; Toussoun, Gilles; Ho Quoc, Christophe; Sebban, Henry; Delay, Emmanuel

2014-01-01

Pyoderma gangrenosum (PG) is a rare disease whose precise etiology remains unknown. It causes rapidly developing skin necrosis and can occur after surgery, or after a nonspecific external stimulus. This condition is difficult to diagnose because it often mimics a fulminant infection. We present a case of very significant local presentation of PG after placement of a venous access device. Fifteen days after placement, the patient developed extensive cutaneous ulcers and necrosis in the subclavicular area, which led to the misdiagnosis of infection. The device was removed and the patient was given antibiotics. Because there was no improvement following antibiotic treatment, combined with the worrying and extensive appearance of the skin and extremely intense pain, the diagnosis of PG was made. The patient was immediately treated with high-dose corticosteroids, resulting in rapid improvement of the lesions and relief of pain. PG should be considered in cases of extensive, antibiotic-resistant ulceration and treatment with corticosteroids should be initiated. Clinical improvement is usually dramatic, with almost immediate suppression of the pain and arrest of the lesion's progression. Early treatment is the best guarantee for an effective recovery.

Autoinflammatory syndromes associated with hidradenitis suppurativa and/or acne

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Vinkel, Caroline; Thomsen, Simon F.

2017-01-01

Autoinflammatory syndromes associated with hidradenitis suppurativa (HS) and/or acne are rare but potentially debilitating disorders if not diagnosed and treated correctly. They share a common pathogenesis involving a dysregulated innate immune system with abnormal interleukin (IL)-1 signaling...... leading to sterile neutrophilic inflammation. The clinical features are recurrent episodes of fever, painful arthritis, and skin lesions consistent with HS, acne, and pyoderma gangrenosum (PG) accompanied by elevated systemic inflammatory markers in blood. So far, several clinically different syndromes...... have been reported in the literature including pyoderma gangrenosum, acne, and pyogenic arthritis (PAPA), pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH), pyoderma gangrenosum, acne, and spondyloarthritis (PASS), pyoderma gangrenosum, acne, pyogenic arthritis, and hidradenitis...

Wegener’s granulomatosis and pyoderma gangrenosum – rare causes of facial ulcerations

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Karolina Kędzierska

2016-03-01

Full Text Available Background: Pyoderma gangrenosum (PG is caused by immune system dysfunction, and particularly improper functioning of neutrophils. At least half of all PG patients also suffer from autoimmunological diseases, one of which is Wegener granulomatosis (WG. The purpose of this article was to compare cases of patients with WG and PG in terms of their clinical course, histopathology, and applied treatment. In both, histopathological features are not fully distinct. Data from microbiological and immunological evaluation and clinical presentation are required to establish the diagnosis. We also present the case of a patient with WG and deep facial skin lesions not responding to standard treatment. Methods: Systematic review of the literature in PubMed using the search terms “Wegener granulomatosis AND Pyoderma gangrenosum” and case report. Results: The finding of 22 reports in the literature (PubMed suggests that it is a rare phenomenon. This study revealed a similar rate of comorbidity of WG and PG in both genders and an increased incidence of both diseases after the age of 50. Among skin lesions there was a dominance of ulceration, most often deep and painful, covering a large area with the presence of advanced necrosis and destruction of the surrounding tissue. The most common location proved to be the cervical-cephalic area. The most popular treatment included steroids with cyclophosphamide. Discussion: The rarity of the coexistence of these two diseases results in a lack of effective therapy. In such cases sulfone derivatives are still effective and provide an alternative to standard immunosuppression methods. Hyperbaric therapy and plasmapheresis can also play an important complementary role.

Pyoderma Gangranosum of the Penis

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Kim, Tae Heung; Oh, Seung Young

2009-01-01

We report a patient who developed pyoderma gangrenosum in the penis with invasion of the distal urethra. The patient was treated with prednisolone and thalidomide, followed by a reconstructive surgical repair using a scrotal island flap. We report this case with a brief review of the literature. PMID:19949683

Topical Medical Cannabis: A New Treatment for Wound Pain-Three Cases of Pyoderma Gangrenosum.

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Maida, Vincent; Corban, Jason

2017-11-01

Pain associated with integumentary wounds is highly prevalent, yet it remains an area of significant unmet need within health care. Currently, systemically administered opioids are the mainstay of treatment. However, recent publications are casting opioids in a negative light given their high side effect profile, inhibition of wound healing, and association with accidental overdose, incidents that are frequently fatal. Thus, novel analgesic strategies for wound-related pain need to be investigated. The ideal methods of pain relief for wound patients are modalities that are topical, lack systemic side effects, noninvasive, self-administered, and display rapid onset of analgesia. Extracts derived from the cannabis plant have been applied to wounds for thousands of years. The discovery of the human endocannabinoid system and its dominant presence throughout the integumentary system provides a valid and logical scientific platform to consider the use of topical cannabinoids for wounds. We are reporting a prospective case series of three patients with pyoderma gangrenosum that were treated with topical medical cannabis compounded in nongenetically modified organic sunflower oil. Clinically significant analgesia that was associated with reduced opioid utilization was noted in all three cases. Topical medical cannabis has the potential to improve pain management in patients suffering from wounds of all classes. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

[Clinical patterns and treatment of pyoderma gangrenosum in a French department].

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Anuset, D; Reguiai, Z; Perceau, G; Colomb, M; Durlach, A; Bernard, P

2016-02-01

Pyoderma gangrenosum (PG) is a rare inflammatory neutrophilic dermatosis for which accurate epidemiological data are limited and therapy remains a challenge. The primary study aim was to examine all cases of PG observed in our regional department over a 15-year period in order to describe the relevant characteristics and outcome under therapy. The medical records of all patients with PG from 1997 to 2012 in the Marne department of France were studied retrospectively. Clinical and histological characteristics, comorbidities, therapeutic modalities and outcome were analysed. Forty-two patients were included (30 women, 12 men). A classical, ulcerative form was found in 39 cases and PG was multifocal in 28 cases. The number of lesions did not differ according to age or the presence of comorbidities. The most frequent first-line treatments were doxycycline (23 cases) and oral corticosteroids (15 cases), regardless of age, number of lesions or existence of comorbidities. Complete remission of PG was obtained in 38 cases (median time to remission: 3 months), with relapse occurring in 17 patients (median time to relapse: 12 months after treatment withdrawal). After a median follow-up of 46 months, 8 patients had died (median time to death: 26 months after treatment initiation). This is the first large French series of patients presenting PG and enabling determination of the annual incidence within the Marne department at around 4.6 cases/1000,000 inhabitants. Our study illustrates the value of first-line treatment with tetracycline, which merits confirmation by further prospective, controlled studies. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial.

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Ormerod, Anthony D; Thomas, Kim S; Craig, Fiona E; Mitchell, Eleanor; Greenlaw, Nicola; Norrie, John; Mason, James M; Walton, Shernaz; Johnston, Graham A; Williams, Hywel C

2015-06-12

To determine whether ciclosporin is superior to prednisolone for the treatment of pyoderma gangrenosum, a painful, ulcerating skin disease with a poor evidence base for management. Multicentre, parallel group, observer blind, randomised controlled trial. 39 UK hospitals, recruiting from June 2009 to November 2012. 121 patients (73 women, mean age 54 years) with clinician diagnosed pyoderma gangrenosum. Clinical diagnosis was revised in nine participants after randomisation, leaving 112 participants in the analysis set (59 ciclosporin; 53 prednisolone). Oral prednisolone 0.75 mg/kg/day compared with ciclosporin 4 mg/kg/day, to a maximum dose of 75 and 400 mg/day, respectively. The primary outcome was speed of healing over six weeks, captured using digital images and assessed by blinded investigators. Secondary outcomes were time to healing, global treatment response, resolution of inflammation, self reported pain, quality of life, number of treatment failures, adverse reactions, and time to recurrence. Outcomes were assessed at baseline and six weeks and when the ulcer had healed (to a maximum of six months). Of the 112 participants, 108 had complete primary outcome data at baseline and six weeks (57 ciclosporin; 51 prednisolone). Groups were balanced at baseline. The mean (SD) speed of healing at six weeks was -0.21 (1.00) cm(2)/day in the ciclosporin group compared with -0.14 (0.42) cm(2)/day in the prednisolone group. The adjusted mean difference showed no between group difference (0.003 cm(2)/day, 95% confidence interval -0.20 to 0.21; P=0.97). By six months, ulcers had healed in 28/59 (47%) participants in the ciclosporin group compared with 25/53 (47%) in the prednisolone group. In those with healed ulcers, eight (30%) receiving ciclosporin and seven (28%) receiving prednisolone had a recurrence. Adverse reactions were similar for the two groups (68% ciclosporin and 66% prednisolone), but serious adverse reactions, especially infections, were more common in

Cicatricial ectropion correction in a patient with pyoderma gangrenosum: case report Correção de ectrópio cicatricial em paciente com pioderma gangrenoso: relato de caso

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Fernando Procianoy

2009-06-01

Full Text Available A 19 year old female with pyoderma gangrenosum was referred to the oculoplastic clinic for evaluation of severe cicatricial ectropion of the right lower eyelid. Examination evidenced important scarring of lower eyelid and malar region with secondary ectropion. A full-thickness skin graft associated with a lateral tarsal strip procedure and scar tissue release was performed. The patient's corticosteroid dose was raised for the procedure, and after surgery there was no healing problem or ulcer formation in the eyelid or in the graft donor site. As pyoderma gangrenosum is associated with a pathergy phenomenon in up to 25% of the cases, the onset of new lesions is a relevant concern when performing surgery in these patients. In this case, the surgery was safely performed under corticosteroid immunosuppression.Paciente do sexo feminino de 19 anos com pioderma gangrenoso foi encaminhada ao setor de Plástica Ocular para avaliação de ectrópio cicatricial grave da pálpebra inferior direita. O exame evidenciou cicatrização importante na pálpebra inferior e região malar com um ectrópio secundário. Foi realizado liberação do tecido cicatricial e um enxerto de pele total associado a "tarsal strip". A dose de corticóide da paciente foi aumentada para a realização do procedimento e não houve problemas de cicatrização ou formação de úlceras na pálpebra ou no sítio doador após a cirurgia. Como o pioderma gangrenoso é associado ao fenômeno de patergia em até 25% dos casos, o surgimento de novas lesões é uma preocupação relevante ao indicar cirurgia nestes pacientes. Neste caso, a cirurgia foi realizada com segurança sob imunossupressão com corticóide.

Saddle-nose and bilateral cauliflower ear deformities with pyoderma gangrenosum-like ulcers, cavitary pulmonary lesions, digital gangrene and pulselessness in a young female.

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Subhadarshani, Sweta; Gupta, Vishal; Chahal, Anurag; Verma, Kaushal K

2017-06-15

We report a young female who presented with saddle-nose and bilateral cauliflower ear deformities along with pyoderma gangrenosum-like ulcers, digital gangrene and pulselessness. Subsequently, she was found to have bilateral conductive hearing loss, a corneal opacity, mild aortic regurgitation and radiological evidence of cavitary changes in lungs and aortoarteritis. Our patient had a constellation of symptoms which posed a diagnostic challenge. Finally, a diagnosis of relapsing polychondritis with several unusual features was made. Overlap with Takayasu's arteritis and granulomatosis with polyangitis, which has been reported rarely in the literature, cannot be excluded. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study.

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Thomas, Kim S; Ormerod, Anthony D; Craig, Fiona E; Greenlaw, Nicola; Norrie, John; Mitchell, Eleanor; Mason, James M; Johnston, Graham A; Wahie, Shyamal; Williams, Hywel C

2016-11-01

Pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. We sought to estimate the effectiveness of topical therapies in the treatment of patients with PG. This was a prospective cohort study of UK secondary care patients with a clinical diagnosis of PG that was suitable for topical treatment (recruited between July 2009 and June 2012). Participants received topical therapy after normal clinical practice (primarily topical corticosteroids [classes I-III] and tacrolimus 0.03% or 0.1%). The primary outcome was speed of healing at 6 weeks. Secondary outcomes included the following: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality of life; treatment failure; and recurrence. Sixty-six patients (22-85 years of age) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28 of 66 (43.8%) ulcers healed by 6 months. The median time to healing was 145 days (95% confidence interval, 96 days to ∞). Initial ulcer size was a significant predictor of time to healing (hazard ratio, 0.94 [95% confidence interval, 0.88-1.00); P = .043). Four patients (15%) had a recurrence. Our study did not include a randomized comparator. Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

An Unusual Presentation of Pyoderma Gangrenosum Leading to Systemic Inflammatory Response Syndrome

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Ali Didan

2017-09-01

Full Text Available This is a report of an atypical presentation of pyoderma gangrenosum (PG in a 26-year-old male who had a negative septic screen. The patient had a life-threatening presentation requiring an intensive care unit (ICU admission for vasopressor support. It was thought that the likely cause of circulatory collapse was an overwhelming cytokine reaction or systemic inflammatory response syndrome (SIRS secondary to extensive PG lesions rather than septic shock. The patient presented with multiple large ulcers, the largest being 4 cm in diameter on the central chest. He developed fevers and circulatory shock preceding his ICU admission. Microbiological specimens, including blood cultures and wound swabs, were negative for any growth (bacterial, fungal, and tuberculosis. No infective foci could be identified as a cause of hemodynamic instability. During admission, the patient’s condition was complicated by multi-organ dysfunction. Wound debridement extending to the deep fascia on the anterior chest, back, bilateral shoulders, and right upper thigh was deemed necessary and performed by the plastic surgery team. Histopathology showed abundant neutrophils but could not confirm an infective process. Overall, the patient made an impressive recovery with almost complete healing of all lesions following oral prednisolone alone. Based on the history and clinical and laboratory findings, a diagnosis of PG complicated by a SIRS was favored. Very few cases of neutrophilic dermatoses have been described in this way. A similar presentation has been described in a 76-year-old female with lower-leg ulcers who developed circulatory shock and required an amputation. Lesions continued to appear despite antibiotics and surgical treatment. Septic screen was negative. She was subsequently diagnosed with PG and recovered rapidly after steroid therapy.

Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome.

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Lindwall, Elvira; Singla, Shikha; Davis, William E; Quinet, Robert J

2015-08-01

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disease that usually presents in childhood with recurrent sterile arthritis. As the child ages into puberty, cutaneous features develop and arthritis subsides. We report the case of a now 25-year-old male patient with PAPA syndrome with the E250K mutation in PSTPIP1. We also present a systematic literature review of other PAPA cases. We conducted a literature search of PubMed using the following search terms: E250K mutation, PSTPIP1, and PAPA. PAPA syndrome is caused by mutations on chromosome 15q affecting the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene, also known as CD2-binding protein 1 (CD2BP1). The reported cases of PAPA syndrome currently in the literature involve mutations in A230T and E250Q. One case of a novel E250K mutation has been reported, which presented with a different phenotype to previously described cases of PAPA syndrome. With variation present between disease presentations from case to case, it is possible that the spectrum of PAPA syndrome is wider than currently thought. Further research is needed which may uncover an as-yet undiscovered genetic abnormality linking these interrelated diseases together. Copyright © 2015 Elsevier Inc. All rights reserved.

Pyoderma gangrenosum: A commonly overlooked ulcerative condition

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Daniel Zunsheng Tay

2014-01-01

Full Text Available Background: Pyoderma ga ngrenosum (PG is a rare, inflammatory, destructive neutrophilic dermatosis, which mimics other ulcerative conditions. Materials and Methods: In a retrospective study based on patients diagnosed with PG over a 3-year period (2010-2013, we evaluated demographics, anatomical sites, number of lesions, subtypes, histopathology, associated conditions, treatment regimens, healing time, and recurrence. Results: Of our five patients, there were three males and two females, age ranging between 19 and 58 years (mean age 38 years. Four had single lesions localized to the lower limbs while one had multiple lesions (more than five over bilateral hands and legs. Ulcerative subtype was observed in all the patients. One exhibited pathergy. Skin biopsies were done in four patients, revealing dense neutrophilic infiltrates in three cases and leukocytoclastic vasculitis in one. Associated systemic diseases were observed in all patients, four having inflammatory bowel disease and one having both systemic lupus erythematosus and anti-phospholipid syndrome. The patients were all treated with systemic corticosteroids either alone or in combination with immunosuppressants (e.g., azathioprine, mycophenolate mofetil, tacrolimus, and wound dressing. Split-thickness skin graft was done in one patient. Complete healing was achieved in all patients, ranging from one to 3 months after diagnosis. No recurrence was reported. Conclusions: Systemic corticosteroids, either alone or in combination with steroid-sparing agents are the mainstay of treatment. Should family physicians encounter a rapidly progressing ulcer that has poor response to usual wound management, timely referral to dermatology should be made.

Ciclosporin compared with prednisolone therapy for patients with pyoderma gangrenosum: cost-effectiveness analysis of the STOP GAP trial.

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Mason, J M; Thomas, K S; Ormerod, A D; Craig, F E; Mitchell, E; Norrie, J; Williams, H C

2017-12-01

Pyoderma gangrenosum (PG) is a painful, ulcerating skin disease with poor evidence for management. Prednisolone and ciclosporin are the most commonly used treatments, although not previously compared within a randomized controlled trial (RCT). To compare the cost-effectiveness of ciclosporin and prednisolone-initiated treatment for patients with PG. Quality of life (QoL, EuroQoL five dimensions three level questionnaire, EQ-5D-3L) and resource data were collected as part of the STOP GAP trial: a multicentre, parallel-group, observer-blind RCT. Within-trial analysis used bivariate regression of costs and quality-adjusted life years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. In the base case analysis, when compared with prednisolone, ciclosporin was cost-effective due to a reduction in costs [net cost: -£1160; 95% confidence interval (CI) -2991 to 672] and improvement in QoL (net QALYs: 0·055; 95% CI 0·018-0·093). However, this finding appears driven by a minority of patients with large lesions (≥ 20 cm 2 ) (net cost: -£5310; 95% CI -9729 to -891; net QALYs: 0·077; 95% CI 0·004-0·151). The incremental cost-effectiveness of ciclosporin for the majority of patients with smaller lesions was £23 374/QALY, although the estimate is imprecise: the probability of being cost-effective at a willingness-to-pay of £20 000/QALY was 43%. Consistent with the clinical findings of the STOP GAP trial, patients with small lesions should receive treatment guided by the side-effect profiles of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, ciclosporin-initiated treatment may be more cost-effective for patients with large lesions. © 2017 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

MESALAZİN VE STEROİD İLE TEDAVİ EDİLEN PYODERMA GANGRENOZUMUN EŞLİK ETTİĞİ ÜLSERATİF KOLİT VAKASI

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Balkan, Ayhan; Balkan, Yasemin; Namıduru, Mustafa; Mete, Ayşe; Mete, A. Ö.; Konduk, Buğra; Yıldırım, Abdullah; Gülşen, Murat

2015-01-01

Pyoderma gangrenosum (PG) is a serious skin lesion which may accompanying numerous diseases and it can cause of painful, and recurrent ulcer. The lesions may arise as single or multiple lesions secondary to systemic diseases such as ulcerative colitis, Crohn’s disease, polyarthritis, monoclonal gammopathy or spontaneously without any underlying disease. A 25-year-old male patient was admitted with complaints of fever, abdominal pain, bloody diarrhea, painful and infected deep ulcers on head, ...

Two cases of bowel perforation associated with sunitinib treatment for renal cell carcinoma.

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Hoshino, Yoshinori; Hasegawa, Hirotoshi; Ishii, Yoshiyuki; Endo, Takashi; Ochiai, Hiroki; Okabayashi, Koji; Kaneko, Gou; Mikami, Shuji; Mukai, Makio; Oya, Mototsugu; Kitagawa, Yuko

2012-08-01

Sunitinib, a multitargeted tyrosine kinase inhibitor, is widely used in the treatment of carcinoma. Adverse events associated with this treatment, including fatigue, diarrhea, and hematotoxicity, have been reported in clinical trials. Bowel perforation is a surgical emergency that requires immediate treatment depending on the location and progression of the tumor. We report 2 cases of bowel perforation during sunitinib treatment. The patients presented with diffuse peritonitis, and emergency exploratory laparotomy was performed. We speculate that the underlying mechanisms were decrease in capillary density of the normal mucosa in case 1 and tumor shrinkage because of sunitinib treatment in case 2. To the best of our knowledge, this is the first study to report the pathological findings implicating bowel perforation due to sunitinib treatment. Further investigations are needed to clarify the risk factors for intestinal perforations associated with sunitinib treatment.

Pioderma gangrenoso superficial como complicación de mamoplastia Superficial granulomatous pypoderma gangrenosum as a complication in mammoplasty

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R. González de Vicente

2011-03-01

Full Text Available El Pioderma Gangrenoso (PG es una rara enfermedad de etiología desconocida, sospechándose que pudiera ser debida a trastornos de autoinmunidad. Presentamos 2 casos de PG Granulomatoso en el postoperatorio mediato (3-6 semanas en pacientes sometidas a mamoplastia (mastopexia con prótesis. Ambos casos se solucionaron mediante tratamiento con corticoesteroides.Pyoderma Gangrenosum (PG is a rare disease whose etiology is unknown, suspecting that could be due to autoimmune disorders. We present 2 cases of Granulomatous PG in mediate postoperatory (3-6 weeks in patients undergoing mammoplasty (mastopexy with prosthesis. Both cases were solved by treatment with corticosteroids.

Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease.

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Knickelbein, Jared E; Jacobs-El, Naima; Wong, Wai T; Wiley, Henry E; Cukras, Catherine A; Meyerle, Catherine B; Chew, Emily Y

2017-01-01

To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling. Observational case review. Three patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate. Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits. Visual acuity, size of RCH, and degree of exudation. Three patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction. Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other

Identification of a homozygous PSTPIP1 mutation in a patient with a PAPA-like syndrome responding to canakinumab treatment.

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Geusau, Alexandra; Mothes-Luksch, Nadine; Nahavandi, Hesam; Pickl, Winfried F; Wise, Carol A; Pourpak, Zahra; Ponweiser, Elisabeth; Eckhart, Leopold; Sunder-Plassmann, Raute

2013-02-01

Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (OMIM 604416) is a rare autosomal dominant inherited autoinflammatory syndrome characterized by pyogenic sterile arthritis and less frequently accompanied by pyoderma gangrenosum and acne. It is associated with dominant missense mutations in the proline-serine-threonine phosphatase-interacting protein 1 gene (PSTPIP1) located on chromosome 15. The patient was diagnosed as having features of a PAPA-like syndrome in which cutaneous manifestations, such as pyoderma gangrenosum and acne fulminans, predominated. Sequencing of the PSTPIP1 gene was performed in the patient and his extended family. The patient's DNA analysis revealed a homozygous nucleotide exchange c.773G>C in the PSTPIP1 gene, leading to the substitution of glycine 258 by alanine (p.Gly258Ala), a previously reported heterozygous polymorphism. Heterozygous changes were identified in both of the patient's parents and in 7 other family members, all of whom were asymptomatic. The patient was treated with canakinumab, a human anti-interleukin 1β monoclonal antibody, which led to rapid remission of the symptoms. To our knowledge, this is the first reported case of the resolution of dermatological symptoms associated with a PAPA-like syndrome using canakinumab treatment. Further study of the p.Gly258Ala variant is warranted to determine whether this mutation has a role in causing an apparently recessive cutaneous syndrome resembling PAPA syndrome.

Diseases associated with hidranitis suppurativa: part 2 of a series on hidradenitis.

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Scheinfeld, Noah

2013-06-15

Hidradenitis suppurativa (HS), a pathologic follicular disease, impacts patients' lives profoundly and usually occurs in isolation. The diseases with the strongest association are obesity, depression, and pain. HS is associated with many diseases including acne conglobata (AC), dissecting cellulitis, pilonidal cysts, and obesity. Pyoderma fistulans sinifica (fox den disease) appears to be the same entity as Hurley Stage 2 of 3 HS. The rate of acne vulgaris in HS patients mirrors unaffected controls. The most common, albeit still uncommon, association is with seronegative, haplotype unlinked arthritis (most importantly B27), in particular spondolyarthritis. Crohn disease and HS occur together at a rate that varies from 0.6% to 38% in retrospective cases series. Ulcerative colitis occurred with HS in 14% of patients in one series. The next most common association is with pyoderma gangrenosum, but this association is likely under-reported. Synovitis-Acne-Pustulosis Hyperostosis-Osteitis (SAPHO) syndrome, which is rare, has more than 10 reports linking it to HS. Nine case reports have linked Dowling-Degos disease (DDD) to HS and two reports related HS to Fox-Fordyce disease (FF), but because both occur in the axilla this might be a mere coincidence. HS is rarely associated with ophthalmic pathology. Specifically, more than 5 reports link it to Keratitis-Ichthyosis-Deafness syndrome (KID); greater than10 cases link it to interstitial keratitis and 2 cases are linked to Behçet's disease. The presence of proteinuria and acute nephritis link HS to the kidney, especially since and reports have documented resolution of HS after renal transplant. Florid steatocystoma multiplex, Sjogren Syndrome, and HS have been linked and their reports likely underestimate their coincidence because all these entities involve occlusion (albeit by different mechanisms). Three reports link HS and amyloid, but both share some common genetic underpinnings and thus the coincidence of these

Efficacy of Enrofloxacin in the Treatment of Recurrent Pyoderma in Dogs

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B. Sudhakara Reddy

2014-07-01

Full Text Available Dogs with a history of more than three episodes of skin infections in a period of one year were selected for a study on recurrent pyoderma. Oral enrofloxacin along with appropriate simultaneous medication for the underlying associated conditions were chosen as therapy for recurrent pyoderma in dogs. Response to therapy was excellent in all the cases. Improvement was noticed by 12 to 20 days and 20 to 26 days in recurrent superficial and deep pyoderma respectively. Relapse occurred in one dog by 45 days due to re-introduction of allergic food. Enrofloxacin proved to be an effective, safe and convenient antibiotic for the treatment of recurrent pyoderma in dogs.

Ecthyma gangrenosum caused by Stenotrophomonas maltophilia in ...

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Ecthyma gangrenosum caused by Stenotrophomonas maltophilia in a neutropenic leukaemic infant: A case report. D K Das, S Shukla. Abstract. Ecthyma gangrenosum (EG) is a cutaneous lesion, mostly caused by pseudomonas in immunocompromised patients. Other bacterial and fungal pathogens have also been ...

Perfil clinicopatológico dos pacientes com pioderma gangrenoso do Hospital das Clínicas de Porto Alegre (RS - Brasil (2000-2006 Clinic and pathological profile of the patients with pyoderma gangrenosum at Hospital de Clínicas de Porto Alegre (RS - Brazil (2000-2006

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Mariana Tremel Barbato

2008-10-01

Full Text Available FUNDAMENTOS: O pioderma gangrenoso é doença neutrofílica pouco freqüente. Caracteriza-se por lesões cutâneas ulceradas, dolorosas, com bordas subminadas e violáceas. Os membros inferiores configuram o local mais acometido. Sua etiologia é incerta, mas em 50% dos casos encontra-se associação com outras doenças. A histopatologia é inespecífica, e o diagnóstico, essencialmente clínico. OBJETIVO: Avaliar o perfil clinicopatológico de pacientes com pioderma gangrenoso. MÉTODO: Estudo retrospectivo dos pacientes diagnosticados no período de 2000 a 2006 no Serviço de Dermatologia do Hospital de Clínicas de Porto Alegre. RESULTADOS: Foram observados 16 pacientes cuja idade média foi 49 anos, com predomínio do sexo feminino (62,5%. O período médio entre início da doença e diagnóstico foi de 1,6 ano. A forma clínica predominante foi a ulcerativa (81,25%, e 87,5% das lesões localizavam-se nos membros inferiores. O sintoma mais freqüentemente associado foi dor local (37,5%. Doze pacientes (66% apresentaram doenças sistêmicas concomitantes. Doença de Crohn, diabetes e colagenoses foram as principais comorbidades encontradas. O tratamento mais utilizado foi a corticoterapia sistêmica, associada ou não a outros medicamentos (50%, tendo 43,75% dos pacientes apresentado recidiva do quadro. CONCLUSÕES: Os dados avaliados condizem com os encontrados na literatura. As doenças associadas mais prevalentes foram ileíte regional, diabetes melitus e afecções do tecido conectivo. O tratamento mais utilizado incluiu corticoterapia sistêmica. A maioria dos pacientes apresentou cicatrização completa , porém o número de recidivas foi elevado.BACKGROUND: Pyoderma gangrenosum is an infrequent neutrophilic dermatosis. It presents more frequently with painful cutaneous ulcers, with undermined violaceous borders. The legs are most commonly affected. Etiology is uncertain, although there is an association with other diseases in 50% of

UK Dermatology Clinical Trials Network's STOP GAP trial (a multicentre trial of prednisolone versus ciclosporin for pyoderma gangrenosum): protocol for a randomised controlled trial.

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Craig, Fiona F; Thomas, Kim S; Mitchell, Eleanor J; Williams, Hywel C; Norrie, John; Mason, James M; Ormerod, Anthony D

2012-04-28

Pyoderma gangrenosum (PG) is a rare inflammatory skin disorder characterised by painful and rapidly progressing skin ulceration. PG can be extremely difficult to treat and patients often require systemic immunosuppression. Recurrent lesions of PG are common, but the relative rarity of this condition means that there is a lack of published evidence regarding its treatment. A systematic review published in 2005 found no randomised controlled trials (RCTs) relating to the treatment of PG. Since this time, one small RCT has been published comparing infliximab to placebo, but none of the commonly used systemic treatments for PG have been formally assessed. The UK Dermatology Clinical Trials Network's STOP GAP Trial has been designed to address this lack of trial evidence. The objective is to assess whether oral ciclosporin is more effective than oral prednisolone for the treatment of PG. The trial design is a two-arm, observer-blind, parallel-group, randomised controlled trial comparing ciclosporin (4 mg/kg/day) to prednisolone (0.75 mg/kg/day). A total of 140 participants are to be recruited over a period of 4 years, from up to 50 hospitals in the UK and Eire. Primary outcome of velocity of healing at 6 weeks is assessed blinded to treatment allocation (using digital images of the ulcers). Secondary outcomes include: (i) time to healing; (ii) global assessment of improvement; (iii) PG inflammation assessment scale score; (iv) self-reported pain; (v) health-related quality of life; (vi) time to recurrence; (vii) treatment failures; (viii) adverse reactions to study medications; and (ix) cost effectiveness/utility. Patients with a clinical diagnosis of PG (excluding granulomatous PG); measurable ulceration (that is, not pustular PG); and patients aged over 18 years old who are able to give informed consent are included in the trial. Randomisation is by computer generated code using permuted blocks of randomly varying size, stratified by lesion size, and

The clinical spectrum and antibiotic sensitivity patterns of staphylococcal pyodermas in the community and hospital

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Shireen Furtado

2014-01-01

Full Text Available Context: The uncontrolled use of antibiotics has resulted in a relentless spread of multiresistant strains of Staphylococcus aureus. There are studies conducted in medical colleges in Chandigarh, Chennai, Mumbai and Vellore comparing pyodermas in the community and hospital setting based on clinical and bacteriological parameters. Aims: This study, conducted over 1½ years from March 2009 to August 2010, aimed at analyzing the clinical spectrum and antibiotic sensitivity pattern of community and hospital-associated (HA staphylococcal pyoderma. It also assessed the prevalence of methicillin-resistant S. aureus (MRSA in the community and hospital cohort settings. Subjects and Methods: The study comprised of 200 cases of staphylococcal pyodermas, derived from the community (150 cases and hospital (50 cases. Patients were evaluated based on their clinical presentation; antibiotic susceptibility was tested using the Kirby-Bauer disk diffusion method. Statistical Analysis Used: Statistical significance between individual attributes between the community and HA staphylococcal pyoderma groups was analyzed using Chi-square test and mean differences using student′s t-test. Results: Factors associated with community-associated (CA pyodermas were young age (P = 0.0021, primary pyodermas, and involvement of extremities, while those with HA pyodermas were middle age, secondary pyodermas, and significantly increased body surface involvement (P = 0.041. Incidence of CA-MRSA was 11.3%, while that of HA-MRSA was 18%. Conclusions: A high level of resistance to first-line drugs such as penicillin, ciprofloxacin and cotrimoxazole was observed, more so in the hospital strain than in the community strain. S. aureus demonstrated good susceptibility to cephalosporins. Though the two strains of MRSA differed clinically, they showed 100% sensitivity to vancomycin and linezolid.

UK Dermatology Clinical Trials Network’s STOP GAP trial (a multicentre trial of prednisolone versus ciclosporin for pyoderma gangrenosum: protocol for a randomised controlled trial

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Craig Fiona F

2012-04-01

Full Text Available Abstract Background Pyoderma gangrenosum (PG is a rare inflammatory skin disorder characterised by painful and rapidly progressing skin ulceration. PG can be extremely difficult to treat and patients often require systemic immunosuppression. Recurrent lesions of PG are common, but the relative rarity of this condition means that there is a lack of published evidence regarding its treatment. A systematic review published in 2005 found no randomised controlled trials (RCTs relating to the treatment of PG. Since this time, one small RCT has been published comparing infliximab to placebo, but none of the commonly used systemic treatments for PG have been formally assessed. The UK Dermatology Clinical Trials Network’s STOP GAP Trial has been designed to address this lack of trial evidence. Methods The objective is to assess whether oral ciclosporin is more effective than oral prednisolone for the treatment of PG. The trial design is a two-arm, observer-blind, parallel-group, randomised controlled trial comparing ciclosporin (4 mg/kg/day to prednisolone (0.75 mg/kg/day. A total of 140 participants are to be recruited over a period of 4 years, from up to 50 hospitals in the UK and Eire. Primary outcome of velocity of healing at 6 weeks is assessed blinded to treatment allocation (using digital images of the ulcers. Secondary outcomes include: (i time to healing; (ii global assessment of improvement; (iii PG inflammation assessment scale score; (iv self-reported pain; (v health-related quality of life; (vi time to recurrence; (vii treatment failures; (viii adverse reactions to study medications; and (ix cost effectiveness/utility. Patients with a clinical diagnosis of PG (excluding granulomatous PG; measurable ulceration (that is, not pustular PG; and patients aged over 18 years old who are able to give informed consent are included in the trial. Randomisation is by computer generated code using permuted blocks of randomly varying size

Nephrotic Syndrome and Acute Renal Failure Apparently Induced by Sunitinib

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Ying-Shou Chen

2009-10-01

Full Text Available We report a case of nephrotic syndrome and acute renal failure apparently induced by sunitinib. A 67-year-old man with a history of metastatic renal cell carcinoma presented with progressive kidney dysfunction with proteinuria, general edema, and body weight gain of 21 kg after undergoing 3 weeks of sunitinib therapy. The patient had taken no other over-the-counter medications, and all other possible causes of nephrotic syndrome were excluded. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 6, indicating a high probability that the observed presentations were associated with use of the drug. However, despite the discontinuation of sunitinib, his condition deteriorated, and hemodialysis was initiated for respiratory distress. A renal biopsy was performed, which revealed ischemic acute tubular necrosis with minimal change nephropathy. In conclusion, nephrologists and oncologists should be aware that nephrotic syndrome with ischemic acute tubular necrosis is a possible adverse effect of sunitinib. For early diagnosis of this condition and to avoid renal damage, we recommend differential diagnosis of serum creatinine and proteinuria in patients undergoing sunitinib therapy.

Incidence of bowel wall oedema on computed tomography exams and association with diarrhoea in renal cell carcinoma patients treated with sunitinib

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Cornelissen, Liesbeth; Claus, Filip; Keyzer, Frederik de [KU Leuven, Radiology, Department of Imaging and Pathology, University Hospitals Leuven, Leuven (Belgium); Wolter, Pascal; Dumez, Herlinde; Beuselinck, Benoit [KU Leuven, Department of Medical Oncology and Laboratory of Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven (Belgium); Lerut, Evelyne [KU Leuven, Pathology, Department of Imaging and Pathology, University Hospitals Leuven, Leuven (Belgium); Poppel, Hendrik van [KU Leuven, Department of Urology, University Hospitals Leuven, Leuven (Belgium)

2014-08-28

The purpose of this study was to retrospectively assess the incidence of bowel wall oedema on computed tomography (CT) in patients with renal cell carcinoma (RCC) treated with sunitinib, and to investigate its association with diarrhoea. We conducted a retrospective analysis of all RCC patients treated with sunitinib at our hospital between December 2005 and December 2011. The presence or absence of bowel wall oedema on these CT examinations was scored. The presence of diarrhoea preceding, during, or after sunitinib treatment was identified from the patient files and retrospectively graded. For 54 of 87 patients, bowel wall oedema was present on at least one CT examination. Of these 54 patients, the right-sided colonic segment was affected in 87 %. Diarrhoea was the most common reported adverse event during treatment, with 58 patients (67 %) having grade 1/2 diarrhoea and 9 patients (10 %) having grade 3. There was a statistically significant correlation between the incidence of CT-scored bowel oedema and diarrhoea during sunitinib treatment (P = 0.004). This study shows a very high incidence of bowel wall oedema and a strong correlation between the incidence of bowel wall oedema and diarrhoea in patients treated with sunitinib. (orig.)

Prognostic relevance of sunitinib toxicities and comparison of continuous vs. intermittent sunitinib dosing schedule in metastatic renal cell cancer patients

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Çetin Ordu

2016-06-01

Full Text Available Aim of the study : Sunitinib-related side effects may develop as a result of the pharmacokinetic pathway affects the of the drug. Material and methods : Data on mRCC patients were obtained from the hospital archives. Outcomes of patients were evaluated in terms of related prognostic factors, sunitinib adverse events during the treatment, and two different sunitinib dosing schedules. Results : Seventy patients diagnosed with mRCC and treated with sunitinib were analyzed for prognostic factors and survival rates. During the mean follow-up of 33.5 months, 38 (54% patients were alive and 32 (46% patients died. The median time of overall survival (OS and progression-free survival (PFS was 27 months (12–61 and 19 months (5–45, respectively. In univariate analysis, good prognostic risk group according to the Memorial Sloan-Kettering Cancer Center (MSKCC, hypothyroidism as sunitinib toxicity and patients on sunitinib treatment more than 1 year were favorable prognostic factors for OS. Leukopenia and fatigue as sunitinib toxicity were poor prognostic factors for OS. PFS and OS of the patients were not significantly different when we compared intermittent (4/2 vs. continuous treatment dosing schedules. Conclusions : As a result of this trial, having hypothyroidism as an adverse effect of sunitinib was a favorable prognostic factor for OS and PFS in mRCC patients. It was also found that 4/2 and continuous dosing schedules of sunitinib did not give rise to different outcomes in mRCC patients.

Autophagy plays an important role in Sunitinib-mediated cell death in H9c2 cardiac muscle cells

International Nuclear Information System (INIS)

Zhao Yuqin; Xue Tao; Yang Xiaochun; Zhu Hong; Ding Xiaofei; Lou Liming; Lu Wei; Yang Bo; He Qiaojun

2010-01-01

Sunitinib, which is a multitargeted tyrosine-kinase inhibitor, exhibits antiangiogenic and antitumor activity, and extends survival of patients with metastatic renal-cell carcinoma (mRCC) and gastrointestinal stromal tumors (GIST). This molecule has also been reported to be associated with cardiotoxicity at a high frequency, but the mechanism is still unknown. In the present study, we observed that Sunitinib showed high anti-proliferative effect on H9c2 cardiac muscle cells measured by PI staining and the MTT assay. But apoptotic markers (PARP cleavage, caspase 3 cleavage and chromatin condensation) were uniformly negative in H9c2 cells after Sunitinib treatment for 48 h, indicating that another cell death pathway may be involved in Sunitinib-induced cardiotoxicity. Here we found Sunitinib dramatically increased autophagic flux in H9c2 cells. Acidic vesicle fluorescence and high expression of LC3-II in H9c2 cells identified autophagy as a Sunitinib-induced process that might be associated with cytotoxicity. Furthermore, knocking down Beclin 1 by RNA-interference to block autophagy in H9c2 cells revealed that the death rate was decreased when treated with Sunitinib in comparison to control cells. These results confirmed that autophagy plays an important role in Sunitinib-mediated H9c2 cells cytotoxicity. Taken together, the data presented here strongly suggest that autophagy is associated with Sunitinib-induced cardiotoxicity, and that inhibition of autophagy constitutes a viable strategy for reducing Sunitinib-induced cardiomyocyte death thereby alleviating Sunitinib cardiotoxicity.

Facial Nerve Paralysis seen in Pseudomonas sepsis with ecthyma gangrenosum

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Suleyman Ozdemir

2013-02-01

Full Text Available Ecthyma gangrenosum is a skin lesion which is created by pseudomonas auriginosa. Peripheral facial paralysis and mastoiditis as a rare complication of otitis media induced by pseudomonas auriginosa.In this study, 4 months child who has ecthyma gangrenosum and facial nerve paralysis was reported. [Cukurova Med J 2013; 38(1.000: 126-130

Ulcerative colitis presenting as leukocytoclastic vasculitis of skin

OpenAIRE

Akbulut, Sabiye; Ozaslan, Ersan; Topal, Firdevs; Albayrak, Levent; Kayhan, Burcak; Efe, Cumali

2008-01-01

A number of cutaneous changes are known to occur in the course of inflammatory bowel diseases (IBD), including pyoderma gangrenosum, erythema nodosum, perianal disease, erythematous eruptions, urticaria, and purpura. However, occurrence of skin manifestations prior to the development of ulcerative colitis is a rare occasion. Here, we report a case of ulcerative colitis associated with leukocytoclastic vasculitis in which the intestinal symptoms became overt 8 mo after the development of skin ...

Ulcerative colitis presenting as leukocytoclastic vasculitis of skin.

Science.gov (United States)

Akbulut, Sabiye; Ozaslan, Ersan; Topal, Firdevs; Albayrak, Levent; Kayhan, Burcak; Efe, Cumali

2008-04-21

A number of cutaneous changes are known to occur in the course of inflammatory bowel diseases (IBD), including pyoderma gangrenosum, erythema nodosum, perianal disease, erythematous eruptions, urticaria, and purpura. However, occurrence of skin manifestations prior to the development of ulcerative colitis is a rare occasion. Here, we report a case of ulcerative colitis associated with leukocytoclastic vasculitis in which the intestinal symptoms became overt 8 mo after the development of skin lesions.

Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice.

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Ravaud, Alain; Bello, Carlo L

2011-06-01

Targeted agents such as sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, have greatly improved the prognosis for patients with metastatic renal cell carcinoma (mRCC). In this review we analyse data from sunitinib preclinical and clinical studies in detail and consider the key implications for the effective use of sunitinib in clinical practice. Sunitinib has shown efficacy and acceptable tolerability in patients with mRCC in phase II and III clinical studies. In a pivotal phase III study in treatment-naïve patients with mRCC, median progression-free survival for sunitinib-treated patients was double of that with interferon-α (P relationship between clinical end points and sunitinib exposure showed that increased sunitinib exposure was associated with a greater probability of objective response, longer time to tumour progression and overall survival, as well as some increased risk of specific adverse events. It is important to consider the relationship between exposure and response to maximize clinical benefit from sunitinib treatment.

Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations

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Cohen, J.D.; Babiarz, J.E.; Abrams, R.M.; Guo, L.; Kameoka, S.; Chiao, E.; Taunton, J.; Kolaja, K.L.

2011-01-01

Sunitinib, an oral tyrosine kinase inhibitor approved to treat advanced renal cell carcinoma and gastrointestinal stroma tumor, is associated with clinical cardiac toxicity. Although the precise mechanism of sunitinib cardiotoxicity is not known, both the key metabolic energy regulator, AMP-activated protein kinase (AMPK), and ribosomal S 6 kinase (RSK) have been hypothesized as causative, albeit based on rodent models. To study the mechanism of sunitinib-mediated cardiotoxicity in a human model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) having electrophysiological and contractile properties of native cardiac tissue were investigated. Sunitinib was cardiotoxic in a dose-dependent manner with an IC 50 in the low micromolar range, observed by a loss of cellular ATP, an increase in oxidized glutathione, and induction of apoptosis in iPSC-CMs. Pretreatment of iPSC-CMs with AMPK activators AICAR or metformin, increased the phosphorylation of pAMPK-T172 and pACC-S79, but only marginally attenuated sunitinib mediated cell death. Furthermore, additional inhibitors of AMPK were not directly cytotoxic to iPSC-CMs up to 250 μM concentrations. Inhibition of RSK with a highly specific, irreversible, small molecule inhibitor (RSK-FMK-MEA) did not induce cytotoxicity in iPSC-CMs below 250 μM. Extensive electrophysiological analysis of sunitinib and RSK-FMK-MEA mediated conduction effects were performed. Taken together, these findings suggest that inhibition of AMPK and RSK are not a major component of sunitinib-induced cardiotoxicity. Although the exact mechanism of cardiotoxicity of sunitinib is not known, it is likely due to inhibition of multiple kinases simultaneously. These data highlight the utility of human iPSC-CMs in investigating the potential molecular mechanisms underlying drug-induced cardiotoxicity. -- Highlights: ► Cytoxic effect of sunitinib on human stem cell derived cardiomyocytes ► Sunitinib causes ATP depletion, LDH release, GSH

Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.

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Cheng, Ann-Lii; Kang, Yoon-Koo; Lin, Deng-Yn; Park, Joong-Won; Kudo, Masatoshi; Qin, Shukui; Chung, Hyun-Cheol; Song, Xiangqun; Xu, Jianming; Poggi, Guido; Omata, Masao; Pitman Lowenthal, Susan; Lanzalone, Silvana; Yang, Liqiang; Lechuga, Maria Jose; Raymond, Eric

2013-11-10

Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

Prevalence of methicillin-resistant Staphylococcus aureus (MRSA in community-acquired primary pyoderma

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Patil Rahul

2006-01-01

Full Text Available Background: Although prevalence of MRSA strains is reported to be increasing, there are no studies of their prevalence in community-acquired primary pyodermas in western India. Aims: This study aimed at determining the prevalence of MRSA infection in community-acquired primary pyodermas. Methods: Open, prospective survey carried out in a tertiary care hospital in Mumbai. Materials and Methods: Eighty-six patients with primary pyoderma, visiting the dermatology outpatient, were studied clinically and microbiologically. Sensitivity testing was done for vancomycin, sisomycin, gentamicin, framycetin, erythromycin, methicillin, cefazolin, cefuroxime, penicillin G and ciprofloxacin. Phage typing was done for MRSA positive strains. Results : The culture positivity rate was 83.7%. Staphylococcus aureus was isolated in all cases except two. Barring one, all strains of Staphylococcus were sensitive to methicillin. Conclusions: Methicillin resistance is uncommon in community-acquired primary pyodermas in Mumbai. Treatment with antibacterials active against MRSA is probably unwarranted for community-acquired primary pyodermas.

Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations

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Cohen, J.D., E-mail: jennifer.cohen@roche.com [Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States); Babiarz, J.E., E-mail: joshua.babiarz@roche.com [Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States); Abrams, R.M., E-mail: rory.abrams@roche.com [Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States); Guo, L., E-mail: liang.guo@roche.com [Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States); Kameoka, S., E-mail: sei.kameoka@roche.com [Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States); Chiao, E., E-mail: eric.chiao@roche.com [Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States); Taunton, J., E-mail: taunton@cmp.ucsf.edu [Howard Hughes Medical Institute, Cellular and Molecular Pharmacology, University California San Francisco, San Francisco, CA 94158 (United States); Kolaja, K.L., E-mail: kyle.kolaja@roche.com [Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States)

2011-11-15

Sunitinib, an oral tyrosine kinase inhibitor approved to treat advanced renal cell carcinoma and gastrointestinal stroma tumor, is associated with clinical cardiac toxicity. Although the precise mechanism of sunitinib cardiotoxicity is not known, both the key metabolic energy regulator, AMP-activated protein kinase (AMPK), and ribosomal S 6 kinase (RSK) have been hypothesized as causative, albeit based on rodent models. To study the mechanism of sunitinib-mediated cardiotoxicity in a human model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) having electrophysiological and contractile properties of native cardiac tissue were investigated. Sunitinib was cardiotoxic in a dose-dependent manner with an IC{sub 50} in the low micromolar range, observed by a loss of cellular ATP, an increase in oxidized glutathione, and induction of apoptosis in iPSC-CMs. Pretreatment of iPSC-CMs with AMPK activators AICAR or metformin, increased the phosphorylation of pAMPK-T172 and pACC-S79, but only marginally attenuated sunitinib mediated cell death. Furthermore, additional inhibitors of AMPK were not directly cytotoxic to iPSC-CMs up to 250 {mu}M concentrations. Inhibition of RSK with a highly specific, irreversible, small molecule inhibitor (RSK-FMK-MEA) did not induce cytotoxicity in iPSC-CMs below 250 {mu}M. Extensive electrophysiological analysis of sunitinib and RSK-FMK-MEA mediated conduction effects were performed. Taken together, these findings suggest that inhibition of AMPK and RSK are not a major component of sunitinib-induced cardiotoxicity. Although the exact mechanism of cardiotoxicity of sunitinib is not known, it is likely due to inhibition of multiple kinases simultaneously. These data highlight the utility of human iPSC-CMs in investigating the potential molecular mechanisms underlying drug-induced cardiotoxicity. -- Highlights: Black-Right-Pointing-Pointer Cytoxic effect of sunitinib on human stem cell derived cardiomyocytes Black

Biologiske behandlinger af andre dermatologiske sygdomme end psoriasis

DEFF Research Database (Denmark)

Gniadecki, Robert; Skov, Lone

2008-01-01

Psoriasis is the only disease in dermatology where biologics have been studied in placebo controlled trials. However, drugs have been used for several other indications in dermatology, e.g. pyoderma gangrenosum and pemphigus. We give a brief overview of the indications for biologics in skin disea...

New Described Dermatological Disorders

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Müzeyyen Gönül

2014-01-01

Full Text Available Many advances in dermatology have been made in recent years. In the present review article, newly described disorders from the last six years are presented in detail. We divided these reports into different sections, including syndromes, autoinflammatory diseases, tumors, and unclassified disease. Syndromes included are “circumferential skin creases Kunze type” and “unusual type of pachyonychia congenita or a new syndrome”; autoinflammatory diseases include “chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome,” “pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH syndrome,” and “pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH syndrome”; tumors include “acquired reactive digital fibroma,” “onychocytic matricoma and onychocytic carcinoma,” “infundibulocystic nail bed squamous cell carcinoma,” and “acral histiocytic nodules”; unclassified disorders include “saurian papulosis,” “symmetrical acrokeratoderma,” “confetti-like macular atrophy,” and “skin spicules,” “erythema papulosa semicircularis recidivans.”

Extraskeletal myxoid chondrosarcoma: tumor response to sunitinib

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Stacchiotti Silvia

2012-10-01

Full Text Available Abstract Background Extraskeletal myxoid chondrosarcoma (EMCS is a rare soft tissue sarcoma of uncertain differentiation, characterized in most cases by a translocation that results in the fusion protein EWSR1-CHN (the latter even called NR4A3 or TEC. EMCS is marked by >40% incidence of metastases in spite of its indolent behaviour. It is generally resistant to conventional chemotherapy, and, to the best of our knowledge, no data have been reported to date about the activity of tirosin-kinase inhibitor (TKI in this tumor. We report on two consecutive patients carrying an advanced EMCS treated with sunitinib. Methods Since July 2011, 2 patients with progressive pretreated metastatic EMCS (Patient1: woman, 58 years, PS1; Patient2: man, 63 years, PS1 have been treated with continuous SM 37.5 mg/day, on an individual use basis. Both patients are evaluable for response. In both cases diagnosis was confirmed by the presence of the typical EWSR1-CHN translocation. Results Both patients are still on treatment (11 and 8 months. Patient 1 got a RECIST response after 4 months from starting sunitinib, together with a complete response by PET. An interval progression was observed after stopping sunitinib for toxicity (abscess around previous femoral fixation, but response was restored after restarting sunitinib. Patient 2 had an initial tumor disease stabilization detected by CT scan at 3 months. Sunitinib was increased to 50 mg/day, with evidence of a dimensional response 3 months later. Conclusions Sunitinib showed antitumor activity in 2 patients with advanced EMCS. Further studies are needed to confirm these preliminary results.

Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.

LENUS (Irish Health Repository)

Gallagher, David J

2012-02-01

BACKGROUND: Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond. OBJECTIVE: To identify predictors of response to sunitinib. DESIGN, SETTING, AND PARTICIPANTS: Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib. MEASUREMENTS: BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria. RESULTS AND LIMITATIONS: Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3\\/4 hypertension compared with grade 0. Response was associated with low HIF-1alpha expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 x 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1alpha (p = 0.008). Results are limited by small numbers. CONCLUSIONS: Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.

Nasal carriage of Staphylococcus schleiferi from healthy dogs and dogs with otitis, pyoderma or both.

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May, Elizabeth R; Kinyon, Joann M; Noxon, James O

2012-12-07

In veterinary medicine, Staphylococcus schleiferi was previously assumed to be an inhabitant of carnivore skin, however, more recently, it has been repeatedly documented in the literature as both an inhabitant and as a pathogen. In order to determine the frequency of nasal carriage, and the methicillin susceptibility pattern of S. schleiferi from healthy dogs as well as dogs with otitis and/or pyoderma, a prospective study including 24 dogs with healthy ears and skin, 27 dogs with healthy ears and pyoderma, 15 dogs with otitis without pyoderma and 20 dogs with both otitis and pyoderma was performed. Specimens were obtained and cultured and isolates were identified as S. schleiferi based on growth and biochemical characteristics. S. schleiferi was isolated from the nares of 1 healthy dog, 3 dogs with recurrent pyoderma, 2 dogs with recurrent otitis, and 1 dog with both recurrent otitis and pyoderma. One of the S. schleiferi isolates was methicillin resistant. Nasal carriage of S. schleiferi does occur in healthy dogs as well as dogs with otitis and pyoderma. Methicillin resistant and sensitive S. schleiferi can be found in the nares of dogs with diseased ears and skin. Copyright © 2012 Elsevier B.V. All rights reserved.

Ecthyma gangrenosum caused by Stenotrophomonas maltophilia in ...

African Journals Online (AJOL)

Ecthyma gangrenosum (EG) is a well- described skin lesion, mostly seen in immunocompromised patients. The lesion characteristically progresses rapidly from small indurated papulovesicles to necrotic ulcers with surrounding erythema and a central black eschar.[1]. Although rare, the presence of EG is indicative of ...

Effect of sunitinib combined with ionizing radiation on endothelial cells

International Nuclear Information System (INIS)

Zhang Haiping; Jiao Xiaodong; Li Rui; Wang Jiejun; Takayama, Koichi; Su Bo

2011-01-01

The aims of present study were to evaluate the efficacy of combining sunitinib with ionizing radiation (IR) on endothelial cells in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) were exposed to IR with or without sunitinib pretreatment. Apoptosis assay and cell cycle distribution were analyzed by flow cytometry. Clonogenic survival assay at 3 Gy dose with or without sunitinib was performed. The activity of phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway was detected by Western immunoblot. Lewis lung carcinoma mouse model was built to examine the effect of combination therapy on endothelial cells in vivo. Microvasculature changes were detected by immunohistochemistry using anti-CD31 antibody. Our results showed combination therapy of sunitinib and IR significantly increased apoptosis of endothelial cells and inhibited colony formation compared to sunitinib or radiotherapy alone. It also resulted in cell cycle redistribution (decreasing cells in S phase and increasing cells in G2/M phase). The activity of PI3K/Akt signal pathway was inhibited, which could be the potential mechanisms that account for the enhanced radiation response induced by sunitinib. In vivo analysis showed that combination therapy significantly decreased microvasculature formation. The results demonstrated that combination therapy of sunitinib and IR has the potential to increase the cytotoxic effects on endothelial cells. (author)

Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma.

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Celia Prior

Full Text Available To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC and to evaluate in vitro their mechanism of action in sunitinib resistance.We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41. The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101. In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance.TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074. High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance.We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.

Pyoderma Vegetans: A Case Report in a Child Suspected to Primary Immunodeficiency and Review of the Literature

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Mahboubeh Mansouri

2015-07-01

Full Text Available Pyoderma vegetans (PV is a rare inflammatory disorder characterized by vegetating pustules and plaques affecting the skin and mucosal membranes. It is believed that this entity is mostly associated with inflammatory bowel disease (IBD, chronic malnutrition, human immunodeficiency virus (HIV, malignancies, and other immunocompromised states. Pyoderma vegetans occurs more commonly in young and middle-aged adults. There is no sex predilection for this entity. The lesions could heal spontaneously, but usually recur and become chronic. Our patient was an 11-year-old girl suspected to have primary combined immunodeficiency complicated by chronic recurrent vegetating pustular lesions on the face and postauricular area since one year of age. The histological features of the lesions were consistent with pyoderma vegetans. This is the first case of PV beginning from early infancy in the setting of primary immunodeficiency and in an unusual location.

Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

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Lau, Christine Li Ling; Chan, Sook Tyng; Selvaratanam, Manimegahlai; Khoo, Hui Wen; Lim, Adeline Yi Ling; Modamio, Pilar; Mariño, Eduardo L; Segarra, Ignacio

2015-08-01

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P brain (P male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P brain, liver, and kidney (all P male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P female mice and in kidney (male and female mice) but decreased 55% in brain (P differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Ecthyma gangrenosum in a patient with non-Hodgkin lymphoma

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Čolović Nataša

2007-01-01

Full Text Available Introduction. Ecthyma gangrenosum is a rare disease of the skin that causes the localized necrosis of the skin and subcutaneous fat tissue, leading to the multiple ulcerations surrounded by local hyperaemia. The ulcerations are usually localized in groins, and perianal area. In the majority of cases ecthyma is caused by a Pseudomonas aeruginosa sepsis. The disease usually appears in immunocompromized, most frequently hematological patients. Case report. We presented a 78-year-old woman who had been treated for non-Hodgkin lymphoma for the last 18 years. She had recently been given cytotoxics which led to neutropenia. The patient suddenly developed high fever, chill and diarrhea, followed by ecthyma gangrenosum cutaneous lesions in groins, axillas, right side of the neck and umbilicus. Pseudomonas aeruginosa and Proteus mirabilis, that were sensitive to several antibiotics were isolated. The treatment included rehydratation, antibiotics, surgical debridement and regular dressing with antiseptics. The healing of all lesions was achieved after sixteen weeks of the treatment. Conclusion. If haemorrhagic- necrotic lesions of the skin are developed in immunocompromised, usually haematologic patients, an Ecthyma gangrenosum has to be considered immediately, material for identification of a cause has to be taken, followed by immediate administration of antibiotics effective against Pseudomonas aeruginosa. Surgical debridement and other therapeutic modalities are to be considered in some patients. .

Oxytetracycline in Pyoderma

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A K Sharma

1983-01-01

Full Text Available One hundred patients with moderate to severe pyoderma were treated with oral oxytetracycline. The most common organism isolated were coagulase positive Staph pyogenes and Str betahemolyticus. Of 100 patients; 87 showed a successful therapeutic response. The predictive value of in vitro test for bacterial susceptibility to oxytetracycline (30 mcg disc was 88% for "sensitive" reports but 17% for "resistant" reports.Judged by clinical response the incidence of false sensitive reports was 12% (9/87 but that of false resistant reports was 83 (22/26.

Colostomy for Perianal Sepsis With Ecthyma Gangrenosum in Immunocompromised Children.

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Vuille-dit-Bille, Raphael N; Berger, Christoph; Meuli, Martin; Grotzer, Michael A

2016-01-01

Perianal sepsis with ecthyma gangrenosum is a severe and potentially mutilating complication in immunocompromised children. Therapies include antimicrobial treatment, incision and drainage, generous tissue debridement, and skin transplantation. We describe 3 children with acute lymphoblastic leukemia having sepsis with Pseudomonas aeruginosa in febrile neutropenia and severe perianal infections treated relatively early with a protective colostomy. Indications for colostomy were nonhealing wounds, and ceaseless pain. All patients showed a rapid reduction of pain. Complete wound healing was seen in 2 patients, and considerable pain reduction and increased quality of life were seen in a third patient during palliative care. These results suggest that a protective colostomy should be considered early in the management of immunocompromised children with ecthyma gangrenosum.

EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome.

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Sato, Mototaka; Nakai, Yasutomo; Nakata, Wataru; Yoshida, Takahiro; Hatano, Koji; Kawashima, Atsunari; Fujita, Kazutoshi; Uemura, Motohide; Takayama, Hitoshi; Nonomura, Norio

2013-01-01

Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC. EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined. EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib. Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.

EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome.

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Mototaka Sato

Full Text Available Extracellular matrix metalloproteinase inducer (EMMPRIN has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC.EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined.EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni. EMMPRIN-overexpressing RCC cells were resistant to sunitinib.Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.

Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice.

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Tan, Siok Yean; Wong, Mei Mei; Tiew, Angela Lu Wun; Choo, Yai Wen; Lim, Suat Hun; Ooi, Ing Hong; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L; Segarra, Ignacio

2016-10-01

Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features. Male and female mice were administered 6 sunitinib doses (60 mg/kg) PO every 12 h and 30 min before the last dose were administered vehicle (control groups), 250 mg/kg paracetamol, 30 mg/kg diclofenac, 50 mg/kg mefenamic acid or 30 mg/kg ibuprofen (study groups), euthanized 6 h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed. Ibuprofen halved sunitinib plasma concentration in female mice (p Diclofenac and paracetamol female mice showed 45 and 25 % higher plasma concentrations than male mice which were 27 % lower in mefenamic acid female mice. Paracetamol increased 2.2 (p diclofenac, paracetamol, mefenamic acid and ibuprofen (p diclofenac group in male mice (liver, brain) and female mice (liver, kidney). These results portray gender-based sunitinib pharmacokinetic differences and NSAIDs selective effects on male or female mice, with potential clinical translatability.

Pyoderma Gangrenosum–Like Ulcer in a Patient With X-Linked Agammaglobulinemia

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Murray, Patrick R.; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B.; Ecker, David J.; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L.

2011-01-01

Background Pyoderma gangrenosum–like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient’s culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. Observation An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when sub-cultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. Conclusions This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum–like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum–like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy. PMID:20479300

ORIGINAL ARTICLE: Multidrug Resistance and Phage Pattern of Staphylococcus aureus in Pyoderma Cases

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Sanjay M. Wavare

2012-01-01

Full Text Available Background: Pyoderma is common in India and other tropical countries. Staphylococcus aureus is the commonest causative agent ofpyoderma. Aims and Objectives: To know the antibiotic susceptibility and bacteriophage pattern of Staphylococcus aureus isolated from pyoderma infection. Materials and Methods: One hundred clinically diagnosed pyoderma cases were investigated bacteriologically. A total of 59 isolates of S. aureus were subjected to antibioticsusceptibility testing by Kirby Bauer’s disk diffusion method and phage typing by routine test dilution X 100 bacteriophages. Results: Most of the strains were resistant to penicillin, ampicillin and were susceptible to gentamicin, streptomycin and erythromycin. Multidrug resistance was also high among these strains. Regarding the phage types, Phage type 52 (15 strains, 96 (8 strains and 71(16strains were predominant among the typed strains (55.95% of S. aureus. The most common group was mixed phage group (17% followed by phage group I (13.55%. Conclusion: Knowledge of antibioticsusceptibility pattern is essential to give proper antibiotic therapy and avoid unnecessary medication with non-effective drugs, which may increase resistance. Gentamicin, streptomycin and erythromycin are the drugs of choice in that order. Association of phage typing and antibiotic sensitivity of S. aureus showed the predominance of phage group III with greater frequency of penicillin resistance.

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours

NARCIS (Netherlands)

Lankheet, N.; Kloth, J.S.; Gadellaa-van Hooijdonk, C.G.M.; Cirkel, G.A.; Mathijssen, R.H.; Lolkema, M.P.; Schellens, J.H.; Voest, E.E.; Sleijfer, S.; Jonge, M.J. de; Haanen, J.B.; Beijnen, J.H.; Huitema, A.D.; Steeghs, N.

2014-01-01

Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

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Ravaud, Alain; Motzer, Robert J; Pandha, Hardev S; George, Daniel J; Pantuck, Allan J; Patel, Anup; Chang, Yen-Hwa; Escudier, Bernard; Donskov, Frede; Magheli, Ahmed; Carteni, Giacomo; Laguerre, Brigitte; Tomczak, Piotr; Breza, Jan; Gerletti, Paola; Lechuga, Mariajose; Lin, Xun; Martini, Jean-Francois; Ramaswamy, Krishnan; Casey, Michelle; Staehler, Michael; Patard, Jean-Jacques

2016-12-08

Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC Clinical

Non-Septicemic Echthyma Gangrenosum

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Mittal Radha Rani

1997-01-01

Full Text Available A 35 year male suffering from acid-peptic disease since last 15 years developed multiple, progressive necrotic gangrenous ulcers with pus discharge since one month. He also had cellulites and a big serpiginous necrotic ulcer of left ring finger resembling decubitus ulcer. Smears of pus from both types of ulcers revealed gram-negative bacilli. Culture of pus from both sites showed growth of pseudomonas aeruginosa. Blood culture was negative. Diagnosis of Echthyma gangrenosum (EG was established histopathologically as gram-negative bacilli invaded the dermal vessels. Complete cure occurred after 3 months of treatment with different antibiotics; 80% of ulcers healed with cefadroxyl therapy.

Sunitinib-induced hypertension, neutropenia and thrombocytopenia as predictors of good prognosis in metastatic renal cell carcinoma patients

DEFF Research Database (Denmark)

Rautiola, Juhana; Donskov, Frede; Peltola, Katriina

2016-01-01

OBJECTIVES: To evaluate the clinical significance of hypertension, neutropenia and thrombocytopenia as possible new biomarkers of sunitinib efficacy in non-trial metastatic renal cell carcinoma (mRCC) patients. MATERIALS AND METHODS: 181 consecutive mRCC patients were treated with sunitinib. Thir...... of sunitinib efficacy patients with mRCC. Our results may help to individualize sunitinib dosing during therapy based on these common sunitinib-related AEs....

Sunitinib in the treatment of gastrointestinal stromal tumor: patient selection and perspectives

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Mulet-Margalef N

2016-12-01

Full Text Available Nuria Mulet-Margalef, Xavier Garcia-del-Muro Sarcoma Multidisciplinary Unit and Medical Oncology Department, Institut Català d’Oncologia Hospitalet, IDIBELL, Barcelona, Spain Abstract: Gastrointestinal stromal tumor (GIST is the most common mesenchymal tumor of the gastrointestinal tract. In advanced setting and after progression to imatinib, the multitargeted receptor tyrosine kinase inhibitor sunitinib has clearly demonstrated a clinical benefit in terms of response rate and progression-free survival with an acceptable toxicity profile. The recommended schedule for sunitinib administration is 50 mg per day 4 weeks ON and 2 weeks OFF; however, potential alternative schedules are also reviewed in the present article. Several biomarkers have been explored to better select candidates for sunitinib therapy, such as the value of early changes in standardized uptake value assessed by positron emission tomography with 18F-fluorodeoxyglucose, circulating biomarkers, clinical biomarkers such as the appearance of arterial hypertension during treatment that correlates with better outcomes, and the GIST genotype. GISTs with KIT mutations at exon 9 and the so-called wild-type GISTs seem to better respond to sunitinib. Nonetheless, further investigation is required to confirm these findings as well as to understand the mechanisms of sunitinib resistance such as the development of new KIT mutations or conformational changes in KIT receptor. Keywords: sunitinib, GIST, KIT, refractory GIST

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

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Keizman, Daniel; Gottfried, Maya; Ish-Shalom, Maya; Maimon, Natalie; Peer, Avivit; Neumann, Avivit; Hammers, Hans; Eisenberger, Mario A; Sinibaldi, Victoria; Pili, Roberto; Hayat, Henry; Kovel, Svetlana; Sella, Avishay; Boursi, Ben; Weitzen, Rony; Mermershtain, Wilmosh; Rouvinov, Keren; Berger, Raanan; Carducci, Michael A

2014-01-01

Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p 3 (HR: 2.95, p smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer

International Nuclear Information System (INIS)

Brooks, Colin; Sheu, Tommy; Bridges, Kathleen; Mason, Kathy; Kuban, Deborah; Mathew, Paul; Meyn, Raymond

2012-01-01

Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells. The radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib’s ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay. Clonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone. We conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was

Optimal treatment scheduling of ionizing radiation and sunitinib improves the antitumor activity and allows dose reduction

International Nuclear Information System (INIS)

Kleibeuker, Esther A; Hooven, Matthijs A ten; Castricum, Kitty C; Honeywell, Richard; Griffioen, Arjan W; Verheul, Henk M; Slotman, Ben J; Thijssen, Victor L

2015-01-01

The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose-scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting

Pyoderma gangraenosum as a complication to knee arthroscopy

DEFF Research Database (Denmark)

Madsen, Jakob Torp; Skov, Ole; Andersen, Klaus E

2009-01-01

Pyoderma gangraenosum (PG) is a rare immunologic ulcerative disease, which sometimes develop as a complication to surgery. PG is often misdiagnosed as an infected wound, but treatment is completely different. We report a case of PG as a complication to arthroscopic partial meniscectomy that resul...

Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results.

Science.gov (United States)

Motzer, Robert J; Ravaud, Alain; Patard, Jean-Jacques; Pandha, Hardev S; George, Daniel J; Patel, Anup; Chang, Yen-Hwa; Escudier, Bernard; Donskov, Frede; Magheli, Ahmed; Carteni, Giacomo; Laguerre, Brigitte; Tomczak, Piotr; Breza, Jan; Gerletti, Paola; Lechuga, Mariajose; Lin, Xun; Casey, Michelle; Serfass, Lucile; Pantuck, Allan J; Staehler, Michael

2018-01-01

nephrectomy experienced a clinical benefit with adjuvant sunitinib. ClinicalTrials.gov NCT00375674. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.

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Motzer, Robert J; Tannir, Nizar M; McDermott, David F; Arén Frontera, Osvaldo; Melichar, Bohuslav; Choueiri, Toni K; Plimack, Elizabeth R; Barthélémy, Philippe; Porta, Camillo; George, Saby; Powles, Thomas; Donskov, Frede; Neiman, Victoria; Kollmannsberger, Christian K; Salman, Pamela; Gurney, Howard; Hawkins, Robert; Ravaud, Alain; Grimm, Marc-Oliver; Bracarda, Sergio; Barrios, Carlos H; Tomita, Yoshihiko; Castellano, Daniel; Rini, Brian I; Chen, Allen C; Mekan, Sabeen; McHenry, M Brent; Wind-Rotolo, Megan; Doan, Justin; Sharma, Padmanee; Hammers, Hans J; Escudier, Bernard

2018-04-05

Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of

Disseminated refractory pyoderma gangraenosum during an ulcerative colitis flare. Treatment with infliximab.

Science.gov (United States)

Zampeli, Vasiliki A; Lippert, Undine; Nikolakis, Georgios; Makrantonaki, Evgenia; Tzellos, Thrasivoulos G; Krause, Ulf; Zouboulis, Christos C

2015-09-30

Pyoderma gangraenosum is an immune-mediated, inflammatory, neutrophilic dermatosis of unknown etiology, which represents one of the extraintestinal manifestations of inflammatory bowel disease. It is a rare disease that occurs in less than 1% of patients with inflammatory bowel disease and with the same ratio in patients with Crohn's disease and ulcerative colitis. A 36-year-old woman was diagnosed with ulcerative colitis 6 years before admission to our dermatology department with an acute disseminated pyoderma gangraenosum with mucosal involvement, during a flare of ulcerative colitis. Disease progression was interrupted by intravenous administration of the tumor necrosis factor-α inhibitor infliximab at 5 mg/kg at weeks 0, 2, and 6 (1st cycle) and every 8 weeks thereafter. Improvement of intestinal, skin and oral manifestations was evident already after the 1st cycle of treatment and has been maintained since (at least 16 months). This case report is one of very few on disseminated pyoderma gangraenosum with oral involvement complicating ulcerative colitis, where infliximab was shown to have a rapid efficacy on skin, mucosal and bowel symptoms.

Hypothyroidism Side Effect in Patients Treated with Sunitinib or Sorafenib: Clinical and Structural Analyses

Science.gov (United States)

Shu, Mao; Zai, Xiaoli; Zhang, Beina; Wang, Rui; Lin, Zhihua

2016-01-01

Tyrosine kinase inhibitors (TKIs) provide more effective targeted treatments for cancer, but are subject to a variety of adverse effects, such as hypothyroidism. TKI-induced hypothyroidism is a highly complicated issue, because of not only the unrealized toxicological mechanisms, but also different incidences of individual TKI drugs. While sunitinib is suspected for causing thyroid dysfunction more often than other TKIs, sorafenib is believed to be less risky. Here we integrated clinical data and in silico drug-protein interactions to examine the pharmacological distinction between sunitinib and sorafenib. Statistical analysis on the FDA Adverse Event Reporting System (FAERS) confirmed that sunitinib is more concurrent with hypothyroidism than sorafenib, which was observed in both female and male patients. Then, we used docking method and identified 3 proteins specifically binding to sunitinib but not sorafenib, i.e., retinoid X receptor alpha, retinoic acid receptors beta and gamma. As potential off-targets of sunitinib, these proteins are well known to assemble with thyroid hormone receptors, which can explain the profound impact of sunitinib on thyroid function. Taken together, we established a strategy of integrated analysis on clinical records and drug off-targets, which can be applied to explore the molecular basis of various adverse drug reactions. PMID:26784451

[Knockdown of ATG5 enhances the sensitivity of human renal carcinoma cells to sunitinib].

Science.gov (United States)

Li, Peng; Han, Qi; Tang, Ming; Zhang, Keqin

2017-03-01

Objective To investigate the expression levels of autophagy-related gene 5 (ATG5) and microtubule-associated protein 1 light chain 3 (LC3) and their effects on sunitinib resistance in human renal carcinoma cells. Methods After clinic-pathologic feature and survival analysis, 99 renal clear cell carcinoma tissues with different histological grades were used to detect the expression of ATG5 and LC3 by immunohistochemistry. Renal carcinoma cell line A-498 was infected with lentivirus-mediated ATG5 shRNA. Western blot analysis was performed to confirm the efficiency of ATG5 knockdown. Proliferation rate of A-498 cells in control group and ATG5 low expression group was determined by flow cytometry. Finally, the survival rate was detected by MTT assay after A-498 cells were treated with different concentrations of sunitinib. Results The expression levels of ATG5 and LC3 in renal clear cell carcinoma tissues were significantly higher than those in para-tumor tissues. The expression levels of ATG5 and LC3 were associated with classification, histological grade, TNM stage and survival rate, rather than gender, age, location, tumor size. Compared with the control group, the protein expressions of ATG5 and LC3 significantly decreased in A-498 cells with ATG5 low expression. The cell proliferation rate in ATG5 downregulation group was lower than that in the control group. Compared with control group, the survival rate in ATG5 low expression group were significantly reduced in a dose-dependent manner after sunitinib treatment. Conclusion Autophagy is active in renal clear cell carcinoma, and the drug sensitivity to sunitinib in renal cancer cells can be enhanced by the downregulation of ATG5.

Ecthyma gangrenosum like lesions in disseminated mycobacterial tuberculosis infection in a renal transplant recipient

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Navjyot Kaur

2017-01-01

Full Text Available Ecthyma gangrenosum (EG is a relatively rare skin manifestation that is most commonly described in Pseudomonas aeruginosa bacteremia. It is more frequently seen in immunocompromised individuals. We report a case of 60-year-old renal transplant recipient on triple immunosuppressants and diabetes mellitus type 2 on insulin therapy who developed EG-like lesions due to disseminated mycobacterial tuberculosis (MTB infection. To the best of our knowledge, this is the first case report of EG-like lesions associated with disseminated kochs.

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

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Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

2015-01-01

Background Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Methods Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Results Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. Conclusion While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. PMID:26109878

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

International Nuclear Information System (INIS)

Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

2015-01-01

Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer

A programme of research to set priorities and reduce uncertainties for the prevention and treatment of skin disease

OpenAIRE

Thomas, K. S.; Batchelor, J. M.; Bath-Hextall, F.; Chalmers, J. R.; Clarke, T.; Crowe, S.; Delamere, F. M.; Eleftheriadou, V.; Evans, N.; Firkins, L.; Greenlaw, N.; Lansbury, L.; Lawton, S.; Layfield, C.; Leonardi-Bee, J.

2016-01-01

BACKGROUND: Skin diseases are very common and can have a large impact on the quality of life of patients and caregivers. This programme addressed four diseases: (1) eczema, (2) vitiligo, (3) squamous cell skin cancer (SCC) and (4) pyoderma gangrenosum (PG). OBJECTIVE: To set priorities and reduce uncertainties for the treatment and prevention of skin disease in our four chosen diseases. DESIGN: Mixed methods including eight systematic reviews, three prioritisation exercises, tw...

[Treatment with sunitinib and hypothyroidism--a case report and overview of literature].

Science.gov (United States)

Kreze, A; Stáhalová, V; Zadrazilová, A; Koskuba, J; Kosák, M

2009-01-01

In the article the authors present the case of a patient with clear cell renal carcinoma, where after nephrectomy local metastases appeared. The treatment of choice was sunitinib. After 20 cycles of therapy heavy hypothyroidism was verified which required substitution by thyroxine. Elevated levels of TSH appeared in up to 70% and hypothyrodism in up to 40% of thus treated patients. Also described is the mechanism of action of sunitinib. There seems to exist a correlation between the "adverse effects" of the drug and a better result of the therapy of cancer, however, prospective studies are absent. Most experts agree that the thyroid function during treatment with sunitinib needs to be monitored.

Transformation of Nonfunctioning Pancreatic Neuroendocrine Carcinoma Cells into Insulin Producing Cells after Treatment with Sunitinib

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Jung Hun Ohn

2013-06-01

Full Text Available We report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma. We describe the initial clinical presentation, laboratory results, pathologic findings, and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy. A 46-year-old woman presented to the emergency department with loss of consciousness from hypoglycemia. Serum C-peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia. She had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib, a small molecule tyrosine kinase inhibitor. Immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin-producing cells after sunitinib therapy. Transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin/adriamycin relieved the hypoglycemia. A nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin-producing tumor after treatment with sunitinib, causing endogenous hyperinsulinemia and severe hypoglycemia.

Reversible Posterior Leukoencephalopathy Syndrome Developing After Restart of Sunitinib Therapy for Metastatic Renal Cell Carcinoma

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Shinji Fukui

2016-01-01

Full Text Available A 64-year-old Japanese man had started molecular-targeted therapy with sunitinib for lymph node metastasis 5 years after nephrectomy for left renal cell carcinoma (clear cell carcinoma, G2, pT2N0M0. He was transported to our emergency department because of generalized tonic-clonic seizure, vision loss, and impaired consciousness with acute hypertension after 8 cycles of treatment (2 years after the initiation of sunitinib therapy, including a drug withdrawal period for one year. MRI of the brain (FLAIR images showed multiple high-intensity lesions in the white matter of the occipital and cerebellar lobes, dorsal brain stem, and left thalamus. Reversible posterior leukoencephalopathy syndrome caused by sunitinib was suspected. In addition to the immediate discontinuation of sunitinib therapy, the administration of antihypertensive agents and anticonvulsants improved the clinical symptoms without neurological damage. Physicians should be aware that sunitinib causes reversible posterior leukoencephalopathy syndrome. The early recognition of reversible posterior leukoencephalopathy syndrome is critical to avoid irreversible neurological damage.

Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

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Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

2014-01-01

The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

In vitro biologic efficacy of sunitinib drug-eluting beads on human colorectal and hepatocellular carcinoma-A pilot study.

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Steven Lahti

Full Text Available Sunitinib drug eluting beads (DEB are a novel anti-angiogenic bead preparation for use in transarterial chemoembolization. However, systematic studies of sunitinib DEB's effect on cancer cells have not been reported. Herein, we assess their direct biologic efficacy against carcinoma cell lines and correlate cell viability with drug release in vitro.Sunitinib-HCl (10mg/mL in Milli-Q water was mixed with LC Bead® 300-500μm (Biocompatibles UK Ltd.. Loading and release were assessed by measurement of drug UV absorbance using UV-visible spectrophotometer. Viability of human colorectal cancer (CRC, HCT116 and HT29 and hepatocellular carcinoma (HCC, HepG2 cells upon exposure to sunitinib DEB was measured using a bioluminescent assay. Drug concentration during exposure was quantified using HPLC.When added to cultured HepG2 cells, sunitinib DEB rapidly inhibited viability with a significant decrease observed within 1 hour of incubation. Viability of HCT116 and HT29 cells decreased relatively slower, with significant reductions observed after 8 and 24 hours, respectively. After 24 hours there was nearly complete inhibition of all three cell lines. There was no difference in viability observed between cells treated with 5 μl, 10 μL, or 20 μL of sunitinib DEB. HPLC analysis of the cell culture supernatant demonstrated saturation of the cell medium within approximately 4 hours for each amount added, with sunitinib achieving a final concentration of 17.61 μM (SE ±1.01.Sunitinib can be efficiently loaded to and released from LC beads, and the resulting sunitinib DEB demonstrate strong in vitro inhibition of human CRC and HCC cells.

Primary cutaneous anaplastic large cell lymphoma masquerading as large pyogenic granuloma

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Anupama Bains

2016-01-01

Full Text Available Primary cutaneous anaplastic large cell lymphoma (pcALCL forms 9% of the cutaneous T-cell lymphomas. It usually presents as solitary reddish brown ulcerating nodule or indurated plaque. Sometimes, it mimics other dermatological diseases such as eczema, pyoderma gangrenosum, pyogenic granuloma, morphea, and squamous cell carcinoma. Our case presented with large pyogenic granuloma like lesion with regional lymphadenopathy. Since pcALCL is rare, one can misdiagnose such cases and therefore high index of suspicion is necessary.

Sunitinib in mRCC: A systematic review of UK Real World Data

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David Andrew Montgomery

2015-08-01

Full Text Available BackgroundReal world data are increasingly used to inform drug reimbursement decisions, but it is unclear how well outcomes from real world studies compare to those of clinical trials. This systematic review seeks to compare outcomes for sunitinib in routine UK clinical practice with the sunitinib registrational and expanded access program clinical trials. MethodSystematic review of the real world published literature was undertaken. UK observational studies recording first or second line sunitinib efficacy were included. A qualitative summary of the results and comparison to the controlled clinical trials was conducted. 15 real world studies were included, 14 of which were only available as posters/presentations. ResultsReal world study reporting quality was generally low, making comparisons with the clinical trials difficult. Practice relating to starting dose, dose modification, timing of therapy initiation and other factors varied between centres. Median progression free survival and adverse events were generally comparable to the clinical trial outcomes, but overall survival was not. ConclusionsThere are few published data on sunitinib use in UK clinical practice. Studies are characterised by lack of peer reviewed publication and heterogeneity in design, reporting and analysis. For use of real world data in the reimbursement setting, data collection and reporting will need to improve.

A phase I/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy (HAART) in HIV-positive patients with cancer: AIDS Malignancy Consortium Trial AMC 061

Science.gov (United States)

Rudek, Michelle A; Moore, Page C.; Mitsuyasu, Ronald T.; Dezube, Bruce J.; Aboulafia, David; Gerecitano, John; Sullivan, Ryan; Cianfrocca, Mary E.; Henry, David H.; Ratner, Lee; Haigentz, Missak; Dowlati, Afshin; Little, Richard F.; Ivy, S. Percy; Deeken, John F.

2014-01-01

Background Treatment of non-AIDS defining cancers (NADCs) may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium assessing targeted therapies and HAART in HIV+ cancer patients (ClinicalTrials.gov NCT00890747). Methods Patients were stratified into two arms based on whether they were taking ritonavir, a potent CYP3A4 inhibitor, in a modified phase I study of sunitinib. Patients in arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50mg/day). Arm 2 (ritonavir-based HAART) used a phase I, 3+3 dose escalation design (from 25 to 50mg/day). Cycles were with four weeks on treatment followed by a two week break (6 weeks total). Pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. Results Nineteen patients were enrolled and evaluable. Patients on Arm 1 tolerated treatment with one observed dose limiting toxicity (DLT). In Arm 2, a DLT was experienced at 37.5mg, and an additional 3 of 5 patients experienced grade 3 neutropenia, an uncommon toxicity of sunitinib. No patient had a response, but 10 had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. Conclusions Patients on non-ritonavir based HAART regimens tolerated standard dosing of sunitinib. Patients on ritonavir-based therapy treated with 37.5mg/day experienced higher toxicities. Dose reduction of sunitinib to 37.5mg may be warranted in patients on ritonavir. PMID:24474568

Sunitinib efficacy in the treatment of metastatic skin adnexal carcinomas: report of two patients with hidradenocarcinoma and trichoblastic carcinoma.

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Battistella, M; Mateus, C; Lassau, N; Chami, L; Boukoucha, M; Duvillard, P; Cribier, B; Robert, C

2010-02-01

Adnexal carcinomas are rare and diverse cutaneous tumours. They are locally aggressive and have the potential for distant metastasis. Metastatic adnexal carcinomas are very resistant to conventional chemotherapies. Sunitinib, an oral tyrosine kinase inhibitor, is reportedly effective for the treatment of various solid cancers. Its use in adnexal carcinomas has never been reported. The first patient had metastatic clear cell hidradenocarcinoma and was stabilized over 8 months with sunitinib, before she relapsed. The second patient had a metastatic malignant hair follicle tumour (trichoblastic carcinoma) and achieved a partial remission with sunitinib, and disease stabilized after 10 months. Dynamic contrast-enhanced ultrasound (DCE-US) performed to evaluate tumour vascularization during treatment depicted a dramatic and early decrease in the tumour blood volume. Sunitinib was effective in controlling the disease in our two patients. DCE-US using linear raw data may have an early predictive value for tumour response to sunitinib. Further studies involving larger cohorts of patients are warranted in order to confirm the efficacy of sunitinib in these rare tumours.

Delayed diagnosis of bullous pyoderma gangrenosum with acute ...

African Journals Online (AJOL)

2016-05-10

May 10, 2016 ... Infectious Disease, School of Medicine, Inönü University, Malatya, Turkey. Access this article online .... because prompt administration of glucocorticoids or other immunosuppressive ... corneal keratolysis. Am J Clin Pathol ...

Antimicrobial susceptibility and Ribosomal-RNA gene restriction patterns among Staphylococcus-intermedius from healthy dogs and from dogs sufferning from pyoderma or otitis-externa

DEFF Research Database (Denmark)

Pedersen, Karl; Wegener, Henrik Caspar

1995-01-01

A total of 60 Staphlococcus intermedius strains from dogs were investigated by their sensitivity to various antibiotics (50 strains) and by their rRNA gene restriction patterns (ribotyping) (60 strains). Fifteen isolates were from healthy dogs, 9 with otitis externa, and 36 with pyoderma, including......, enrofloxacin, and sulphonamides with trimethoprim. There were no significant differences in antimicrobial susceptibility patterns observed among isolates from pyoderma, otitis externa or healthy dogs. Among the 60 strains studied by ribotyping, 10 different ribotypes were identified: 6 different ribotypes...... among isolates from otitis externa, 8 among isolates from pyoderma, and 5 among isolates from healthy dogs. One ribotype (profile C) was dominant among the isolates from healthy dogs while another ribotype (profile A) was dominant among strains from dogs suffering from pyoderma. This profile...

Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-Line Sunitinib (QUASAR: Results of a Phase I Trial

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Carlo Buonerba

2018-03-01

Full Text Available Sunitinib is the most commonly prescribed drug for advanced renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on–and off–target effects, including hand and foot syndrome and fatigue. It was hypothesized that sunitinib-induced fatigue may be related to off target inhibition of the AMPK enzyme, which results in impairment of energy-producing processes at a systemic level. Quercetin is a naturally occurring flavonol with established AMPK-stimulating activity. While clinical use of quercetin is limited by its poor bio-availability, quercetin-3-O-β-d-glucopyranoside, that is isoquercetin, has an improved pharmacokinetic profile. On the grounds of the in vitro stimulatory activity with respect to AMPk, we hypothesized that oral isoquercetin could improve fatigue in kidney cancer patients receiving sunitinib. Given the lack of data on the safety of isoquercetin given concomitantly with sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day. In the 12-patient study cohort included in this study, isoquercetin was administered concomitantly with 50 mg sunitinib for a median 81 days (IQR, 75.5, 86.5. None of the 12 patients required isoquercetin suspension or isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT fatigue score (6.8 points; 95% CI: 2.8–10.8; p = 0.002 and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1–28.8; p < 0.001 after isoquercetin consumption vs. baseline. In this phase I trial, isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events.

Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-Line Sunitinib (QUASAR): Results of a Phase I Trial.

Science.gov (United States)

Buonerba, Carlo; De Placido, Pietro; Bruzzese, Dario; Pagliuca, Martina; Ungaro, Paola; Bosso, Davide; Ribera, Dario; Iaccarino, Simona; Scafuri, Luca; Liotti, Antonietta; Romeo, Valeria; Izzo, Michela; Perri, Francesco; Casale, Beniamino; Grimaldi, Giuseppe; Vitrone, Francesca; Brunetti, Arturo; Terracciano, Daniela; Marinelli, Alfredo; De Placido, Sabino; Di Lorenzo, Giuseppe

2018-01-01

Sunitinib is the most commonly prescribed drug for advanced renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on-and off-target effects, including hand and foot syndrome and fatigue. It was hypothesized that sunitinib-induced fatigue may be related to off target inhibition of the AMPK enzyme, which results in impairment of energy-producing processes at a systemic level. Quercetin is a naturally occurring flavonol with established AMPK-stimulating activity. While clinical use of quercetin is limited by its poor bio-availability, quercetin-3-O-β-d-glucopyranoside, that is isoquercetin, has an improved pharmacokinetic profile. On the grounds of the in vitro stimulatory activity with respect to AMPk, we hypothesized that oral isoquercetin could improve fatigue in kidney cancer patients receiving sunitinib. Given the lack of data on the safety of isoquercetin given concomitantly with sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day). In the 12-patient study cohort included in this study, isoquercetin was administered concomitantly with 50 mg sunitinib for a median 81 days (IQR, 75.5, 86.5). None of the 12 patients required isoquercetin suspension or isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT fatigue score (6.8 points; 95% CI: 2.8-10.8; p = 0.002) and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1-28.8; p < 0.001) after isoquercetin consumption vs. baseline. In this phase I trial, isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events.

Volume-based predictive biomarkers of sequential FDG-PET/CT for sunitinib in cancer of unknown primary: identification of the best benefited patients

International Nuclear Information System (INIS)

Ma, Yifei; Xu, Wei; Xiao, Jianru; Bai, Ruojing; Li, Yiming; Yu, Hongyu; Yang, Chunshan; Shi, Huazheng; Zhang, Jian; Li, Jidong; Wang, Chenguang

2017-01-01

To test the performance of sequential "1"8F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in predicting survival after sunitinib therapies in patients with cancer of unknown primary (CUP). CUP patients were enrolled for sequential PET/CT scanning for sunitinib and a control group. Univariate and multivariate analysis were applied to test the efficacy of sunitinib therapy in CUP patients. Next, sequential analyses involving PET/CT parameters were performed to identify and validate sensitive PET/CT biomarkers for sunitinib therapy. Finally, time-dependent receiver operating characteristic (TDROC) analyses were performed to compare the predictive accuracy. Multivariate analysis proved that sunitinib group had significantly improved survival (p < 0.01) as compared to control group. After cycle 2 of therapy, multivariate analysis identified volume-based PET/CT parameters as sensitive biomarkers for sunitinib (p < 0.01). TDROC curves demonstrated whole-body total lesion glycolysis reduction (Δ WTLG) and follow-up WTLG to have good accuracy for efficacy prediction. This evidence was validated after cycle 4 of therapy with the same method. Sunitinib therapy proved effective in treatment of CUP. PET/CT volume-based parameters may help predict outcome of sunitinib therapy, in which Δ WTLG and follow-up WTLG seem to be sensitive biomarkers for sunitinib efficacy. Patients with greater reduction and lower WTLG at follow-up seem to have better survival outcome. (orig.)

Volume-based predictive biomarkers of sequential FDG-PET/CT for sunitinib in cancer of unknown primary: identification of the best benefited patients

Energy Technology Data Exchange (ETDEWEB)

Ma, Yifei [Second Military Medical University, Department of Orthorpedic Oncology, Changzheng Hospital, Shanghai (China); Second Military Medical University, Department of Pathology, Changzheng Hospital, Shanghai (China); Xu, Wei; Xiao, Jianru [Second Military Medical University, Department of Orthorpedic Oncology, Changzheng Hospital, Shanghai (China); Bai, Ruojing [Geriatrics Institute, Department of Geriatrics, Tianjin Medical University General Hospital, Laboratory of Neuro-Trauma and Neurodegenerative Disorder, Tianjin (China); Li, Yiming [Neurosurgery Institute, Department of Neuro-oncology, Beijing (China); Yu, Hongyu [Second Military Medical University, Department of Pathology, Changzheng Hospital, Shanghai (China); Yang, Chunshan [Panorama Medical Imaging Center, Department of PET/CT Radiology, Shanghai (China); Department of PET/CT Radiology Center, Shanghai (China); Shi, Huazheng; Zhang, Jian [Department of PET/CT Radiology Center, Shanghai (China); Li, Jidong [The First People' s Hospital of Shangqiu, Department of Stomatology, Shangqiu, Henan Province (China); Wang, Chenguang [Second Military Medical University, Department of Radiology, Changzheng Hospital, Shanghai (China)

2017-02-15

To test the performance of sequential {sup 18}F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in predicting survival after sunitinib therapies in patients with cancer of unknown primary (CUP). CUP patients were enrolled for sequential PET/CT scanning for sunitinib and a control group. Univariate and multivariate analysis were applied to test the efficacy of sunitinib therapy in CUP patients. Next, sequential analyses involving PET/CT parameters were performed to identify and validate sensitive PET/CT biomarkers for sunitinib therapy. Finally, time-dependent receiver operating characteristic (TDROC) analyses were performed to compare the predictive accuracy. Multivariate analysis proved that sunitinib group had significantly improved survival (p < 0.01) as compared to control group. After cycle 2 of therapy, multivariate analysis identified volume-based PET/CT parameters as sensitive biomarkers for sunitinib (p < 0.01). TDROC curves demonstrated whole-body total lesion glycolysis reduction (Δ WTLG) and follow-up WTLG to have good accuracy for efficacy prediction. This evidence was validated after cycle 4 of therapy with the same method. Sunitinib therapy proved effective in treatment of CUP. PET/CT volume-based parameters may help predict outcome of sunitinib therapy, in which Δ WTLG and follow-up WTLG seem to be sensitive biomarkers for sunitinib efficacy. Patients with greater reduction and lower WTLG at follow-up seem to have better survival outcome. (orig.)

Feline superficial pyoderma: a retrospective study of 52 cases (2001-2011).

Science.gov (United States)

Yu, Hui W; Vogelnest, Linda J

2012-10-01

Superficial pyoderma is traditionally considered rare in cats but may be more prevalent than previously reported. To better characterize superficial pyoderma in cats. Fifty-two cats from a dermatology referral population over a 10 year period. This study was retrospective. Cases were included if neutrophils and intracellular bacteria were reported from surface cytology of skin lesions. Medical records were reviewed for signalment, historical and clinical data, cytology results, primary skin diagnoses and treatment details. Disease prevalence was 20%, with no breed or sex predispositions. The estimated median age of onset was 2 years, affecting 54% of cats by 3 years and 23% after 9 years. Fewer cases presented during winter (15%) compared with other seasons. Skin lesions were typically multifocal, affecting the face (62%), neck (37%), limbs (33%) and ventral abdomen (29%) most commonly. Crusting (83%), alopecia (67%), ulceration/erosion (54%) and erythema (46%) were common lesion types. Pruritus was reported in 92% of cats. Underlying hypersensitivities (confirmed in 60%; suspected in 19%), and atopic dermatitis specifically (confirmed in 48%), were the most frequent primary dermatoses. Cats were treated with a variety of systemic and/or topical antimicrobials. The overall apparent response was considered good in 61% and poor in 27% of cats. Recurrence was confirmed or suspected in 42% of cats. Feline superficial pyoderma was more prevalent in this study population than previously reported. Young cats with hypersensitivities and older cats were more commonly affected, and a variety of lesion types and distributions occurred. © 2012 The Authors. Veterinary Dermatology © 2012 ESVD and ACVD.

RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer.

Science.gov (United States)

Vishnu, Prakash; Colon-Otero, Gerardo; Kennedy, Gregory T; Marlow, Laura A; Kennedy, William P; Wu, Kevin J; Santoso, Joseph T; Copland, John A

2012-03-01

The aim was to evaluate antitumor activity of the combination of ixabepilone and sunitinib in pre-clinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and to investigate the mechanism of synergy of such drug combination. HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established. Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes. The molecular mechanism of antitumor synergy was examined using shRNA silencing. The combination of ixabepilone and sunitinib demonstrated robust antitumor synergy in naïve and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis. The GTPase, RhoB, was synergistically upregulated in cells treated with ixabepilone and sunitinib. Using shRNA, RhoB was demonstrated to mediate antitumor synergy. These results were validated in two other EOC cell lines. Ixabepilone plus sunitinib demonstrated antitumor synergy via RhoB in naïve and paclitaxel-resistant cells resulting in apoptosis. This study demonstrates a novel mechanism of action leading to antitumor synergy and provides 'proof-of-principle' for combining molecular targeted agents with cytotoxic chemotherapy to improve antitumor efficacy. RhoB could be envisioned as an early biomarker of response to therapy in a planned Phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib. To the best of our knowledge, this is the first demonstration of antitumor synergy between these two classes of drugs in EOC and the pivotal role of RhoB in this synergy. Copyright © 2011 Elsevier Inc. All rights reserved.

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.

Science.gov (United States)

Mulder, Sasja F; Jacobs, Joannes F M; Olde Nordkamp, Michel A M; Galama, Joep M D; Desar, Ingrid M E; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F A; Vissers, Kris C P; Punt, Cornelis J A; de Vries, I Jolanda M; van Herpen, Carla M L

2011-07-01

The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.

The Concept of Ecthyma Gangrenosum Illustrated by a Fusarium oxysporum Infection in an Immunocompetent Individual

NARCIS (Netherlands)

de Hoog, S.

2016-01-01

Ecthyma gangrenosum (EG) involves necrotic cutaneous lesions caused by bacteria, mainly Pseudomonas aeruginosa, and is usually seen in immunocompromised patients with septicemia. However, clinically similar infections have been published with fungi as etiologic agents. We present a case of an

Ecthyma gangrenosum in Saudi Arabia

International Nuclear Information System (INIS)

Obasi, Obasi E.; Raddadi, Ali A.; Osoba, Abimbola O.

2007-01-01

We report a diagnosis of ecthyma gangrenosum (EG) in 4 females of mean age 54.8 (range 43-64) years, within 10 months. Severe drug reaction treated with high dose systemic corticosteroids in patient 1, acute myelocytic leukemia treated with high dose dexamethasone and multiple broad-spectrum antibiotics in patient 2precede the onset of EG. Patients 3 and 4 had vasculitic purpura and hemodialysis. In addition, patient 3 was receiving multiple broad-spectrum antibiotics plus anti-tuberculosis (TB) drugs for gastric TB, while patient 4 was on melphalan and high dose systemic corticosteroids. Pseudomonas aeruginosa was isolated from blood culture of the first 3 patients and skin culture of patient one. Blister aspirate from patient 4 yielded Candida albicans. Factors enhancing skin invasion by pathogenic organisms in our patients were breached skin integrity, therapy with high dose corticosteroids and multiple broad-spectrum antibiotics, hematologic malignancies and chemotherapy with severe neutropenia. (author)

Lincosamide resistance is less frequent in Denmark in Staphylococcus pseudintermedius from first-time canine superficial pyoderma compared with skin isolates from clinical samples with unknown clinical background.

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Larsen, Rikke; Boysen, Lene; Berg, June; Guardabassi, Luca; Damborg, Peter

2015-06-01

Antimicrobial resistance may be overestimated in bacterial isolates from clinical samples because veterinarians often submit samples in cases of treatment failure or recurrent cases, which are more frequently associated with resistant strains. To assess to what extent the prevalence of antimicrobial resistance in Staphylococcus pseudintermedius isolated from first-time superficial pyoderma differs from canine skin isolates from clinical samples with unknown clinical background. Two study groups were enrolled in Denmark between March 2012 and October 2013: 57 dogs with first-time superficial pyoderma and no prior antimicrobial treatment (Group A); and 289 different dogs for which skin specimens were submitted for culture during the study (Group B). One S. pseudintermedius isolate from each dog was confirmed by MALDI-TOF mass spectrometry and tested for antimicrobial susceptibility by broth microdilution. Resistance levels in the two groups were compared by Fisher's exact test. Clindamycin resistance was less frequent in Group A (14%) than in Group B (27%) (P = 0.02). Similar trends were observed for amoxicillin-clavulanic acid (1.8 versus 4.8%), chloramphenicol (8.8 versus 14.5%), enrofloxacin (1.8 versus 3.5%), oxacillin (1.8 versus 4.8%) and trimethoprim/sulfamethoxazole (3.5 versus 5.9%). Oxacillin resistance was significantly associated with resistance to six of seven non-β-lactams. The prevalence of lincosamide resistance is markedly influenced by patients' clinical and antimicrobial treatment history. To limit selection of multidrug-resistant bacteria, lincosamides are appropriate empirical choices for treatment of first-time superficial pyoderma even though resistance is not infrequent. Culture and susceptibility testing are, however, recommended for all pyoderma patients. © 2015 ESVD and ACVD.

Questionnaire survey of detrimental fur animal epidemic necrotic pyoderma in Finland.

Science.gov (United States)

Nordgren, Heli; Vapalahti, Katariina; Vapalahti, Olli; Sukura, Antti; Virtala, Anna-Maija

2017-08-03

In 2007, a previously unrecorded disease, fur animal epidemic necrotic pyoderma (FENP), was detected in farmed mink (Neovision vision), foxes (Vulpes lagopus) and Finnraccoons (Nyctereutes procyonoides) in Finland. Symptoms included severe pyoderma with increased mortality, causing both animal welfare problems and economic losses. In 2011, an epidemiologic questionnaire was mailed to all members of the Finnish Fur Breeders' Association to assess the occurrence of FENP from 2009 through the first 6 months of 2011. The aim was to describe the geographical distribution and detailed clinical signs of FENP, as well as sources of infection and potential risk factors for the disease. A total of 239 farmers (25%) returned the questionnaire. Clinical signs of FENP were observed in 40% (95% CI 34-46%) of the study farms. In addition, the survey clarified the specific clinical signs for different animal species. The presence of disease was associated with the importation of mink, especially from Denmark (OR 9.3, 95% CI 2.6-33.0). The transmission route between Finnish farms was associated with fur animal purchases. Some risk factors such as the farm type were also indicated. As such, FENP was detected more commonly on farms with more than one species of fur animal in comparison to farms with, for example, only foxes (OR 4.6, 95% CI 2.4-8.6), and the incidence was higher on farms with over 750 breeder mink compared to smaller farms (OR 3.8, 95% CI 1.6-9.0). Contact between fur animals and birds and other wildlife increased the risk of FENP on farms. Responses also indicated that blocking the entry of wildlife to the animal premises protected against FENP. FENP was most likely introduced to Finland by imported mink and spread further within the country via domestically purchased fur animals. Some potential risk factors, such as the type and size of the farm and contact with wildlife, contributed to the spread of FENP. Escape-proof shelter buildings block the entry of wildlife

Neuroprotective effects of the anti-cancer drug sunitinib in models of HIV neurotoxicity suggests potential for the treatment of neurodegenerative disorders.

Science.gov (United States)

Wrasidlo, Wolf; Crews, Leslie A; Tsigelny, Igor F; Stocking, Emily; Kouznetsova, Valentina L; Price, Diana; Paulino, Amy; Gonzales, Tania; Overk, Cassia R; Patrick, Christina; Rockenstein, Edward; Masliah, Eliezer

2014-12-01

Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier. We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity. Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology. Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders. © 2014 The British Pharmacological Society.

Addition of sunitinib to cetuximab and irinotecan in patients with heavily pre-treated advanced colorectal cancer

DEFF Research Database (Denmark)

Qvortrup, Camilla; Jensen, Benny Vittrup; Jørgensen, Trine Lembrecht

2010-01-01

Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented.......Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented....

Costo Efectividad del Tratamiento de Tumores Neuroendócrinos Pancreáticos Avanzados no Operables con Sunitinib en México.

Science.gov (United States)

Muciño Ortega, Emilio; Chi-Chan, Alfredo; Peniche-Otero, Gustavo; Gutiérrez-Colín, Consuelo I; Herrera-Rojas, Joaquín; Galindo-Suárez, Rosa María

2012-12-01

Sunitinib had showed a substantial clinical benefit in patients with non-resectable pancreatic Neuroendocrine Tumors (NET). The objective of this study was to estimate the cost-effectiveness of sunitinib in the treatment of non-resectable pancreatic NET, from the perspective of the Social Security Mexican Institute (IMSS). A Markov model (2-week cycles) was used to estimate the health and economic consequences of sunitinib 37.5mg/day+best supportive care (BSC) regarding placebo+BSC (ten-years horizon, discount rate: 5%). Effectiveness measures were: overall survival (OS), progression-free survival (PFS) and quality adjusted life years (QALY). Resource utilization (BSC, adverse events management, medical follow-up) was estimated through a survey with Mexican oncologists (n=10). Unit costs of medication and medical resources were obtained from institutional sources. Sensitivity analyses were performed and acceptability curves were constructed. Sunitinib+BSC gained 0.49 years (PFS), 1.18 years (OS) and 0.70 QALY against placebo+BSC. Sunitinib+BSC increased medical direct costs (2011 US$) per patient in $20,854, which was driven by acquisition costs of sunitinib and medical follow up before progression. ICER's were $42,157, $17,662 and $29,808 per progression-free year, life-year and QALY gained, respectively, which remained robust through±25% changes in main parameters. At willingness to pay higher than $40,000, $22,400 and $37,600 sunitinib+BSC becomes the most cost-effective alternative in regards to PFS, OS and QALYs, respectively. At IMSS, sunitinib+BSC would provide substantial clinical benefits to patients suffering unresectable pancreatic NET, although the latter would increase medical costs of treatment and clinical follow up. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

The use of 24-h ambulatory blood pressure monitoring (ABPM) during the first cycle of sunitinib improves the diagnostic accuracy and management of hypertension in patients with advanced renal cancer.

Science.gov (United States)

Bamias, A; Manios, E; Karadimou, A; Michas, F; Lainakis, G; Constantinidis, C; Deliveliotis, C; Zakopoulos, N; Dimopoulos, M A

2011-07-01

Hypertension (HT) complicates treatment with antiangiogenic agents, including the tyrosine kinase inhibitor (TKI) sunitinib. To prospectively evaluate the prevalence and management of HT in patients with advanced renal cell carcinoma (RCC) receiving sunitinib we used 24-h ABPM and we treated HT according to guidelines of the Joint National Committee on Prevention, Detection and Evaluation and the Treatment of High Blood Pressure (JNC7). Normal 24-h ABPM at the baseline and at 2, 4 and 6 weeks of the first cycle was ensured with the successive use of hydrochlorothiazide+irbesartan, nebivolol and amlodipine. Office BP measurements were used in subsequent cycles to monitor HT. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. Forty patients were included in this analysis. Twenty-one patients (53%) had baseline HT, while 12 of 14 (84%) normotensive patients required anti-HT treatment during the 1st cycle of sunitinib. HT was infrequent in subsequent cycles and increase of anti-HT medication was required in only 2 cases. Two patients permanently discontinued sunitinib due to HT. The remaining 34 (94%) required no dose modifications for HT. One cardiac event (2.8%) was observed. There was no correlation of HT with sunitinib efficacy. Sunitinib-associated HT is more frequent than previously reported. The use of 24-h ABPM for diagnosis and tailoring of HT according to JNC7 guidelines may achieve uninterrupted, full dose therapy in most patients. The substitution of such protocols for currently used Toxicity Criteria may be warranted. Copyright © 2011 Elsevier Ltd. All rights reserved.

Sunitinib treatment in patients with advanced renal cell cancer: the Brazilian National Cancer Institute (INCA) experience.

Science.gov (United States)

Coelho, Rafael Corrêa; Reinert, Tomás; Campos, Franz; Peixoto, Fábio Affonso; de Andrade, Carlos Augusto; Castro, Thalita; Herchenhorn, Daniel

2016-01-01

The aim of this study was to assess the impact of sunitinib treatment in a non-screened group of patients with metastatic renal cell cancer (mRCC) treated by the Brazilian Unified Health System (SUS) at a single reference institution. Retrospective cohort study, which evaluated patients with mRCC who received sunitinib between May 2010 and December 2013. Fifty-eight patients were eligible. Most patients were male 41 (71%), with a median age of 58 years. Nephrectomy was performed in 41 (71%) patients with a median interval of 16 months between the surgery and initiation of sunitinib. The most prevalent histological subtype was clear cell carcinoma, present in 52 (91.2%) patients. In 50 patients (86%), sunitinib was the first line of systemic treatment. The main adverse effects were fatigue (57%), hypothyroidism (43%), mucositis (33%) and diarrhea (29%). Grade 3 and 4 adverse effects were infrequent: fatigue (12%), hypertension (12%), thrombocytopenia (7%), neutropenia (5%) and hand-foot syndrome (5%). Forty percent of patients achieved a partial response and 35% stable disease, with a disease control rate of 75%. Median progression free survival was 7.6 months and median overall survival was 14.1 months. Sunitinib treatment was active in the majority of patients, especially those with low and intermediate risk by MSKCC score, with manageable toxicity. Survival rates were inferior in this non-screened population with mRCC treated in the SUS. Copyright© by the International Brazilian Journal of Urology.

Sunitinib treatment in patients with advanced renal cell cancer: the Brazilian National Cancer Institute (INCA experience

Directory of Open Access Journals (Sweden)

Rafael Corrêa Coelho

Full Text Available ABSTRACT Purpose: The aim of this study was to assess the impact of sunitinib treatment in a non-screened group of patients with metastatic renal cell cancer (mRCC treated by the Brazilian Unified Health System (SUS at a single reference institution. Material and Methods: Retrospective cohort study, which evaluated patients with mRCC who received sunitinib between May 2010 and December 2013. Results: Fifty-eight patients were eligible. Most patients were male 41 (71%, with a median age of 58 years. Nephrectomy was performed in 41 (71% patients with a median interval of 16 months between the surgery and initiation of sunitinib. The most prevalent histological subtype was clear cell carcinoma, present in 52 (91.2% patients. In 50 patients (86%, sunitinib was the first line of systemic treatment. The main adverse effects were fatigue (57%, hypothyroidism (43%, mucositis (33% and diarrhea (29%. Grade 3 and 4 adverse effects were infrequent: fatigue (12%, hypertension (12%, thrombocytopenia (7%, neutropenia (5% and hand-foot syndrome (5%. Forty percent of patients achieved a partial response and 35% stable disease, with a disease control rate of 75%. Median progression free survival was 7.6 months and median overall survival was 14.1 months. Conclusion: Sunitinib treatment was active in the majority of patients, especially those with low and intermediate risk by MSKCC score, with manageable toxicity. Survival rates were inferior in this non-screened population with mRCC treated in the SUS.

Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer.

Science.gov (United States)

Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan; Sengeløv, Lisa; Saad, Fred; Houede, Nadine; Ostler, Peter; Stenzl, Arnulf; Daugaard, Gedske; Jones, Robert; Laestadius, Fredrik; Ullèn, Anders; Bahl, Amit; Castellano, Daniel; Gschwend, Juergen; Maurina, Tristan; Chow Maneval, Edna; Wang, Shaw-Ling; Lechuga, Maria Jose; Paolini, Jolanda; Chen, Isan

2014-01-10

We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%). The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.

Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice.

Science.gov (United States)

Chew, Chii Chii; Ng, Salby; Chee, Yun Lee; Koo, Teng Wai; Liew, Ming Hui; Chee, Evelyn Li-Ching; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L; Segarra, Ignacio

2017-08-01

Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC 0→∞ 38% in plasma (p diclofenac increased the liver uptake efficiency in male (27%, p diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.

Antimicrobial susceptibility profiles of Staphylococcus intermedius isolates from clinical cases of canine pyoderma in South Africa

Directory of Open Access Journals (Sweden)

Catherine A. Blunt

2013-05-01

Full Text Available Successful treatment of canine pyoderma has become compromised owing to the development of antimicrobial resistance with accompanying recurrence of infection. Canine skin samples submitted to a veterinary diagnostic laboratory for microbiological culture and sensitivity between January 2007 and June 2010, from which Staphylococcus intermedius was isolated, were selected for this investigation. Antimicrobial resistance of S. intermedius was most prevalent with reference to ampicillin followed by resistance to tetracycline and then potentiated sulphonamides. In general, antimicrobial resistance was low and very few methicillin-resistant isolates were detected. Temporal trends were not noted, except for ampicillin, with isolates becoming more susceptible, and potentiated sulphonamides (co-trimoxazole, with isolates becoming more resistant. In general, both the Kirby–Bauer disc diffusion and broth dilution minimum inhibitory concentration tests yielded similar results for the antimicrobial agents tested. The main difference was evident in the over-estimation of resistance by the Kirby–Bauer test for ampicillin, co-trimoxazole, penicillin and doxycycline. Knowledge of trends in bacterial resistance is important for veterinarians when presented with canine pyoderma. Analysis of antimicrobial susceptibility profiles of S. intermedius isolated from canine pyodermas will guide veterinarians’ use of the most appropriate agent and encourage prudent use of antimicrobials in companion animals.

Pyoderma Gangrenosum: A Clinical Observation in an Adult Nigerian

African Journals Online (AJOL)

infective ulceration of the skin of unknown aetiology and rarely reported amongst Nigerians. It is believed to be a reactive inflammatory dermatosis and partly a spectrum of neutrophilic dermatoses. PG usually starts as a painful nodule or ...

Effectiveness of a combined (4% chlorhexidine digluconate shampoo and solution) protocol in MRS and non-MRS canine superficial pyoderma: a randomized, blinded, antibiotic-controlled study.

Science.gov (United States)

Borio, Stefano; Colombo, Silvia; La Rosa, Giuseppe; De Lucia, Michela; Damborg, Peter; Guardabassi, Luca

2015-10-01

There is a lack of studies comparing topical antiseptics to systemic antibiotics in the treatment of canine superficial pyoderma. To compare the efficacy of topical chlorhexidine with systemic amoxicillin-clavulanic acid for the treatment of canine superficial pyoderma. A randomized controlled trial was conducted in dogs with superficial pyoderma. Group T (n = 31) was treated topically with 4% chlorhexidine digluconate shampoo (twice weekly) and solution (once daily) for 4 weeks. Group S (n = 20) was treated orally with amoxicillin-clavulanic acid (25 mg/kg) twice daily for 4 weeks. Bacterial culture and susceptibility testing were performed on clinical specimens collected before treatment. Severity of lesions and number of intracellular bacteria were evaluated using four-point scales to calculate a total pyoderma score for each dog. Pruritus was assessed by owners using a visual analog scale (range 0-10). Scores were analysed for statistical differences between groups T and S. Staphylococcus pseudintermedius was isolated from 48 dogs, including eight meticillin-resistant strains (MRSP). Although the number of dogs was small, no significant differences in pyoderma and pruritus scores were observed between groups throughout the study except for day 1, when group S had a significantly higher total score than group T (P = 0.03). Treatment with chlorhexidine products resulted in resolution of clinical signs in all dogs including those infected with MRSP. Topical therapy with chlorhexidine digluconate products may be as effective as systemic therapy with amoxicillin-clavulanic acid. This finding supports the current recommendations to use topical antiseptics alone for the management of superficial pyoderma. © 2015 The Authors. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of the ESVD and ACVD.

The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system

DEFF Research Database (Denmark)

Kappers, Mariëtte H W; Smedts, Frank M M; Horn, Thomas

2011-01-01

of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature...... be prevented with the endothelin receptor antagonist macitentan (¿BP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (¿BP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine...

The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system

DEFF Research Database (Denmark)

Kappers, Mariëtte H W; Smedts, Frank M M; Horn, Thomas

2011-01-01

of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature...... be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine...

Long-term benefit of sunitinib in patients with metastatic renal cell carcinoma in Latin America: retrospective analysis of patient clinical characteristics

Directory of Open Access Journals (Sweden)

Smaletz O

2016-11-01

Full Text Available Oren Smaletz,1 Matias Chacón,2 Ludmila de Oliveira Koch,1 Daniela R de Carvalho Rocha,1 Fernanda C Cardoso1 1Department of Oncology, Hospital Israelita Albert Einstein, São Paulo, Brazil; 2Medical Oncology Department, Alexander Fleming Institute, Buenos Aires, Argentina Objective: To describe the clinical characteristics of Latin American patients with metastatic renal cell carcinoma (mRCC who experienced a progression-free survival (PFS for at least 15 months following treatment with sunitinib. Patients and methods: In this retrospective analysis, mRCC patients in two institutions in Latin America received sunitinib at a starting dose of either 50 mg/day for 4 weeks followed by 2 weeks off treatment (Schedule 4/2 in repeated 6-week cycles or sunitinib 37.5 mg on a continuous daily dosing schedule. Clinical characteristics, tolerability, and PFS data were collected. Results: Twenty-nine patients with long-term clinical benefit from sunitinib were identified between September 2005 and August 2009. Median PFS was 23 months (range: 15–54 months. Two of the 29 patients with prolonged PFS achieved a complete response and additional eleven had a partial response. Most patients were aged <60 years, had good performance status, favorable or intermediate Memorial Sloan Kettering Cancer Center prognostic risk, and disease limited to one or two sites. Dose reduction was necessary in all patients who started sunitinib at 50 mg/day administered on Schedule 4/2. Adverse events leading to dose reduction included grade 3 hand–foot syndrome, mucositis, fatigue, and hypertension. At the time of data cutoff, four patients were still receiving sunitinib treatment. Conclusion: Extended PFS can be achieved in Latin American patients with mRCC treated with sunitinib. Although the small sample size and retrospective nature of this evaluation preclude the identification of pretreatment predictive factors contributing to this benefit, the current analysis warrants

The Global Epidemiology of Impetigo: A Systematic Review of the Population Prevalence of Impetigo and Pyoderma.

Science.gov (United States)

Bowen, Asha C; Mahé, Antoine; Hay, Roderick J; Andrews, Ross M; Steer, Andrew C; Tong, Steven Y C; Carapetis, Jonathan R

2015-01-01

We conducted a comprehensive, systematic review of the global childhood population prevalence of impetigo and the broader condition pyoderma. PubMed was systematically searched for impetigo or pyoderma studies published between January 1 1970 and September 30 2014. Two independent reviewers extracted data from each relevant article on the prevalence of impetigo. Sixty-six articles relating to 89 studies met our inclusion criteria. Based on population surveillance, 82 studies included data on 145,028 children assessed for pyoderma or impetigo. Median childhood prevalence was 12·3% (IQR 4·2-19·4%). Fifty-eight (65%) studies were from low or low-middle income countries, where median childhood prevalences were 8·4% (IQR 4·2-16·1%) and 14·5% (IQR 8·3-20·9%), respectively. However, the highest burden was seen in underprivileged children from marginalised communities of high-income countries; median prevalence 19·4%, (IQR 3·9-43·3%). Based on data from studies published since 2000 from low and low-middle income countries, we estimate the global population of children suffering from impetigo at any one time to be in excess of 162 million, predominantly in tropical, resource-poor contexts. Impetigo is an under-recognised disease and in conjunction with scabies, comprises a major childhood dermatological condition with potential lifelong consequences if untreated.

The Global Epidemiology of Impetigo: A Systematic Review of the Population Prevalence of Impetigo and Pyoderma.

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Asha C Bowen

Full Text Available We conducted a comprehensive, systematic review of the global childhood population prevalence of impetigo and the broader condition pyoderma.PubMed was systematically searched for impetigo or pyoderma studies published between January 1 1970 and September 30 2014. Two independent reviewers extracted data from each relevant article on the prevalence of impetigo.Sixty-six articles relating to 89 studies met our inclusion criteria. Based on population surveillance, 82 studies included data on 145,028 children assessed for pyoderma or impetigo. Median childhood prevalence was 12·3% (IQR 4·2-19·4%. Fifty-eight (65% studies were from low or low-middle income countries, where median childhood prevalences were 8·4% (IQR 4·2-16·1% and 14·5% (IQR 8·3-20·9%, respectively. However, the highest burden was seen in underprivileged children from marginalised communities of high-income countries; median prevalence 19·4%, (IQR 3·9-43·3%.Based on data from studies published since 2000 from low and low-middle income countries, we estimate the global population of children suffering from impetigo at any one time to be in excess of 162 million, predominantly in tropical, resource-poor contexts. Impetigo is an under-recognised disease and in conjunction with scabies, comprises a major childhood dermatological condition with potential lifelong consequences if untreated.

Antibacterial drugs in the form of sprays for the topical treatment of pyodermas and dermatoses complicated with a secondary infection

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YE. V. Matushevskaya

2014-01-01

Full Text Available The article covers issues related to the application of topical antibacterial drugs for the treatment of pyodermic skin diseases. The author describes mechanisms of action and advantages of the topical form of antibiotics and GCS for the topical treatment of pyodermas. The article substantiates indications for the administration of topical GCS drugs in a combination with antibacterial drugs. The efficacy and safety of antibacterial and combination topical drugs such as Neomycin, Oxycort and Polcortolon TC in the form sprays for the treatment of pyodermas and complicated forms of chronic dermatosis.

Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

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Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan

2014-01-01

PURPOSE: We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg...

A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma.

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Stenner, Frank; Chastonay, Rahel; Liewen, Heike; Haile, Sarah R; Cathomas, Richard; Rothermundt, Christian; Siciliano, Raffaele D; Stoll, Susanna; Knuth, Alexander; Buchler, Tomas; Porta, Camillo; Renner, Christoph; Samaras, Panagiotis

2012-01-01

To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45-5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference -1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02-4.3, p = 0.003). The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use. Copyright © 2012 S. Karger AG, Basel.

Ecthyma gangrenosum in the periorbital region in a previously healthy immunocompetent woman without bacteremia

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Somenath Sarkar

2016-01-01

Full Text Available Ecthyma gangrenosum (EG is a cutaneous lesion classically associated with potentially fatal Pseudomonas septicemia in immunocompromised patients. Other bacterial and fungal pathogens have also been implicated. Although EG typically occurs in immunocompromised or neutropenic patients, it may occasionally affect a previously healthy person. The cutaneous findings are characteristic with small indurated papulovesicles progressing rapidly to necrotic ulcers with surrounding erythema and a central black Eschar. While lesions can occur at any site, most are commonly found over the buttocks, perineum, limbs, and axillae. We describe a case of EG in periorbital region in a previously healthy woman who responded to appropriate antibiotic treatment for Pseudomonas. It is very important to establish the diagnosis early so that appropriate systemic antibiotic therapy can be initiated to reduce morbidity and potential mortality.

Tissue Biomarkers in Predicting Response to Sunitinib Treatment of Metastatic Renal Cell Carcinoma.

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Trávníček, Ivan; Branžovský, Jindřich; Kalusová, Kristýna; Hes, Ondřej; Holubec, Luboš; Pele, Kevin Bauleth; Ürge, Tomáš; Hora, Milan

2015-10-01

To identify tissue biomarkers that are predictive of the therapeutic effect of sunitinib in treatment of metastatic clear cell renal cell carcinoma (mCRCC). Our study included 39 patients with mCRCC treated with sunitinib. Patients were stratified into two groups based on their response to sunitinib treatment: non-responders (progression), and responders (stable disease, regression). The effect of treatment was measured by comparing imaging studies before the initiation treatment with those performed at between 3rd and 7th months of treatment, depending on the patient. Histological samples of tumor tissue and healthy renal parenchyma, acquired during surgery of the primary tumor, were examined with immunohistochemistry to detect tissue targets involved in the signaling pathways of tumor growth and neoangiogenesis. We selected mammalian target of rapamycine, p53, vascular endothelial growth factor, hypoxia-inducible factor 1 and 2 and carbonic anhydrase IX. We compared the average levels of biomarker expression in both, tumor tissue, as well as in healthy renal parenchyma. Results were evaluated using the Student's t-test. For responders, statistically significant differences in marker expression in tumor tissue versus healthy parenchyma were found for mTOR (4%/16.7%; p=0.01031), p53 (4%/12.7%; p=0.042019), VEGF (62.7%/45%; p=0.019836) and CAIX (45%/15.33%; p=0.001624). A further significant difference was found in the frequency of high expression (more than 60%) between tumor tissue and healthy parenchyma in VEGF (65%/35%; p=0.026487) and CAIX (42%/8%; p=0.003328). CAIX was expressed at high levels in the tumor tissue in both evaluated groups. A significantly higher expression of VEGF in CRCC in comparison to healthy parenchyma can predict a better response to sunitinib. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The Concept of Ecthyma Gangrenosum Illustrated by a Fusarium oxysporum Infection in an Immunocompetent Individual.

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Jiang, Yanping; Al-Hatmi, Abdullah M S; Xiang, Yining; Cao, Yu; van den Ende, Albert H G Gerrits; Curfs-Breuker, Ilse; Meis, Jacques F; Lu, Hongguang; de Hoog, G Sybren

2016-10-01

Ecthyma gangrenosum (EG) involves necrotic cutaneous lesions caused by bacteria, mainly Pseudomonas aeruginosa, and is usually seen in immunocompromised patients with septicemia. However, clinically similar infections have been published with fungi as etiologic agents. We present a case of an EG-like lesion due to Fusarium oxysporum confirmed by clinical diagnosis, culture and molecular identification and discuss the definition of EG.

Skin rash and arthritis a simplified appraisal of less common associations.

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Cozzi, A; Doria, A; Gisondi, P; Girolomoni, G

2014-06-01

Skin and joint manifestations are part of the clinical spectrum of many disorders. Well-known associations include psoriatic arthritis and arthritis associated with autoimmune connective tissue diseases. This review focuses on less common associations where skin lesions can provide easily accessible and valuable diagnostic clues, and directly lead to the specific diagnosis or limit the list of possibilities. This may also affect health care resources as diagnostic tests are often low-specific, highly expensive and poorly available. This group of diseases can be divided into two subsets, based on the presence/absence of fever, and then further classified according to elementary skin lesions (macular, urticarial, maculo-papular, vesico-bullous, pustular, petechial and nodular). In most instances joint involvement occurs as peripheral migrating polyarthritis. Erythematosus macular or urticarial rashes occur in most febrile disorders such as monogenic autoinflammatory syndromes, Schnitzler's syndrome, Still's disease and rheumatic fever and afebrile diseases as urticarial vasculitis. Pustular rash may be observed in chronic recurrent multifocal osteomyelitis (CRMO) and pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome (both febrile) as well as in Behcet's disease and Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome (both non-febrile). Papular lesions are typical of secondary syphilis, sarcoidosis, interstitial granulomatous dermatitis, papular petechial of cutaneous small-vessel vasculitis and nodular lesions of polyarteritis nodosa and multicentric reticulohistiocytosis all of which are afebrile. Differential diagnosis includes infections and drug reactions which may mimic several of these conditions. To biopsy the right skin lesion at the right time it is essential to obtain relevant histological information. © 2013 European Academy of Dermatology and Venereology.

Clinical Outcomes of Patients with Advanced Gastrointestinal Stromal Tumors: Safety and Efficacy in a Worldwide Treatment-use Trial of Sunitinib

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Reichardt, Peter; Kang, Yoon-Koo; Rutkowski, Piotr; Schuette, Jochen; Rosen, Lee S; Seddon, Beatrice; Yalcin, Suayib; Gelderblom, Hans; Williams, Charles C; Fumagalli, Elena; Biasco, Guido; Hurwitz, Herbert I; Kaiser, Pamela E; Fly, Kolette; Matczak, Ewa; Chen, Liang; Lechuga, Maria José; Demetri, George D

2015-01-01

BACKGROUND To provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain sunitinib; to obtain broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. METHODS Imatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule (IDS) of 50 mg/day in 6-week cycles (4 weeks on treatment, 2 weeks off). Tumor assessment frequency was per local practice, with response assessed by investigators per Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post-hoc analyses evaluated different patterns of treatment management. RESULTS At final data cutoff, 1124 patients comprised the intent-to-treat population; 15% had a baseline Eastern Cooperative Oncology Group performance status ≥2. Median treatment duration was 7.0 months. Median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0–9.4), and median OS was 16.6 months (95% CI, 14.9–18.0) with 36% of patients alive at the time of analysis. Patients in whom the IDS was modified exhibited longer median OS (23.5 months) than those treated strictly per the IDS (11.1 months). The most common treatment-related grade 3/4 adverse events (AEs) were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related AEs associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each. CONCLUSIONS This treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure. PMID:25641662

Body composition by computed tomography as a predictor of toxicity in patients with renal cell carcinoma treated with sunitinib.

LENUS (Irish Health Repository)

Cushen, Samantha J

2014-04-21

Sunitinib is a standard first-line option for metastatic renal cell carcinoma (mRCC). Body composition is a prognostic factor in cancer patients and patients with loss of skeletal muscle mass and fat-free mass (FFM) are prone to dose-limiting toxicity (DLT) during targeted drug therapy. We investigated whether body composition by computed tomography predicted DLT from sunitinib in mRCC.

Clinical efficacy of sunitinib combined with autologous DC and CIK for patients with metastatic renal cell carcinoma

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Liang ZHANG

2014-01-01

Full Text Available Objective　To analyze the clinical efficacy and safety of sunitinib combined with autologous dentritic cell (DC and cytokine induced killer cell (CIK for patients suffering from metastatic renal cell carcinoma (mRCC. Methods　Clinical data of 27 mRCC patients treated with sunitinib combined with autologous DC and CIK were reviewed retrospectively. Efficacy, quality of life, immunology and safety of this treatment were evaluated. Results　Follow-up time ranged from 4 to 25 months. Out of all the patients, sunitinib was reduced in 1 and discontinued in 2 due to side effects; 1 patient quit for personal reasons; 14 patients developed progressive disease. The progression-free survival (PFS was 4 to 19.5 months. Ten patients died from tumor, the overall survival time (OS was 6 to 21 months. The median PFS was 16 months (95%CI 12.5-19.5. The OS was not achieved. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST. All the patients received treatment over 1 cycle. After one course of treatment, among 27 patients, 0 had complete remission (CR, 4 had partial remission (PR, 17 had stable disease (SD, and 6 had progressive disease (PD. The overall objective remission rate (ORR and disease control rate (DCR were 14.8% (4/27 and 77.8% (21/27, respectively. Sunitinib and autologous transfusion of DC and CIK improved the immune function and quality of life. The major adverse events were fatigue, hand-foot syndrome, hypertension, hypothyroidism, thrombocytopenia, neutropenia and fever. Most of the adverse events were ameliorated by supportive treatment or dose reduction. Conclusions　 Sunitinib combined with autologous DC and CIK may be beneficial in the treatment of mRCC with acceptable toxic reactions, and it may be considered as a new approach for the comprehensive treatment of RCC. DOI: 10.11855/j.issn.0577-7402.2013.12.06

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

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Corn, Paul G.; Song, Danny Y.; Heath, Elisabeth; Maier, Jordan; Meyn, Raymond; Kuban, Deborah; DePetrillo, Thomas A.; Mathew, Paul

2013-01-01

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

Energy Technology Data Exchange (ETDEWEB)

Corn, Paul G., E-mail: pcorn@mdanderson.org [Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Song, Danny Y. [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (United States); Heath, Elisabeth; Maier, Jordan [Karmanos Cancer Institute, Wayne State University, Detroit, Michigan (United States); Meyn, Raymond [Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Kuban, Deborah [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); DePetrillo, Thomas A. [Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusetts (United States); Mathew, Paul, E-mail: pmathew@tuftsmedicalcenter.org [Department of Hematology-Oncology, Tufts Medical Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

2013-07-01

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.

Pseudomonas aeruginosa septic shock associated with ecthyma gangrenosum in an infant with agammaglobulinemia Choque séptico por Pseudomonas aeruginosa associado a éctima gangrenosa em criança com agamaglobulinemia

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João Fernando Lourenço de ALMEIDA

2002-01-01

Full Text Available Ecthyma gangrenosum (EG due to Pseudomonas aeruginosa is a rare and invasive infection that can be associated with agammaglobulinemia. The cornerstone of the treatment is based on prompt recognition with appropriate antibiotic coverage and intravenous immunoglobulin. The authors report a case of EG emphasizing the clinical and therapeutic aspects of this condition.Éctima Gangrenosa (EG por Pseudomonas aeruginosa é uma infecção rara e invasiva que pode ser associada com agamaglobulinemia. O tratamento fundamental é baseado no pronto reconhecimento com cobertura de antibiótico apropriada e imunoglobulina intravenosa. Os autores relatam caso de EG dando ênfase aos aspectos clínicos e terapêuticos desta condição.

Real-World Economic Outcomes During Time on Treatment Among Patients Who Initiated Sunitinib or Pazopanib as First Targeted Therapy for Advanced Renal Cell Carcinoma: A Retrospective Analysis of Medicare Claims Data.

Science.gov (United States)

Vogelzang, Nicholas J; Pal, Sumanta K; Ghate, Sameer R; Li, Nanxin; Swallow, Elyse; Peeples, Miranda; Zichlin, Miriam L; Meiselbach, Mark K; Perez, Jose Ricardo; Agarwal, Neeraj

2018-06-01

The median age at renal cell carcinoma (RCC) diagnosis is 64 years. However, few studies have assessed the real-world time on treatment (TOT), health resource utilization (HRU), costs, or treatment compliance associated with targeted therapy use among patients in this age group with RCC. To assess the HRU, costs, and compliance during TOT among Medicare patients aged ≥ 65 years with advanced RCC (aRCC) who initiated first targeted therapy with pazopanib or sunitinib. Patients with aRCC were identified in the 100% Medicare + Part D databases administered by the Centers for Medicare & Medicaid Services. Eligible patients initiated first targeted therapy with sunitinib or pazopanib (index drug) on or after their first diagnosis of secondary neoplasm between October 19, 2009, and January 1, 2014, and were aged ≥ 65 years as of 1 year before first targeted therapy initiation (index date). Included patients were stratified into pazopanib and sunitinib cohorts based on first targeted therapy and matched 1:1 on baseline characteristics using propensity scores. TOT was defined as the time from the index date to treatment discontinuation (prescription gap > 90 days) or death. Compliance was defined as the ratio of drug supply days to TOT. Monthly all-cause costs and costs associated with RCC diagnosis (medical and pharmacy in 2015 U.S. dollars) and HRU (inpatient [admissions, readmissions, and days], outpatient, and emergency room visits) were assessed in the 1-year post-index period during TOT. Matched cohorts' TOT was compared using Kaplan-Meier analyses and univariable Cox models, and compliance, HRU, and costs were compared using Wilcoxon signed-rank tests. Of 1,711 included patients, 526 initiated pazopanib and 1,185 initiated sunitinib. Before matching, more patients in the pazopanib cohort were white, diagnosed in 2010-2014 versus 2006-2009, and had lung metastases compared with the sunitinib cohort (all P < 0.05). The pazopanib cohort also had higher mean

Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft.

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Hao, Fangran; Wang, Siyuan; Zhu, Xiao; Xue, Junsheng; Li, Jingyun; Wang, Lijie; Li, Jian; Lu, Wei; Zhou, Tianyan

2017-02-01

To investigate the anti-tumor effect of sunitinib in combination with dopamine in the treatment of nu/nu nude mice bearing non-small cell lung cancer (NSCLC) A549 cells and to develop the combination PK/PD model. Further, simulations were conducted to optimize the administration regimens. A PK/PD model was developed based on our preclinical experiment to explore the relationship between plasma concentration and drug effect quantitatively. Further, the model was evaluated and validated. By fixing the parameters obtained from the PK/PD model, simulations were built to predict the tumor suppression under various regimens. The synergistic effect was observed between sunitinib and dopamine in the study, which was confirmed by the effect constant (GAMA, estimated as 2.49). The enhanced potency of dopamine on sunitinib was exerted by on/off effect in the PK/PD model. The optimal dose regimen was selected as sunitinib (120 mg/kg, q3d) in combination with dopamine (2 mg/kg, q3d) based on the simulation study. The synergistic effect of sunitinib and dopamine was demonstrated by the preclinical experiment and confirmed by the developed PK/PD model. In addition, the regimens were optimized by means of modeling as well as simulation, which may be conducive to clinical study.

A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study.

Science.gov (United States)

Biagi, J J; Oza, A M; Chalchal, H I; Grimshaw, R; Ellard, S L; Lee, U; Hirte, H; Sederias, J; Ivy, S P; Eisenhauer, E A

2011-02-01

Sunitinib is a multitargeted receptor tyrosine kinase inhibitor. We conducted a two-stage phase II study to evaluate the objective response rate of oral sunitinib in recurrent epithelial ovarian cancer. Eligibility required measurable disease and one or two prior chemotherapies, at least one platinum based. Platinum-sensitive or -resistant disease was allowed. Initial dose schedule was sunitinib 50 mg daily, 4 of 6 weeks. Observation of fluid accumulations during off-treatment periods resulted in adoption of continuous 37.5 mg daily dosing in the second stage of accrual. Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand-foot syndrome and hypertension. No gastrointestinal perforation occurred. Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting.

Sunitinib indirectly enhanced anti-tumor cytotoxicity of cytokine-induced killer cells and CD3⁺CD56⁺ subset through the co-culturing dendritic cells.

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Adisak Wongkajornsilp

Full Text Available Cytokine-induced killer (CIK cells have reached clinical trials for leukemia and solid tumors. Their anti-tumor cytotoxicity had earlier been shown to be intensified after the co-culture with dendritic cells (DCs. We observed markedly enhanced anti-tumor cytotoxicity activity of CIK cells after the co-culture with sunitinib-pretreated DCs over that of untreated DCs. This cytotoxicity was reliant upon DC modulation by sunitinib because the direct exposure of CIK cells to sunitinib had no significant effect. Sunitinib promoted Th1-inducing and pro-inflammatory phenotypes (IL-12, IFN-γ and IL-6 in DCs at the expense of Th2 inducing phenotype (IL-13 and regulatory phenotype (PD-L1, IDO. Sunitinib-treated DCs subsequently induced the upregulation of Th1 phenotypic markers (IFN-γ and T-bet and the downregulation of the Th2 signature (GATA-3 and the Th17 marker (RORC on the CD3⁺CD56⁺ subset of CIK cells. It concluded that sunitinib-pretreated DCs drove the CD3⁺CD56⁺ subset toward Th1 phenotype with increased anti-tumor cytotoxicity.

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy

DEFF Research Database (Denmark)

Ravaud, Alain; Motzer, Robert J; Pandha, Hardev S

2016-01-01

interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent...

Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results

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Motzer, Robert J; Ravaud, Alain; Patard, Jean-Jacques

2018-01-01

BACKGROUND: Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03). OBJECTIVE: To report...... sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman...... grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively. CONCLUSIONS...

Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study.

Science.gov (United States)

George, Daniel J; Martini, Jean-François; Staehler, Michael; Motzer, Robert J; Magheli, Ahmed; Escudier, Bernard; Gerletti, Paola; Li, Sherry; Casey, Michelle; Laguerre, Brigitte; Pandha, Hardev S; Pantuck, Allan J; Patel, Anup; Lechuga, Maria J; Ravaud, Alain

2018-04-01

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated. Results: Baseline characteristics were similar in patients with ( n = 191) and without ( n = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8 + T-cell density ≥ versus < median [median (95% CI), not reached (6.83-not reached) versus 3.47 years (1.73-not reached); hazard ratio (HR) 0.40 (95% CI, 0.20-0.81); P = 0.009] treated with sunitinib ( n = 101), but not with placebo ( n = 90). The sensitivity and specificity for CD8 + T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1 + versus PD-L1 - tumors (HR 1.75; P = 0.103). Among all patients with PD-L1 + tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; P = 0.175). Conclusions: Greater CD8 + T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. Clin Cancer Res; 24(7); 1554-61. ©2018 AACR . ©2018 American Association for Cancer Research.

Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes

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Doherty, Kimberly R.; Wappel, Robert L.; Talbert, Dominique R.; Trusk, Patricia B.; Moran, Diarmuid M.; Kramer, James W.; Brown, Arthur M.; Shell, Scott A.; Bacus, Sarah

2013-01-01

Tyrosine kinase inhibitors (TKi) have greatly improved the treatment and prognosis of multiple cancer types. However, unexpected cardiotoxicity has arisen in a subset of patients treated with these agents that was not wholly predicted by pre-clinical testing, which centers around animal toxicity studies and inhibition of the human Ether-à-go-go-Related Gene (hERG) channel. Therefore, we sought to determine whether a multi-parameter test panel assessing the effect of drug treatment on cellular, molecular, and electrophysiological endpoints could accurately predict cardiotoxicity. We examined how 4 FDA-approved TKi agents impacted cell viability, apoptosis, reactive oxygen species (ROS) generation, metabolic status, impedance, and ion channel function in human cardiomyocytes. The 3 drugs clinically associated with severe cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while the relatively cardiac-safe drug erlotinib showed only minor changes in cardiac cell health. Crizotinib, an ALK/MET inhibitor, led to increased ROS production, caspase activation, cholesterol accumulation, disruption in cardiac cell beat rate, and blockage of ion channels. The multi-targeted TKi sunitinib showed decreased cardiomyocyte viability, AMPK inhibition, increased lipid accumulation, disrupted beat pattern, and hERG block. Nilotinib, a second generation Bcr-Abl inhibitor, led to increased ROS generation, caspase activation, hERG block, and an arrhythmic beat pattern. Thus, each drug showed a unique toxicity profile that may reflect the multiple mechanisms leading to cardiotoxicity. This study demonstrates that a multi-parameter approach can provide a robust characterization of drug-induced cardiomyocyte damage that can be leveraged to improve drug safety during early phase development. - Highlights: • TKi with known adverse effects show unique cardiotoxicity profiles in this panel. • Crizotinib increases ROS, apoptosis, and

Cost-effectiveness of sunitinib as second-line treatment for gastrointestinal stromal tumor in the People’s Republic of China

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Li J

2017-01-01

Full Text Available Jian Li,1 Hong Ye Ren,2 Juanjuan Zhang,2 Peng Dong,2 Yan Wang,3 Andrea L Stevens,3 Yi Han,3 Min Huang4 1Laboratory of Carcinogenesis and Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 2Pfizer Inc., Beijing, People’s Republic of China; 3WG Consulting, New York, NY, USA; 4School of Pharmacy, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China Objective: To evaluate the cost-effectiveness of sunitinib as a second-line treatment in patients with advanced gastrointestinal stromal tumors that no longer respond to imatinib 400 mg/d, compared with imatinib 600 mg/d, 800 mg/d, or best supportive care (BSC in the People’s Republic of China. Methods: This study was conducted from the government payer’s perspective with a time horizon of 5 years. Three health states were considered: progression-free survival, disease progression survival, and death, with a cycle length of 6 weeks. Probabilities of disease progression and death were estimated based on survival functions using exponential distribution and progression survival data in the clinical trials. Drug costs were based on drug retail prices and the patient assistance program in the People’s Republic of China, and adverse event management costs were based on published data and/or expert opinion. Uncertainties for parameters in the study were addressed through one-way deterministic and probabilistic sensitivity analysis. Results: When sunitinib was compared with imatinib 600 mg/d and BSC, the incremental cost-effectiveness ratio was RMB75,715 with RMB121,080 per quality-adjusted life-year (QALY gained. Sunitinib demonstrated lower costs and higher QALYs than imatinib 800 mg/d. In the probabilistic sensitivity analysis, the willingness-to-pay per QALY gained was set to be three times the per capita gross domestic product of the People’s Republic of

Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo

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Brian C. Jensen

2017-06-01

Full Text Available Background: More than 90 tyrosine kinases have been implicated in the pathogenesis of malignant transformation and tumor angiogenesis. Tyrosine kinase inhibitors (TKIs have emerged as effective therapies in treating cancer by exploiting this kinase dependency. The TKI erlotinib targets the epidermal growth factor receptor (EGFR, whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGFR and platelet-derived growth factor receptor (PDGFR.TKIs that impact the function of non-malignant cells and have on- and off-target toxicities, including cardiotoxicities. Cardiotoxicity is very rare in patients treated with erlotinib, but considerably more common after sunitinib treatment. We hypothesized that the deleterious effects of TKIs on the heart were related to their impact on cardiac metabolism. Methods: Female FVB/N mice (10/group were treated with therapeutic doses of sunitinib (40 mg/kg, erlotinib (50 mg/kg, or vehicle daily for two weeks. Echocardiographic assessment of the heart in vivo was performed at baseline and on Day 14. Heart, skeletal muscle, liver and serum were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Results: Compared to vehicle-treated controls, sunitinib-treated mice had significant decreases in systolic function, whereas erlotinib-treated mice did not. Non-targeted metabolomics analysis of heart identified significant decreases in docosahexaenoic acid (DHA, arachidonic acid (AA/ eicosapentaenoic acid (EPA, O-phosphocolamine, and 6-hydroxynicotinic acid after sunitinib treatment. DHA was significantly decreased in skeletal muscle (quadriceps femoris, while elevated cholesterol was identified in liver and elevated ethanolamine identified in serum. In contrast, erlotinib affected only one metabolite (spermidine significantly increased. Conclusions: Mice treated with sunitinib exhibited systolic dysfunction within two weeks, with significantly lower heart and skeletal muscle

Sustained systemic response paralleled with ovarian metastasis progression by sunitinib in metastatic renal cell carcinoma: Is this an anti-angiogenic potentiation of cancer?

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Uttam K Mete

2015-01-01

Full Text Available Metastatic renal cell cancer is associated with poor prognosis and survival and is resistant to conventional chemotherapy. Therapeutic targeting of molecular pathways for tumor angiogenesis and other specific activation mechanisms offers improved tumor response and prolonged survival. A 48-year-old, female patient presented with large right renal mass with features suggesting of renal cell cancer without metastasis on contrast enhanced computed tomography (CT. Right radical nephrectomy was done. After 9 months of surgery, she got metastasis in lung, liver and ovary. The patient received sunitinib via an expanded access program. After eight 6-week cycles of sunitinib, a reassessment CT scan confirmed an excellent partial response with the almost complete disappearance (90% of liver and lung metastasis but the adnexal mass had increased in size (>10 times and the possibility was thought of second malignancy. Excision of the mass performed. Histopathology of the mass depicted metastatic renal cell cancer. There is possibility of a ′site-specific anti-angiogenic potentiation mechanism′ of malignancy in relation to sunitinib based upon the preclinical studies, in reference to the index case. Regression of one site with concurrent progression is possible. The exact mechanism of site-specific response, especially organ specific progression by vascular endothelial growth factor inhibitors in metastatic renal cell cancer warrants further study.

Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.

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Perrin, Allison; Sherman, Steven; Pal, Sumanta; Chua, Andrew; Gorritz, Magdaliz; Liu, Zhimei; Wang, Xufang; Culver, Kenneth; Casciano, Roman; Garrison, Louis P

2015-03-01

Everolimus and axitinib are approved in the US to treat patients with advanced renal cell carcinoma (RCC) after failure on sunitinib or sorafenib, and one prior systemic therapy (e.g., sunitinib), respectively. Two indirect comparisons performed to evaluate progression-free survival in patients treated with everolimus vs axitinib suggested similar efficacy between the two treatments. Therefore, this analysis compares the lifetime costs of these two therapies among sunitinib-refractory advanced RCC patients from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory advanced RCC patients and estimate the cost of treating patients with everolimus vs axitinib. The following health states were included: stable disease without adverse events (AEs), stable disease with AEs, disease progression (PD), and death. The model included the following resources: active treatments, post-progression treatments, adverse events, physician and nurse visits, scans and tests, and palliative care. Resource utilization inputs were derived from a US claims database analysis. Additionally, a 3% annual discount rate was applied to costs, and the robustness of the model results was tested by conducting sensitivity analyses, including those on dosing scheme and post-progression treatment costs. Base case results demonstrated that patients treated with everolimus cost an average of $12,985 (11%) less over their lifetimes than patients treated with axitinib. The primary difference in costs was related to active treatment, which was largely driven by axitinib's higher dose intensity. RESULTS remained consistent across sensitivity analyses for AE and PD treatment costs, as well as dose intensity and discount rates. The results suggest that everolimus likely leads to lower lifetime costs than axitinib for sunitinib-refractory advanced RCC patients in the US.

Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review

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Smith, Elisabeth J; Allantaz, Florence; Bennett, Lynda; Zhang, Dongping; Gao, Xiaochong; Wood, Geryl; Kastner, Daniel L; Punaro, Marilynn; Aksentijevich, Ivona; Pascual, Virginia; Wise, Carol A

2010-01-01

PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an autosomal dominant, hereditary auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. These mutations produce a hyper-phosphorylated PSTPIP1 protein and alter its participation in activation of the “inflammasome” involved in interleukin-1 (IL-1β) production. Overproduction of IL-1β is a clear molecular feature of PAPA syndrome. Ongoing research is implicating other biochemical pathways that may be relevant to the distinct pyogenic inflammation of the skin and joints characteristic of this disease. This review summarizes the recent and rapidly accumulating knowledge on these molecular aspects of PAPA syndrome and related disorders. PMID:21532836

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

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Haas, Naomi B; Manola, Judith; Uzzo, Robert G; Flaherty, Keith T; Wood, Christopher G; Kane, Christopher; Jewett, Michael; Dutcher, Janice P; Atkins, Michael B; Pins, Michael; Wilding, George; Cella, David; Wagner, Lynne; Matin, Surena; Kuzel, Timothy M; Sexton, Wade J; Wong, Yu-Ning; Choueiri, Toni K; Pili, Roberto; Puzanov, Igor; Kohli, Manish; Stadler, Walter; Carducci, Michael; Coomes, Robert; DiPaola, Robert S

2016-01-01

Summary Background Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. Methods In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. Findings Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each

Sunitinib in combination with trastuzumab for the treatment of advanced breast cancer: activity and safety results from a phase II study

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Bachelot, Thomas; Wang, Zhixiao; Cesari, Rossano; Tassell, Vanessa; Kern, Kenneth A; Blay, Jean-Yves; Lluch, Ana; Garcia-Saenz, Jose A; Verma, Sunil; Gutierrez, Maya; Pivot, Xavier; Kozloff, Mark F; Prady, Catherine; Huang, Xin; Khosravan, Reza

2014-01-01

This phase II study evaluated the efficacy and safety/tolerability of sunitinib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC). Eligible patients received sunitinib 37.5 mg/day and trastuzumab administered either weekly (loading, 4 mg/kg; then weekly 2 mg/kg) or 3-weekly (loading, 8 mg/kg; then 3-weekly 6 mg/kg). Prior trastuzumab and/or lapatinib treatment were permitted. The primary endpoint was objective response rate (ORR). Sixty patients were enrolled and evaluable for safety; 57 were evaluable for efficacy. The majority of patients (58%) had received no prior chemotherapy in the metastatic setting. The ORR was 37%; the clinical benefit rate (CBR; percent objective response plus stable disease ≥ 24 weeks) was 56%. Among patients who were treatment-naïve or had received only adjuvant therapy, the ORR was 44% and the CBR was 59%. Overall, median overall survival had not been reached and the 1-year survival rate was 91%. The majority of adverse events (AEs) were mild to moderate in severity. Forty percent of patients experienced AEs related to measured left ventricular ejection fraction (LVEF) declines, which occurred more frequently in patients who had received prior anthracycline treatment. Ten percent of patients exhibited symptoms related to LVEF declines. One patient died on study from cardiogenic shock. Antitumor response and several safety parameters appeared to correlate with sunitinib exposure. Sunitinib plus trastuzumab demonstrated antitumor activity in patients with HER2-positive ABC, particularly those who were treatment-naïve or had only received prior adjuvant treatment. Sunitinib plus trastuzumab had acceptable safety and tolerability in patients with HER2-positive ABC who had not received prior anthracycline therapy. clinicaltrials.gov/ct2/show/NCT00243503

Hidradenitis suppurativa: Inside and out

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Sharmila Patil

2018-01-01

Full Text Available Hidradenitis suppurativa is a chronic, disabling, suppurative disease characterized by deep tender subcutaneous nodules; complicated by fibrosis and extensive sinuses affecting primarily the apocrine gland bearing areas. It affects all races in early 20s with greater prevalence seen in women (3 to 5:1. The estimated disease prevalence is 1 - 4 %. The disease is speculated to be caused by follicular structural abnormalities with associated risk factors as smoking, obesity, positive family history and shaving. Certain co-morbidities can also be seen such as inflammatory bowel disease, spondyloarthropathies, epithelial tumors, pyoderma gangrenosum etc. Treatment modalities include counseling of the patient to lose weight if obese, to wear loose clothes, stop smoking and maintain good hygiene. Topical antibiotics, like 1% clindamycin, have shown to give good results along with benzoyl peroxide wash. Orally cocktail of antibiotics can be given, though biologicals remain the best treatment option. Surgical excision can be done in later stages and in recalcitrant cases.

Guidelines for treatment with infliximab for Crohn's disease.

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Hommes, D W; Oldenburg, B; van Bodegraven, A A; van Hogezand, R A; de Jong, D J; Romberg-Camps, M J L; van der Woude, J; Dijkstra, G

2006-01-01

Infliximab is an accepted induction and maintenance treatment for patients with Crohn's disease. The effectiveness of infliximab has been demonstrated for both active luminal disease and for enterocutaneous fistulisation. In addition, infliximab can be administered for extraintestinal symptoms of Crohn's disease, such as pyoderma gangrenosum, uveitis and arthropathy. Maintenance treatment with infliximab is effective and is regarded as safe as long as the necessary safety measures are heeded. Infusion reactions occur in 3 to 17% of the patients and are associated with the formation of antibodies to infliximab. A reduction in infusion reactions is possible by the concurrent administration of steroids and the use of immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Furthermore, immunosuppressants increase the duration of the response to infliximab. For these reasons, the concomitant use of immunosuppressants with infliximab is recommended. Infections and most specifically tuberculosis need to be ruled out before infliximab is administered. Up to now, there are no indications for a connection between an increased risk for malignancies and treatment with infliximab.

Validation of the 16-Gene Recurrence Score in patients with locoregional, high-risk renal cell carcinoma from a phase 3 trial of adjuvant sunitinib.

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Rini, Brian I; Escudier, Bernard; Martini, Jean-Francois; Magheli, Ahmed; Svedman, Christer; Lopatin, Margarita; Knezevic, Dejan; Goddard, Audrey D; Febbo, Phillip G; Li, Rachel; Lin, Xun; Valota, Olga; Staehler, Michael; Motzer, Robert J; Ravaud, Alain

2018-05-17

Adjuvant sunitinib prolonged disease-free survival (DFS) (hazard ratio [HR] 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC post-nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored association of RS results with prediction of sunitinib benefit. The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer-specific survival (RCSS) were analyzed using Cox proportional hazards regression. Results: Baseline characteristics were similar between patients with and without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 (95% CI, 2.15-39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant. Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Copyright ©2018, American Association for Cancer Research.

Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

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Reichardt, Peter; Demetri, George D; Gelderblom, Hans; Rutkowski, Piotr; Im, Seock-Ah; Gupta, Sudeep; Kang, Yoon-Koo; Schöffski, Patrick; Schuette, Jochen; Soulières, Denis; Blay, Jean-Yves; Goldstein, David; Fly, Kolette; Huang, Xin; Corsaro, Massimo; Lechuga, Maria Jose; Martini, Jean-Francois; Heinrich, Michael C

2016-01-15

Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ(2) test) in the same molecular subgroups. Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20%) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy

Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells.

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Kirsi Ketola

Full Text Available Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects.In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression.Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram-sunitinib

Comparison of a chlorhexidine and a benzoyl peroxide shampoo as sole treatment in canine superficial pyoderma.

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Loeffler, A; Cobb, M A; Bond, R

2011-09-03

The clinical and antibacterial efficacy of two shampoos used as a sole antibacterial treatment in dogs with superficial pyoderma were investigated and compared. In a randomised, partially blinded study, a 3 per cent chlorhexidine gluconate shampoo (Chlorhex 3; Leo Animal Health) was compared against a 2.5 per cent benzoyl peroxide shampoo (Paxcutol; Virbac) in 22 dogs with superficial pyoderma. Dogs were washed two to three times weekly with a 10-minute contact time over 21 days. Clinical scores and bacterial counts were assessed on days 1, 8 and 22 and compared within and between treatment groups; overall response was assessed at the end of the study. Twenty dogs completed the study; 15 (68.2 per cent) showed an overall clinical improvement and the clinical signs resolved in three chlorhexidine-treated dogs. In the chlorhexidine-treated group, scores for papules/pustules (P<0.001), investigator-assessed pruritus (P=0.003), total bacterial counts (P=0.003) and counts for coagulase-positive staphylococci (P=0.003) were reduced after three weeks. Scores and bacterial counts did not vary significantly in the benzoyl peroxide-treated group.

Hypothyroidism as a predictive clinical marker of better treatment response to sunitinib therapy.

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Kust, Davor; Prpić, Marin; Murgić, Jure; Jazvić, Marijana; Jakšić, Blanka; Krilić, Dražena; Bolanča, Ante; Kusić, Zvonko

2014-06-01

Tyrosine kinase inhibitors are standard treatment in patients with metastatic renal cell carcinoma (mRCC). Several studies have indicated that side-effects including hypothyroidism may serve as potential predictive biomarkers of treatment efficacy. All patients with clear cell mRCC treated with sunitinib in the first-line setting in our Center between November 2008 and October 2013 were included. Thyroid function was assessed after every 2 cycles. Prognostic factors were tested using Cox proportional hazards model for univariate analysis. During treatment, 29.3% developed hypothyroidism, with a median of peak TSH values of 34.4 mIU/L. Patients who had both TSH >4 mIU/L and were receiving substitution therapy with levothyroxine had prolonged PFS compared to all other patients (25.3 months vs. 9.0 months; p=0.042). The rate of hypothyroidism as a side-effect of sunitinib in patients with mRCC is significant. Patients with symptomatic hypothyroidism experienced significantly longer PFS, but without difference in OS. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

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Wuthrick, Evan J.; Curran, Walter J.; Camphausen, Kevin; Lin, Alexander; Glass, Jon; Evans, James; Andrews, David W.; Axelrod, Rita; Shi, Wenyin; Werner-Wasik, Maria; Haacke, E. Mark; Hillman, Gilda G.; Dicker, Adam P.

2014-01-01

Purpose/Objective(s): Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Methods and Materials: Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acute toxicity, and response was assessed via serial magnetic resonance imaging. Results: Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Conclusions: Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival

A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

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Wuthrick, Evan J., E-mail: evan.wuthrick@osumc.edu [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Curran, Walter J. [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Camphausen, Kevin [Department of Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland (United States); Lin, Alexander [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Glass, Jon; Evans, James; Andrews, David W. [Department of Neurological Surgery, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Axelrod, Rita [Department of Medical Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Shi, Wenyin; Werner-Wasik, Maria [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Haacke, E. Mark [Department of Radiology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan (United States); Department of Biomedical Engineering, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan (United States); Hillman, Gilda G. [Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan (United States); Dicker, Adam P. [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

2014-10-01

Purpose/Objective(s): Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Methods and Materials: Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acute toxicity, and response was assessed via serial magnetic resonance imaging. Results: Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Conclusions: Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival.

Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumor after failure with imatinib and sunitinib treatment: A meta-analysis.

Science.gov (United States)

Zhang, Zhenan; Jiang, Tao; Wang, Wensheng; Piao, Daxun

2017-12-01

This meta-analysis aimed to evaluate the safety and efficacy of regorafenib as a treatment for patients with advanced (metastatic and/or unresectable) gastrointestinal stromal tumor (AGIST) after developing resistance to imatinib and sunitinib. A literature search of databases such as PubMed, Embase, and Cochrane library was conducted up to February 2017. The pooled percentages and the corresponding 95% confidence intervals (CIs) were calculated using the Stata 11.0 software. Four studies involving 243 patients with AGIST were included. Results revealed that approximately 49% (95% CI 30-67), 14% (95% CI 5-23), and 41% (95% CI 21-61) of patients with AGIST showed clinical benefit (including complete response), partial response, and stable disease, respectively, after regorafenib treatment, which was given after failure with imatinib and sunitinib treatments. No complete response was found in the included studies. Pooled progression-free survival was 6.58 months (95% CI 4.62-8.54). Hypertension (20%; 95% CI 7-33), hand-foot skin reaction (22%; 95% CI 17-27), and hypophosphatemia (18%; 95% CI 5-41) were common grade ≥3 regorafenib-related adverse events in patients treated with regorafenib after failure with imatinib and sunitinib treatments. Forty-nine per cent of patients with AGIST benefited after regorafenib treatment after the development of resistance to imatinib and sunitinib. More studies should be performed to improve the clinical survival of patients with AGIST. Close monitoring and appropriate management of grade ≥3 regorafenib-related adverse events should be considered during treatment.

Smoking and skin disease

DEFF Research Database (Denmark)

Thomsen, S F; Sørensen, L T

2010-01-01

Tobacco smoking is a serious and preventable health hazard that can cause or exacerbate a number of diseases and shorten life expectancy, but the role of smoking as an etiologic factor in the development of skin disease is largely unknown. Although epidemiological evidence is sparse, findings...... suggest that tobacco smoking is a contributing factor in systemic lupus erythematosus, psoriasis, palmoplantar pustulosis, cutaneous squamous cell carcinoma, hidradenitis suppurativa, and genital warts. In contrast, smoking may confer some protective effects and mitigate other skin diseases, notably...... pemphigus vulgaris, pyoderma gangrenosum, aphthous ulcers, and Behçet's disease. Various degenerative dermatologic conditions are also impacted by smoking, such as skin wrinkling and dysregulated wound healing, which can result in post-surgical complications and delayed or even arrested healing of chronic...

Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases

DEFF Research Database (Denmark)

Halling, Morten L; Kjeldsen, Jens; Knudsen, Torben

2017-01-01

were significantly increased (P celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC (P ...AIM: To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD). METHODS: In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013....... Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn's disease (CD) and Both...

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

DEFF Research Database (Denmark)

Lankhorst, Stephanie; Baelde, Hans J; Kappers, Mariëtte H W

2015-01-01

Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency...

Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the Memorial Sloan-Kettering prognostic factors model

International Nuclear Information System (INIS)

Bamias, Aristotelis; Anastasiou, Ioannis; Stravodimos, Kostas; Xanthakis, Ioannis; Skolarikos, Andreas; Christodoulou, Christos; Syrigos, Kostas; Papandreou, Christos; Razi, Evangelia; Dafni, Urania; Fountzilas, George; Karadimou, Alexandra; Dimopoulos, Meletios A; Lampaki, Sofia; Lainakis, George; Malettou, Lia; Timotheadou, Eleni; Papazisis, Kostas; Andreadis, Charalambos; Kontovinis, Loukas

2010-01-01

The treatment paradigm in advanced renal cell carcinoma (RCC) has changed in the recent years. Sunitinib has been established as a new standard for first-line therapy. We studied the prognostic significance of baseline characteristics and we compared the risk stratification with the established Memorial Sloan Kettering Cancer Center (MSKCC) model. This is a retrospective analysis of patients treated in six Greek Oncology Units of HECOG. Inclusion criteria were: advanced renal cell carcinoma not amenable to surgery and treatment with Sunitinib. Previous cytokine therapy but no targeted agents were allowed. Overall survival (OS) was the major end point. Significance of prognostic factors was evaluated with multivariate cox regression analysis. A model was developed to stratify patients according to risk. One hundred and nine patients were included. Median follow up has been 15.8 months and median OS 17.1 months (95% CI: 13.7-20.6). Time from diagnosis to the start of Sunitinib (<= 12 months vs. >12 months, p = 0.001), number of metastatic sites (1 vs. >1, p = 0.003) and performance status (PS) (<= 1 vs >1, p = 0.001) were independently associated with OS. Stratification in two risk groups ('low' risk: 0 or 1 risk factors; 'high' risk: 2 or 3 risk factors) resulted in distinctly different OS (median not reached [NR] vs. 10.8 [95% confidence interval (CI): 8.3-13.3], p < 0.001). The application of the MSKCC risk criteria resulted in stratification into 3 groups (low and intermediate and poor risk) with distinctly different prognosis underlying its validity. Nevertheless, MSKCC model did not show an improved prognostic performance over the model developed by this analysis. Studies on risk stratification of patients with advanced RCC treated with targeted therapies are warranted. Our results suggest that a simpler than the MSKCC model can be developed. Such models should be further validated

FDG and FLT-PET for Early measurement of response to 37.5 mg daily sunitinib therapy in metastatic renal cell carcinoma.

Science.gov (United States)

Horn, Kevin P; Yap, Jeffrey T; Agarwal, Neeraj; Morton, Kathryn A; Kadrmas, Dan J; Beardmore, Britney; Butterfield, Regan I; Boucher, Kenneth; Hoffman, John M

2015-09-03

Metastatic renal cell carcinoma has a poor prognosis and an intrinsic resistance to standard treatment. Sunitinib is an oral receptor tyrosine kinase inhibitor that has been used as a first-line targeted therapy in metastatic renal cell carcinoma. While computed tomography (CT) is currently the gold standard for response assessment in oncological trials, numerous studies have shown that positron emission tomography (PET) imaging can provide information predictive of tumor response to treatment earlier than the typical interval for standard of care follow-up CT imaging. In this exploratory study we sought to characterize early tumor response in patients with metastatic renal cell carcinoma treated with continuous daily 37.5 mg sunitinib therapy. Twenty patients underwent dynamic acquisition positron emission tomography (PET) imaging using (18) F-fluorodeoxyglucose (FDG) and (18) F-fluorothymidine (FLT) at baseline and early in treatment (after 1, 2, 3 or 4 weeks) with 37.5 mg continuous daily dosing of sunitinib. Semi-quantitative analyses were performed to characterize the tumor metabolic (FDG) and proliferative (FLT) responses to treatment. Proliferative responses were observed in 9/19 patients and occurred in 2 patients at one week (the earliest interval evaluated) after the initiation of therapy. A metabolic response was observed in 5/19 patients, however this was not observed until after two weeks of therapy were completed. Metabolic progression was observed in 2/19 patients and proliferative progression was observed in 1/19 patients. Baseline FDG-PET tumor maximum standardized uptake values correlated inversely with overall survival (p = 0.0036). Conversely, baseline (18) F-fluorothymidine PET imaging did not have prognostic value (p = 0.56) but showed a greater early response rate at 1-2 weeks after initiating therapy. While preliminary in nature, these results show an immediate and sustained proliferative response followed by a delayed

Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

Science.gov (United States)

Casciano, Roman; Chulikavit, Maruit; Di Lorenzo, Giuseppe; Liu, Zhimei; Baladi, Jean-Francois; Wang, Xufang; Robertson, Justin; Garrison, Lou

2011-01-01

A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies.

Science.gov (United States)

Wuthrick, Evan J; Kamrava, Mitchell; Curran, Walter J; Werner-Wasik, Maria; Camphausen, Kevin A; Hyslop, Terry; Axelrod, Rita; Andrews, David W; Glass, Jon; Machtay, Mitchell; Dicker, Adam P

2011-12-15

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies. Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3. Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤ 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT. Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial

Management of parastomal ulcers

Institute of Scientific and Technical Information of China (English)

Heather Yeo; Farshad Abir; Walter E Longo

2006-01-01

Management of surgically placed ostomies is an important aspect of any general surgical or colon and rectal surgery practice. Complications with surgically placed ostomies are common and their causes are multifactorial. Parastomal ulceration, although rare, is a particularly difficult management problem. We conducted a literature search using MD Consult, Science Direct,OVID, Medline, and Cochrane Databases to review the causes and management options of parastomal ulceration. Both the etiology and treatments are varied.Different physicians and ostomy specialists have used a large array of methods to manage parastomal ulcers;these including local wound care; steroid creams;systemic steroids; and, when conservative measures fail, surgery. Most patients with parastomal ulcers who do not have associated IBD or peristomal pyoderma gangrenosum (PPG) often respond quickly to local wound care and conservative management. Patients with PPG,IBD,or other systemic causes of their ulceration need both systemic and local care and are more likely to need long term treatment and possibly surgical revision of the ostomy. The treatment is complicated, but improved with the help of ostomy specialists.

Molecular structure, vibrational spectroscopic analysis (IR & Raman), HOMO-LUMO and NBO analysis of anti-cancer drug sunitinib using DFT method

Science.gov (United States)

Mıhçıokur, Özlem; Özpozan, Talat

2017-12-01

Oxindole and its derivatives have wide applications in different industries such as in synthetic & natural fibers, dyes for hair and plastic materials in addition to their biological importance. In the present study, one of the oxindole derivatives, N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (Sunitinib), which is used as an anti-cancer drug, was investigated in terms of structural, vibrational spectroscopic and theoretical analysis. The calculations have been performed for gaseous, aqueous and DMSO phases, respectively. Potential Energy Surface (PES) scan has been carrried out to obtain the most stable structures of all the phases of the title molecule using B3LYP/6-31G(d,p) level and the geometrical variations among them are discussed. The solvent effect for Sunitinib in aqueous and DMSO phases have been performed by means of the self-consistent recognition reaction field (SCRF) method as implemented in the integral equation formalism polarized continuum model (IEFPCM). On the other hand, NBO analysis has been carried out to understand probable hydrogen bonding sites and charge transfers. Additionally, the HOMO and the LUMO energies are calculated using B3LYP/6-31G(d,p) to determine the intra molecular charge transfers (ICT) within the molecule and the kinetic stabilities for each phases. The molecular electrostatic potential surface (MESP) has been plotted over the optimized structure to estimate the reactive sites of electrophilic and nucleophilic attacks regarding Sunitinib molecule. The potential energy distribution (PED) has been calculated using VEDA4 program and vibrational assignments of the experimental spectra (IR & Raman) have been elucidated by means of the calculated vibrational spectra. The observed vibrational spectra of Sunitinib is compared with the calculated spectra obtained by using B3LYP functional both with 6-31G(d,p) and 6-311++G(d,p) basis sets. Theoretical results

Síndrome de lisis tumoral en un paciente con cáncer de riñón tratado con sunitinib Tumor lysis syndrome in a patient with a renal carcinoma treated with sunitinib

Directory of Open Access Journals (Sweden)

Ezequiel Rodríguez-Reimúndes

2011-04-01

Full Text Available El síndrome de lisis tumoral (SLT es un trastorno metabólico que ocurre como consecuencia de una destrucción celular masiva. Se caracteriza por la presencia de hiperuricemia, hiperfosfatemia, hipocalcemia e hiperkalemia, y predispone al desarrollo de insuficiencia renal aguda. En la mayoría de los casos el SLT ocurre luego de instaurarse un tratamiento antitumoral y es más frecuente en tumores de alto grado de malignidad y alta sensibilidad a la quimioterapia. Presentamos el caso de un paciente con diagnóstico de cáncer de riñón recidivado que presenta un SLT e insuficiencia renal aguda luego de iniciar tratamiento con sunitinib.The tumor mor lysis syndrome (TLS is a metabolic disorder resulting from a massive tumor breakdown. It is characterized by hyperuricemia, hyperphosphatemia, hypocalcemia and hyperkalemia and predisposes to acute renal failure. TLS usually occurs after the initiation of cytotoxic therapy and is more frequent in the case of neoplasias with a high proliferative rate or that are highly chemo-sensitive. We report the case of a man with a recurrent kidney cancer who presented with a TLS and acute renal failure after initiation of sunitinib.

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination

NARCIS (Netherlands)

Mulder, Sasja F.; Jacobs, Joannes F. M.; Olde Nordkamp, Michel A. M.; Galama, Joep M. D.; Desar, Ingrid M. E.; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F. A.; Vissers, Kris C. P.; Punt, Cornelis J. A.; de Vries, I. Jolanda M.; van Herpen, Carla M. L.

2011-01-01

The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination

NARCIS (Netherlands)

Mulder, S.F.; Jacobs, J.F.M.; Olde Nordkamp, M.A.M.; Galama, J.M.D.; Desar, I.M.E.; Torensma, R.; Teerenstra, S.; Mulders, P.F.; Vissers, K.C.P.; Punt, C.J.A.; Vries, I.J.M. de; Herpen, C.M.L. van

2011-01-01

PURPOSE: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the

[Penile Tuberculosis : A Case Report].

Science.gov (United States)

Imanaka, Takahiro; Nomura, Hironori; Tsujimura, Go; Ko, Yoko; Kinjyo, Takanori; Yoshioka, Iwao; Takada, Shingo; Yahata, Yoko; Mizutani, Tetsu

2017-04-01

A 66-year-old man presented with a chief complaint of glans penis pain, induration, and discharge of pus. He was prescribed a course of antibiotics, but the condition persisted despite treatment. Thus, we differrentially diagnosed the patient with penile tuberculosis and pyoderma gangrenosum, and performed a biopsy of the penis. The biopsy result was thickening of the horny layer epidermis with only a foreign body granuloma composed of inflammatory cells, and did not lead to a definitive diagnosis. Thoraca-abdominal computed tomography revealed axillary lymphadenopathy with necrosis. Suspecting tuberculosis lymphadenitis, we performed T-spot and QuantiFERONtests. The result was T-spot negative and QuantiFERONpositive, so we diagnosed the patient with penile tuberculosis, and started antituberculosis medication. In about half a year after the start of treatment the symptoms subsided, and lymphadenopathy showed reduction.

Comparative evaluation of topical Sodium fusidate cream in common pyodermas with topical gentamicin ointment and systemic antibiotics

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Roy AK

1996-01-01

Full Text Available ABSTRACT: One hundred cases of common pyodermas consisting of four groups, namely impetigo, furunculosis and chronic folliculitis were taken. Each group containing twenty five cases were divided again into three subgroups. From each group, 15 were treated with 2 percent Sodium fusidate cream, 5 were with 0.1 percent Gentamycin sulphate cream and the rest 5 with systemic Erythromycin stearate. In the group of Impetigo, Bockhart′s Impetigo and Furunculosis, topical Sodium fusidate cream showed excellent result, better than Gentamycin topical and equal to that of systemic Erythromycin stearate.

Successful treatment of fusarium solani ecthyma gangrenosum in a patient affected by leukocyte adhesion deficiency type 1 with granulocytes transfusions

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Hassen Assia

2010-10-01

Full Text Available Abstract Background Ecthyma gangrenosum (EG manifests as a skin lesion affecting patients suffering extreme neutropenia and is commonly associated with Pseudomonas aeruginosa in immunocompromised patients. Leukocyte adhesion deficiency I (LAD I which count among primary immunodeficiency syndromes of the innate immunity, is an autosomal recessive disorder characterized in its severe phenotype by a complete defect in CD18 expression on neutrophils, delayed cord separation, chronic skin ulcers mainly due to recurrent bacterial and fungal infections, leucocytosis with high numbers of circulating neutrophils and an accumulation of abnormally low number of neutrophils at sites of infection. Case Presentation We report at our knowledge the first case of a child affected by LAD-1, who experienced during her disease course a multi-bacterial and fungal EG lesion caused by fusarium solani. Despite targeted antibiotics and anti-fungi therapy, the lesion extended for as long as 18 months and only massive granulocytes pockets transfusions in association with G-CSF had the capacity to cure this lesion. Conclusion We propose that granulocytes pockets transfusions will be beneficial to heal EG especially in severely immunocompromised patients.

Oligometastatic state predicts a favorable outcome for renal cell carcinoma patients with bone metastasis under the treatment of sunitinib.

Science.gov (United States)

Lu, Xiaolin; Gu, Weijie; Zhang, Hailiang; Zhu, Yao; Shi, Guohai; Ye, Dingwei

2016-05-03

The aim of the study was to investigate whether RCC patients with oligometastatic state of bone metastasis treated with sunitinib had a favorable clinical outcome. 22 patients were classified into oligometastatic state of bone metastasis with a median OS of 30.1 months (95%CI: 26.3 to 33.8 months). The 45 patients with non-oligometastatic state had a median OS of 12.7 months (95%CI: 9.43 to 16.0 months). Kaplan-Meier analysis showed significant difference between them (Log Rank test p<0.001). When we set patients with only multiple bone (at least 5 sites) metastases as a single group, there was still significant difference between oligometastatic state group and non-oligometastatic state groups. In multivariate Cox proportion hazard ratio analysis, metastatic states (p=0.012), MSKCC score (p=0.002), ECOG (p=0.001) and lymph nodes metastasis (p=0.000) were significantly associated with prognosis. The integration of metastatic state into the MSKCC risk model improved the c-index from 0.651 to 0.752. 67 patients from Fudan University Shanghai Cancer Center with bone metastatic RCC were divided into 2 metastatic states. One included those with oligometastatic state of bone metastasis with less than 5 sites of bone metastasis. The other involved those patients with multiple bone metastases (at least 5 sites) or together with other sites of metastasis. Then patients with only multiple bone (at least 5 sites) metastases were set into a single group. RCC patients with oligometastatic state of bone metastasis treated with sunitinib had a favorable clinical outcome.

First-line sunitinib versus pazopanib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

DEFF Research Database (Denmark)

Ruiz-Morales, Jose Manuel; Swierkowski, Marcin; Wells, J Connor

2016-01-01

BACKGROUND: Sunitinib (SU) and pazopanib (PZ) are standards of care for first-line treatment of metastatic renal cell carcinoma (mRCC). However, how the efficacy of these drugs translates into effectiveness on a population-based level is unknown. PATIENTS AND METHODS: We used the International mR...

Long-Term Natural History and Complications of Collagenous Colitis

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Hugh J Freeman

2012-01-01

Full Text Available Microscopic forms of colitis have been described, including collagenous colitis, a possibly heterogeneous disorder. Collagenous colitis most often appears to have an entirely benign clinical course that usually responds to limited treatment. Sometimes significant extracolonic disorders, especially arthritis, spondylitis, thyroiditis and skin disorders, such as pyoderma gangrenosum, dominate the clinical course and influence the treatment strategy. However, rare fatalities have been reported and several complications, some severe, have been attributed directly to the colitis. Toxic colitis and toxic megacolon may develop. Concomitant gastric and small intestinal inflammatory disorders have been described including celiac disease and more extensive collagenous inflammatory disease. Colonic ulceration has been associated with the use of nonsteroidal anti-inflammatory drugs, while other forms of inflammatory bowel disease, including ulcerative colitis and Crohn disease, may evolve directly from collagenous colitis. Submucosal ‘dissection’, colonic fractures, or mucosal tears and perforation, possibly from air insufflation during colonoscopy, have been reported. Similar changes may result from increased intraluminal pressures that may occur during radiological imaging of the colon. Neoplastic disorders of the colon may also occur during the course of collagenous colitis, including colon carcinoma and neuroendocrine tumours (ie, carcinoids. Finally, lymphoproliferative disease has been reported.

Does pityriasis rosea Koebnerise?

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Nwabudike Lawrence Chukwudi

2013-04-01

Full Text Available The Koebner phenomenon or isomorphic phenomenon is described in dermatology texts as the production of lesions of the original disease, in clinically uninvolved skin, following trauma. The lesions are located at the site of trauma and evidence of a traumatic causation is the linear arrangement of some of the lesions, such as in the case of lichen planus. Other disorders known to exhibit the Koebner phenomenon include psoriasis and vitiligo. A number of other diseases are associated with the Koebner phenomenon. Pathergy is a phenomenon of pustule production following trauma, which occurs in certain disorders such as Pyoderma gangrenosum and Behçet?s disease. In some disorders such as impetigo and verruca vulgaris, inoculation may give the appearance of the Koebner phenomenon. A case of pityriasis rosea and Koebner phenomenon at the site of routine blood assay is described in this work. This author has not thus far encountered any description of the Koebner reaction in relation to pityriasis rosea in the literature, but, perhaps, with this report, other physicians will be more open to this possibility and actually uncover similar cases.

Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib

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Stefania Gorini

2018-01-01

Full Text Available Many cancer therapies produce toxic side effects whose molecular mechanisms await full elucidation. The most feared and studied side effect of chemotherapeutic drugs is cardiotoxicity. Also, skeletal muscle physiology impairment has been recorded after many chemotherapeutical treatments. However, only doxorubicin has been extensively studied for its side effects on skeletal muscle. Chemotherapeutic-induced adverse side effects are, in many cases, mediated by mitochondrial damage. In particular, trastuzumab and sunitinib toxicity is mainly associated with mitochondria impairment and is mostly reversible. Vice versa, doxorubicin-induced toxicity not only includes mitochondria damage but can also lead to a more robust and extensive cell injury which is often irreversible and lethal. Drugs interfering with mitochondrial functionality determine the depletion of ATP reservoirs and lead to subsequent reversible contractile dysfunction. Mitochondrial damage includes the impairment of the respiratory chain and the loss of mitochondrial membrane potential with subsequent disruption of cellular energetic. In a context of increased stress, AMPK has a key role in maintaining energy homeostasis, and inhibition of the AMPK pathway is one of the proposed mechanisms possibly mediating mitochondrial toxicity due to chemotherapeutics. Therapies targeting and protecting cell metabolism and energy management might be useful tools in protecting muscular tissues against the toxicity induced by chemotherapeutic drugs.

Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results.

Science.gov (United States)

Amin, Asim; Dudek, Arkadiusz Z; Logan, Theodore F; Lance, Raymond S; Holzbeierlein, Jeffrey M; Knox, Jennifer J; Master, Viraj A; Pal, Sumanta K; Miller, Wilson H; Karsh, Lawrence I; Tcherepanova, Irina Y; DeBenedette, Mark A; Williams, W Lee; Plessinger, Douglas C; Nicolette, Charles A; Figlin, Robert A

2015-01-01

AGS-003 is an autologous immunotherapy prepared from fully matured and optimized monocyte-derived dendritic cells, which are co-electroporated with amplified tumor RNA plus synthetic CD40L RNA. AGS-003 was evaluated in combination with sunitinib in an open label phase 2 study in intermediate and poor risk, treatment naïve patients with metastatic clear cell renal cell carcinoma (mRCC). Twenty-one intermediate and poor risk patients were treated continuously with sunitinib (4 weeks on, 2 weeks off per 6 week cycle). After completion of the first cycle of sunitinib, patients were treated with AGS-003 every 3 weeks for 5 doses, then every 12 weeks until progression or end of study. The primary endpoint was to determine the complete response rate. Secondary endpoints included clinical benefit, safety, progression free survival (PFS) and overall survival (OS). Immunologic response was also monitored. Thirteen patients (62%) experienced clinical benefit (9 partial responses, 4 with stable disease); however there were no complete responses in this group of intermediate and poor risk mRCC patients and enrollment was terminated early. Median PFS from registration was 11.2 months (95% CI 6.0, 19.4) and the median OS from registration was 30.2 months (95% CI 9.4, 57.1) for all patients. Seven (33%) patients survived for at least 4.5 years, while five (24%) survived for more than 5 years, including 2 patients who remain progression-free with durable responses for more than 5 years at the time of this report. AGS-003 was well tolerated with only mild injection-site reactions. The most common adverse events were related to expected toxicity from sunitinib therapy. In patients who had sequential samples available for immune monitoring, the magnitude of the increase in the absolute number of CD8(+) CD28(+) CD45RA(-) effector/memory T cells (CTLs) after 5 doses of AGS-003 relative to baseline, correlated with overall survival. AGS-003 in combination with sunitinib was

Synthetic miR-145 Mimic Enhances the Cytotoxic Effect of the Antiangiogenic Drug Sunitinib in Glioblastoma.

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Liu, Hongwei; Liu, Zhixiong; Jiang, Bing; Huo, Lei; Liu, Jinfang; Lu, Jingchen

2015-06-01

Although aggressive therapeutic regimen has been applied in the treatment of Glioblastoma (GBM), the prognosis of patients with GBM remains poor. Preclinical studies have demonstrated the efficacy of Suntinib in GBM both in vitro and in vivo. In this study, we showed that the cytotoxicity was enhanced by transfection with miR-145 mimic. In addition, we suggested that the enhanced cytotoxicity of Sunitinib by miR-145 mimic was mediated by inhibition of both P-gp and Bcrp.

Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: Comparison with thyroid function

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Kitajima, Kazuhiro; Takahashi, Satoru; Maeda, Tetsuo; Yoshikawa, Takeshi; Ohno, Yoshiharu; Fujii, Masahiko; Miyake, Hideaki; Fujisawa, Masato; Sugimura, Kazuro

2012-01-01

Objective: Hypothyroidism is a common complication in patients receiving tyrosine kinase inhibitors. We evaluated the relationship between thyroid size evident on CT and thyroid function in patients with advanced renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors. Materials and methods: Forty-two patients with metastatic RCC receiving tyrosine kinase inhibitors (sorafenib n = 25; sunitinib n = 17) and, followed-up for ≥12 months were eligible. Patients who had ever shown an elevated thyroid-stimulating hormone (TSH) level of >10 mU/l were defined as having “hypothyroidism”. CT scans were performed before, and 3, 6, 9, and 12 months after the start of treatment. The area of the thyroid in the maximum section at each examination was measured and compared with that before treatment. Using repeated-measures ANOVA, differences in thyroid size were compared over time between patients with and without “hypothyroidism”, in relation to the type of drug employed. Results: Twenty-one patients (sorafenib 9, sunitinib 12) developed “hypothyroidism” 95 ± 88 days (range 12–315 days) after the start of treatment. In such patients, the thyroid was reduced in size to 89 ± 16% after 3 months, 81 ± 21% after 6 months, 71 ± 21% after 9 months and 68 ± 21% after 12 months, whereas the patients without “hypothyroidism” maintained a thyroid size of 90 ± 12% even after 12 months (p = 0.0030). Among the patients with “hypothyroidism”, those treated with sunitinib tended to show greater thyroid size reduction than those with sorafenib (59 ± 23% vs. 79 ± 13%, after 12 months). Conclusion: Tyrosine kinase inhibitors cause an apparent thyroid size reduction in patients with “hypothyroidism”

Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: Comparison with thyroid function

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Kitajima, Kazuhiro, E-mail: kitajima@med.kobe-u.ac.jp [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Takahashi, Satoru; Maeda, Tetsuo; Yoshikawa, Takeshi; Ohno, Yoshiharu; Fujii, Masahiko [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Miyake, Hideaki; Fujisawa, Masato [Department of Urology, Kobe University Graduate School of Medicine, Kobe (Japan); Sugimura, Kazuro [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan)

2012-09-15

Objective: Hypothyroidism is a common complication in patients receiving tyrosine kinase inhibitors. We evaluated the relationship between thyroid size evident on CT and thyroid function in patients with advanced renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors. Materials and methods: Forty-two patients with metastatic RCC receiving tyrosine kinase inhibitors (sorafenib n = 25; sunitinib n = 17) and, followed-up for ≥12 months were eligible. Patients who had ever shown an elevated thyroid-stimulating hormone (TSH) level of >10 mU/l were defined as having “hypothyroidism”. CT scans were performed before, and 3, 6, 9, and 12 months after the start of treatment. The area of the thyroid in the maximum section at each examination was measured and compared with that before treatment. Using repeated-measures ANOVA, differences in thyroid size were compared over time between patients with and without “hypothyroidism”, in relation to the type of drug employed. Results: Twenty-one patients (sorafenib 9, sunitinib 12) developed “hypothyroidism” 95 ± 88 days (range 12–315 days) after the start of treatment. In such patients, the thyroid was reduced in size to 89 ± 16% after 3 months, 81 ± 21% after 6 months, 71 ± 21% after 9 months and 68 ± 21% after 12 months, whereas the patients without “hypothyroidism” maintained a thyroid size of 90 ± 12% even after 12 months (p = 0.0030). Among the patients with “hypothyroidism”, those treated with sunitinib tended to show greater thyroid size reduction than those with sorafenib (59 ± 23% vs. 79 ± 13%, after 12 months). Conclusion: Tyrosine kinase inhibitors cause an apparent thyroid size reduction in patients with “hypothyroidism”.

Tumor response and clinical outcome in metastatic gastrointestinal stromal tumors under sunitinib therapy: Comparison of RECIST, Choi and volumetric criteria

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Schramm, N., E-mail: Nicolai.schramm@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Englhart, E., E-mail: Elisabeth.Englhart@gmx.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Schlemmer, M., E-mail: Marcus.Schlemmer@med.uni-muenchen.de [Department of Medicine III, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Hittinger, M., E-mail: Markus.Hittinger@uksh.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Übleis, C., E-mail: Christopher.Uebleis@med.uni-muenchen.de [Department of Nuclear Medicine, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Becker, C.R., E-mail: Christoph.becker@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Reiser, M.F., E-mail: Maximilian.Reiser@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Berger, F., E-mail: Frank.Berger@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany)

2013-06-15

Purpose: Purpose of the study was to compare radiological treatment response according to RECIST, Choi and volumetry in GIST-patients under 2nd-line-sunitinib-therapy and to correlate the results of treatment response assessment with disease-specific survival (DSS). Patients and methods: 20 patients (mean: 60.7 years; 12 male/8 female) with histologically proven GIST underwent baseline-CT of the abdomen under imatinib and follow-up-CTs 3 months and 1 year after change to sunitinib. 68 target lesions (50 hepatic, 18 extrahepatic) were investigated. Therapy response (partial response (PR), stable disease (SD), progressive disease (PD)) was evaluated according to RECIST, Choi and volumetric criteria. Response according to the different assessment systems was compared and correlated to the DSS of the patients utilizing Kaplan–Meier statistics. Results: The mean DSS (in months) of the response groups 3 months after therapy change was: RECIST: PR (0/20); SD (17/20): 30.4 (months); PD (3/20) 11.6. Choi: PR (10/20) 28.6; SD (8/20) 28.1; PD (2/20) 13.5. Volumetry: PR (4/20) 29.6; SD (11/20) 29.7; PD (5/20) 17.2. Response groups after 1 year of sunitinib showed the following mean DSS: RECIST: PR (3/20) 33.6; SD (9/20) 29.7; PD (8/20) 20.3. Choi: PR (10/20) 21.5; SD (4/20) 42.9; PD (6/20) 23.9. Volumetry: PR (6/20) 27.3; SD (5/20) 38.5; PD (9/20) 19.3. Conclusion: One year after modification of therapy, only partial response according to RECIST indicated favorable survival in patients with GIST. The value of alternate response assessment strategies like Choi criteria for prediction of survival in molecular therapy still has to be demonstrated.

Tumor response and clinical outcome in metastatic gastrointestinal stromal tumors under sunitinib therapy: Comparison of RECIST, Choi and volumetric criteria

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Schramm, N.; Englhart, E.; Schlemmer, M.; Hittinger, M.; Übleis, C.; Becker, C.R.; Reiser, M.F.; Berger, F.

2013-01-01

Purpose: Purpose of the study was to compare radiological treatment response according to RECIST, Choi and volumetry in GIST-patients under 2nd-line-sunitinib-therapy and to correlate the results of treatment response assessment with disease-specific survival (DSS). Patients and methods: 20 patients (mean: 60.7 years; 12 male/8 female) with histologically proven GIST underwent baseline-CT of the abdomen under imatinib and follow-up-CTs 3 months and 1 year after change to sunitinib. 68 target lesions (50 hepatic, 18 extrahepatic) were investigated. Therapy response (partial response (PR), stable disease (SD), progressive disease (PD)) was evaluated according to RECIST, Choi and volumetric criteria. Response according to the different assessment systems was compared and correlated to the DSS of the patients utilizing Kaplan–Meier statistics. Results: The mean DSS (in months) of the response groups 3 months after therapy change was: RECIST: PR (0/20); SD (17/20): 30.4 (months); PD (3/20) 11.6. Choi: PR (10/20) 28.6; SD (8/20) 28.1; PD (2/20) 13.5. Volumetry: PR (4/20) 29.6; SD (11/20) 29.7; PD (5/20) 17.2. Response groups after 1 year of sunitinib showed the following mean DSS: RECIST: PR (3/20) 33.6; SD (9/20) 29.7; PD (8/20) 20.3. Choi: PR (10/20) 21.5; SD (4/20) 42.9; PD (6/20) 23.9. Volumetry: PR (6/20) 27.3; SD (5/20) 38.5; PD (9/20) 19.3. Conclusion: One year after modification of therapy, only partial response according to RECIST indicated favorable survival in patients with GIST. The value of alternate response assessment strategies like Choi criteria for prediction of survival in molecular therapy still has to be demonstrated

Successful treatment of ulcerative colitis complicated by Sweet's syndrome by corticosteroid therapy and leukocytapheresis.

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Terai, Tomohiro; Sugimoto, Mitsushige; Osawa, Satoshi; Sugimoto, Ken; Furuta, Takahisa; Kanaoka, Shigeru; Ikuma, Mutsuhiro

2011-06-01

Ulcerative colitis is occasionally complicated by dermatological disorders presenting as extra-intestinal manifestations, including erythema nodosum and pyoderma gangrenosum. Sweet's syndrome is considered to be a rare cutaneous disease in patients with ulcerative colitis. To date, only 17 cases of Sweet's syndrome complicating ulcerative colitis have been reported in the English literature. Here, we report a case of a 41-year-old male who had been suffering from ulcerative colitis for 20 years. He was admitted to hospital with hematochezia, diarrhea and fever, and painful erythematous nodules on the face and arms. Histological examination of skin biopsies showed inflammatory cell infiltration composed mainly of neutrophils without evidence of necrotizing vasculitis, and the condition was diagnosed as Sweet's syndrome. The patient was treated with prednisolone and leukocytapheresis and the erythematous nodules on the skin, as well as the abdominal symptoms and endoscopic findings of ulcerative colitis, immediately improved. In this paper we report on this case and review the literature concerning ulcerative colitis and Sweet's syndrome.

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group.

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Buckstein, Rena; Kuruvilla, John; Chua, Neil; Lee, Christina; Macdonald, David A; Al-Tourah, Abdulwahab J; Foo, Alison H; Walsh, Wendy; Ivy, S Percy; Crump, Michael; Eisenhauer, Elizabeth A

2011-05-01

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3-4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity.

[Cutaneous involvement in chronic inflammatory bowel disease : Crohn's disease and ulcerative colitis].

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Richter, L; Rappersberger, K

2016-12-01

Over recent decades, both the incidence and prevalence of chronic inflammatory bowel disease have continued to rise in industrialized countries; the disease is frequently associated with extracutaneous involvement and comorbidity. The purpose of this work was to investigate the frequency and specificity of mucocutaneous manifestations in Crohn's disease (CD) and ulcerative colitis (UC). An extensive search in peer-reviewed journals via PubMed was performed; presented is a summary and analysis of various studies and data, including data of patients treated at our department. CD and UC are frequently associated with mucocutaneous symptoms; however, primary/specific disease-associations are exclusively seen in CD patients. These include peri-anal and -stomal fistulas and ulcerations, "metastatic" Crohn's disease as well as oral granulomatous disease. Moreover, in both CD and UC, there occur several other inflammatory skin conditions such as erythema nodosum, pyoderma gangrenosum, hidradenitis suppurativa, chronic oral aphthous disease, Sweet syndrome, pyostomatitis vegetans, and bowel-associated dermatosis-arthritis syndrome. Malnutrition syndromes (zinc and vitamin deficiencies) are only rarely observed. On skin and oral/genital mucous membranes various different inflammatory manifestations may be observed during the course of CD or UC. However, most data about a direct pathogenic relationship of the gastrointestinal and dermatologic disorders are quite heterogeneous or even contradictory. Nevertheless, knowledge of these conditions and their possible association with CD and UC could be crucial for early diagnosis and initiation of an appropriate therapy and thus be essential to prevent secondary tissue damage.

Brain natriuretic peptide precursor (NT-pro-BNP) levels predict for clinical benefit to sunitinib treatment in patients with metastatic renal cell carcinoma

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Papazisis, Konstantinos T; Kortsaris, Alexandros H; Kontovinis, Lukas F; Papandreou, Christos N; Kouvatseas, George; Lafaras, Christos; Antonakis, Evangelos; Christopoulou, Maria; Andreadis, Charalambos; Mouratidou, Despoina

2010-01-01

Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that has been approved for the treatment of metastatic renal cell carcinoma. Although the majority of sunitinib-treated patients receive a clinical benefit, almost a third of the patients will not respond. Currently there is no available marker that can predict for response in these patients. We estimated the plasma levels of NT-pro-BNP (the N-terminal precursor of brain natriuretic peptide) in 36 patients that were treated with sunitinib for metastatic clear-cell renal carcinoma. From the 36 patients, 9 had progressive disease and 27 obtained a clinical benefit (objective response or disease stabilization). Increases in plasma NT-pro-BNP were strongly correlated to clinical outcome. Patients with disease progression increased plasma BNP at statistically significant higher levels than patients that obtained a clinical benefit, and this was evident from the first 15 days of treatment (a three-fold increase in patients with progressive disease compared to stable NT-pro-BNP levels in patients with clinical benefit, p < 0.0001). Median progression-free survival was 12.0 months in patients with less than 1.5 fold increases (n = 22) and 3.9 months in patients with more than 1.5 fold increases in plasma NT-pro-BNP (n = 13) (log-rank test, p = 0.001). This is the first time that a potential 'surrogate marker' has been reported with such a clear correlation to clinical benefit at an early time of treatment. Due to the relative small number of accessed patients, this observation needs to be further addressed on larger cohorts. More analyses, including multivariate analyses are needed before such an observation can be used in clinical practice

Efficacy of Lincomycin Against the Strains of Staphylococcus Aureus Isolated From Various Types of Pyodermas in Children : in Vitro and in Vivo Study

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Rao Rama

2000-01-01

Full Text Available Lincomycin is chemically distinct from all other available antibiotics except its semi-synthetic derivative clindamycin. Though it has been in the market for over three decades, there were not many clinical studies in India. This study has been undertaken to know its efficacy against Staphylococcus aureus, commonest organism of pyodermas in children. Material was taken from the lesions of 100 fresh cases of various types of pyodermas in children and studied by Gram stain and in 50% human blood agar and nutrient agar according to standard methods. The staphylococci thus isolated were tested for linocomycin susceptibility by using the disc diffusion technique. Lincomycin was given to all these children in a daily dose of 30 mg/kg 5 - 10 days. Treatment failure was defined as persistence of lesions after 10 days of treatment. 75% strains of staphylococci were susceptible to lincomycin in vitro and 95% of the patients responded to 5-10 days treatment. Five out of 100 children did not respond to treatment even after 10 days. No case of relapse was noticed among these 95 children for a period of 2 weeks. No side effects were observed and the drug was very well tolerated. Being highly effective and least toxic linomycin deserves a place in the antimicrobial arsenal of the modern dermatologists.

Vasculitis in the autoinflammatory diseases.

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Peleg, Hagit; Ben-Chetrit, Eldad

2017-01-01

This article addresses the prevalence and relationship between autoinflammatory diseases and vasculitis. Autoimmune diseases (AIDs) are a group of syndromes characterized by episodes of unprovoked inflammation due to dysregulation of the innate immune system. Despite the common occurrence of rashes and other skin lesions in these diseases, vasculitis is reported in only a few. On the other hand, neutrophilic dermatoses are more prevalent. Large vessel vasculitis is reported in patients with Behcet's and Blau's syndromes. Small and medium size vasculitides are reported in familial Mediterranean fever mainly as Henoch-Schonlein purpura and polyarteritis nodosa, respectively. It is rarely described in hyper IgD with periodic fever syndrome, cryopyrin associated periodic syndromes, TNF receptor-associated periodic syndrome, deficiency of interleukin-1 receptor antagonist and pyoderma gangrenosum and acne syndrome. In most AID where bones and skin are mainly involved (CRMO, Majeed syndrome, Cherubism and DITRA) - vasculitis has not been described at all. In AID small vessel vasculitis affects mainly the skin with no involvement of internal organs. In AID, neutrophilic dermatoses are more common and prominent than vasculitis. This may reflect a minor role for interleukin-1 in the pathogenesis of vasculitis. The rarity of vasculitis in AID suggests that in most reported cases its occurrence has been probably coincidental rather than being an integral feature of the disease.

Feasibility, Safety, and Efficacy of an Alternative Schedule of Sunitinib for the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Retrospective Study.

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Buti, Sebastiano; Donini, Maddalena; Bersanelli, Melissa; Gattara, Alessia; Leonardi, Francesco; Passalacqua, Rodolfo

2017-12-01

Standard treatment with sunitinib for patients with metastatic renal cancer provides an 'on-off' schedule (daily administration of a 50-mg capsule for 4 weeks, followed by a 2-week break; consecutive 6-week cycles). We developed an alternative intermittent schedule to reduce the toxicity and symptoms of tumor regrowth during the rest period and to allow prolonged continuation of therapy, maintaining dose intensity. The objective of this study was to provide a retrospective evaluation of the feasibility, safety, and efficacy of an alternative schedule of sunitinib in patients who did not tolerate classical treatment. Patients treated with the classical schedule with at least grade 2 toxicity or recurrence of symptoms during the rest period were switched to an alternative schedule (the same daily dose 5 consecutive days per week for 5 weeks and then the same daily dose on days 1, 3, and 5 in the sixth week; consecutive 6-week cycles). Twenty-five patients were enrolled. The median time from sunitinib initiation to schedule switch was 2.9 months. After the switch, the median therapy duration was 9.2 months. Rate of delay, corrected by cycle number, was 10% for both schedules. After the switch, 48.7% of patients obtained a toxicity reduction (hypertension -82%, stomatitis -71%, cutaneous toxicity -69%). A reduction in 'on-off symptoms' (-86%) was achieved. Overall response rate was 40% and the disease control rate was 80%. Median progression-free survival was 16.4 months and median overall survival was 41.3 months. Despite the small sample size and retrospective nature, we demonstrated the feasibility, safety, and efficacy of the alternative schedule, allowing prolonged treatment and better quality of life.

Bacteriological Study of 100 Cases of Pyodermas with Special Reference to Staphylococci, Their Antibiotic Sensitivity and Phage Pattern

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T V Ramani

1980-01-01

Full Text Available One hundred new cases of pyodenna attending King George Hospital, Vishakhapatnam were investigated bacteriologically with antibiotic sensitivity of all the strains isolated and phage typing of coagulm positive staphylocci. Among these 50 had impetigo and 15 each ahd furunculosis and fouiculitis. The remaining included various other clinical entities. Children under 10 years were observed to have high incidence of pyoderma. A total of 88 strains of staphylococci (77 coagulase positive and 11 coagulase negative strains 25 strains of beta haemolytic streptococci and 3 strains of Klebsiella were isolated. Staphylococci were found to be the commonest aetiological agents either single or in association with other organisms. Of the 76 strains of coagulase positive staphylococci 32 strains were not phage typable and among the 44 typable strains 17 (38% belonged to group III and 15 (36.5% to mixed group. Coagulase positive staphylococci showed high sensitivity to garamycin, kanamycin and erythromycin and high resistance to penicillin and streptomycin. Multiple drug resistance was also high among these strains. Coagulase negative staphylococci were found to be more sensitive with less incidence of multiple drug resistance. Most of multiple drug resistant strains belonged to group III phage types. Beta haemolytic streptococci were found to be highly sensitive to all the antibiotics tested.

Cutaneous Manifestations Of Hepatitis B And C Virus Infections : A Study Of 100 Cases

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Kochhar Atul Mohan

2003-01-01

Full Text Available Infection with hepatitis viruses, especially B and C, is a major public health problem in many countries. One hundred consecutive patients with these infections were studied for cutaneous abnormalities. Females were more commonly affected. Recurrent/chronic vascular changes (92% , urticaria (72%, leucocytoclastic vasculitis (36%, erythema nodosum (28%, Gianotti-Crosti syndrome (12%, lichen planus (8%, pyoderma gangrenosum (2 patients and dermatomyositis like syndrome (1 patient were the prominent cutaneous abnormalities noted in patients with hepatitis B. Likewise, the prominent skin abnormalities notes in hepatitis â€" C Patients were vascular changes (82.2%, chronic urticaria (60.0%, xerosis of skin (56.6%, leucocytoclastic vasculitis (40%, erythema multiforme (23.3%, Sjogren’s syndrome (13.2%, recurrent erythema nodosum (19.8% and Behcet’s syndrome in a single case. Extensive subcutaneous fat atrophy of the face in one case and diffuse hyperpigmentation in 5 cases were the two interesting features noted in out patients, which have not been reported earlier. The pertinent literature is briefly reviewed in the light of above findings.

MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer

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Passadouro M

2014-07-01

Full Text Available Marta Passadouro,1,2 Maria C Pedroso de Lima,1,2 Henrique Faneca11Center for Neuroscience and Cell Biology, 2Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, PortugalAbstract: Pancreatic ductal adenocarcinoma (PDAC is a highly aggressive and mortal cancer, characterized by a set of known mutations, invasive features, and aberrant microRNA expression that have been associated with hallmark malignant properties of PDAC. The lack of effective PDAC treatment options prompted us to investigate whether microRNAs would constitute promising therapeutic targets toward the generation of a gene therapy approach with clinical significance for this disease. In this work, we show that the developed human serum albumin–1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine:cholesterol/anti-microRNA oligonucleotides (+/– (4/1 nanosystem exhibits the ability to efficiently deliver anti-microRNA oligonucleotides targeting the overexpressed microRNAs miR-21, miR-221, miR-222, and miR-10 in PDCA cells, promoting an almost complete abolishment of microRNA expression. Silencing of these microRNAs resulted in a significant increase in the levels of their targets. Moreover, the combination of microRNA silencing, namely miR-21, with low amounts of the chemotherapeutic drug sunitinib resulted in a strong and synergistic antitumor effect, showing that this combined strategy could be of great importance for therapeutic application in PDAC. Keywords: pancreatic cancer gene therapy, anti-microRNAs oligonucleotides, delivery nanosystems, albumin-associated lipoplexes

Streptococcal Immunity Is Constrained by Lack of Immunological Memory following a Single Episode of Pyoderma.

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Manisha Pandey

2016-12-01

Full Text Available The immunobiology underlying the slow acquisition of skin immunity to group A streptococci (GAS, is not understood, but attributed to specific virulence factors impeding innate immunity and significant antigenic diversity of the type-specific M-protein, hindering acquired immunity. We used a number of epidemiologically distinct GAS strains to model the development of acquired immunity. We show that infection leads to antibody responses to the serotype-specific determinants on the M-protein and profound protective immunity; however, memory B cells do not develop and immunity is rapidly lost. Furthermore, antibodies do not develop to a conserved M-protein epitope that is able to induce immunity following vaccination. However, if re-infected with the same strain within three weeks, enduring immunity and memory B-cells (MBCs to type-specific epitopes do develop. Such MBCs can adoptively transfer protection to naïve recipients. Thus, highly protective M-protein-specific MBCs may never develop following a single episode of pyoderma, contributing to the slow acquisition of immunity and to streptococcal endemicity in at-risk populations.

Use of three-dimensional time-resolved phase-contrast magnetic resonance imaging with vastly undersampled isotropic projection reconstruction to assess renal blood flow in a renal cell carcinoma patient treated with sunitinib: a case report.

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Takayama, Tatsuya; Takehara, Yasuo; Sugiyama, Masataka; Sugiyama, Takayuki; Ishii, Yasuo; Johnson, Kevin E; Wieben, Oliver; Wakayama, Tetsuya; Sakahara, Harumi; Ozono, Seiichiro

2014-08-14

New imaging modalities to assess the efficacy of drugs that have molecular targets remain under development. Here, we describe for the first time the use of time-resolved three-dimensional phase-contrast magnetic resonance imaging to monitor changes in blood supply to a tumor during sunitinib treatment in a patient with localized renal cell carcinoma. A 43-year-old Japanese woman with a tumor-bearing but functional single kidney presented at our hospital in July 2012. Computed tomography and magnetic resonance imaging revealed a cT1aN0M0 renal cell carcinoma embedded in the upper central region of the left kidney. She was prescribed sunitinib as neoadjuvant therapy for 8 months, and then underwent partial nephrectomy. Tumor monitoring during this time was done using time-resolved three-dimensional phase-contrast magnetic resonance imaging, a recent technique which specifically measures blood flow in the various vessels of the kidney. This imaging allowed visualization of the redistribution of renal blood flow during treatment, and showed that flow to the tumor was decreased and flows to other areas increased. Of note, this change occurred in the absence of any change in tumor size. The ability of time-resolved three-dimensional phase-contrast magnetic resonance imaging to provide quantitative information on blood supply to tumors may be useful in monitoring the efficacy of sunitinib treatment.

Severe hypothyroidism presenting as myxedema coma in the postoperative period in a patient taking sunitinib: case report and review of literature.

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Lele, Abhijit V; Clutter, Sarah; Price, Eleana; De Ruyter, Martin L

2013-02-01

The case of a 62-year-old Caucasian woman who underwent urgent hip hemiarthroplasty for repair of a pathological fracture is reported. The patient's medical history was significant for renal cell carcinoma, cerebellar metastases, and sunitinib-induced hypothyroidism. Her intraoperative course was complicated by profound hypothermia, bradycardia, augmentation of neuromuscular blockade, delayed emergence, failure of postoperative extubation, and need for mechanical ventilation. The intensive care course was significant for hypothermia requiring forced-air warming, treatment with intravenous thyroxine (T4), and hemodynamic supportive care. Copyright © 2013 Elsevier Inc. All rights reserved.

Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis

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Franziska Paech

2017-06-01

Full Text Available Tyrosine kinase inhibitors (TKIs are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1–100 μM for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis, all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism, imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib, and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism.

[Current therapeutic indications of thalidomide and lenalidomide].

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Ordi-Ros, Josep; Cosiglio, Francisco Javier

2014-04-22

Thalidomide is a synthetic glutamic acid derivative first introduced in 1956 in Germany as an over the counter medications. It was thought to be one of the safest sedatives ever produced as it was effective in small doses, was not addictive, and did not have acute side-effects such as motor impairment, but was quickly removed from market after it was linked to cases of severe birth defects. The Food and Drug Administration approved use in the treatment of erythema nodosum leprosum. Further, it was shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell hystiocytosis, aphthous stomatitis, Behçet syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and others. In May 2006, it was approved for the treating multiple myeloma. New thalidomide analogues have been developed but lack clinical experience. This paper is a review of the history, pharmacology, mechanism of action, clinical applications and side effects of thalidomide and its analogues. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Recent Advances In Topical Therapy In Dermatology

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Mohan Thappa Devinder

2003-01-01

Full Text Available With changing times various newer topical agents are introduced in the field of dermatology. Tacrolimus and pimecrolimus are immunisuppressants, which are effective topically and are tried in the management of atopic dermatitis as well as other disorders including allergic contact dermatitis, atrophic lichen planus, pyoderma gangrenosum. Imiquimod, an immune response modifier, is presently in use for genital warts but has potentials as anti- tumour agent and in various other dermatological conditions when used topically. Tazarotene is a newer addition to the list of topical reginoids, which is effective in psoriasis and has better effect in combination with calcipotriene, phototherapy and topical costicosteroids. Tazarotene and adapelene are also effective in inflammatory acne. Calcipotriol, a vitamin D analogue has been introduced as a topical agent in the treatment of psoriasis. Steroid components are also developed recently which will be devoid of the side effects but having adequate anti-inflammatory effect. Topical photodynamic therapy has also a wide range of use in dermatology. Newer topical agents including cidofovir, capsaicin, topical sensitizers, topical antifungal agents for onychomycosis are also of use in clinical practice. Other promising developments include skin substitutes and growth factors for wound care.

[When to ask for a skin biopsy in a patient with leg ulcer? Retrospective study of 143 consecutive biopsies].

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Stansal, A; Khayat, K; Duchatelle, V; Tella, E; Gautier, V; Sfeir, D; Attal, R; Lazareth, I; Priollet, P

2018-02-01

A vascular cause is found in around 85% of leg ulcer patients, but non-vascular causes are also observed. Their diagnosis is based on a set of clinical arguments and skin biopsy with histological analysis. The aim of this study was to analyze the results of these biopsies and to find common criteria for ulcers whose skin biopsies had led to the diagnosis of a non-vascular ulcer. A retrospective study was carried out on the analysis of 143 skin biopsies of leg ulcers. The reasons for the biopsy were mainly atypical clinical signs and/or the lack of improvement in care after 6 months, as advocated by the French health authorities. The skin biopsies led to a diagnosis of non-vascular ulcer in 4.9% of cases (7/143), including skin cancer (n=5, 3.5%), cutaneous leishmaniasis (n=1, 0.7%) and Pyoderma gangrenosum (n=1, 0.7%). The univariate statistical analysis revealed that an elevated rim and abnormal excessive granulation tissue were significantly more frequently found in these ulcers. All patients with a positive skin biopsy had associated vascular involvement. This study found a 5% rate of non-vascular causes of ulcers, mainly skin cancer. Elevated rims and abnormal excessive granulation tissue were the unusual features most commonly found in these ulcers. All patients whose skin biopsy revealed a non-vascular cause had associated vascular involvement. This information confirms the need to perform a skin biopsy, even in the presence of a vascular disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Deep vein thrombosis, ecythyma gangrenosum and heparin-induced thrombocytopenia occurring in a man with a heterozygous Factor V Leiden mutation

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Mariya Apostolova

2012-11-01

Full Text Available Skin necrosis and limb gangrene are occasional thrombotic manifestations of anticoagulation therapy. We report a man heterozygous for the Factor V Leiden (FVL mutation, and with a history of recurrent deep venous thrombosis, who initially presented with a necrotic skin lesion of the right flank while on warfarin therapy with a therapeutic international normalized ratio. Warfarin was discontinued and he received intravenous heparin. Thereafter he developed thrombocytopenia and pedal erythema and was diagnosed with heparin-induced thrombocytopenia (HIT. Heparin was replaced with argatroban. He ultimately underwent bilateral below-knee amputations for the thrombotic complications of the HIT. The initial necrotic lesion healed with antibiotics and wound care. Pathologic examination of multiple biopsy specimens revealed two separate lesions. One was necrotic tissue infiltrated with methicillin resistant Staphylococcus aureus having features of ecthyma gangrenosum. The second showed thrombotic changes consistent with HIT. The case illustrates the differential diagnosis of skin necrosis and limb gangrene in patients on warfarin and heparin, and also the clinical complexities that can occur in a FVL heterozygote.

Electrochemistry of conjugated planar anticancer molecules: Irinotecan and Sunitinib

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Zotti, Gianni; Berlin, Anna; Vercelli, Barbara

2017-01-01

The evaluation of drug levels is important for personalized therapeutic approaches particularly in cancer care. To this end electrochemistry provides simplicity, low cost, high sensitivity and possibility of miniaturization. Here we report the electrochemistry and UV-visible spectroscopy of two extensively used planar conjugated anticancer molecules, Irinotecan (ITC) and Sunitinib (SUN), in aprotic medium and water. Comparison is made with model compounds without amine ends. The electronic spectra of ITC and SUN in dimethylsulfoxide show similar vibronic patterns (0.2 eV vibrational energy for both) with energy gaps of 3.1 and 2.5 eV respectively. Cyclic voltammetry in acetonitrile shows the same one-electron reduction peak (-1.9 V vs Ag/Ag + ) and oxidation peaks at 1.45 and 0.65 V, both beyond the oxidation of the amine ends (0.45 V). In water the optical energy gaps are unchanged but the vibronic structure is almost lost and the oxidation processes are eased by 0.45 V for SUN and 1.10 V for ITC. The number of oxidatively exchanged electrons in water is two for ITC but four in two subsequent two-electron steps for SUN. The overall oxidation process for ITC likely involves the nucleophilic attack of a water molecule to the quinoline moiety. The first two-electron oxidation of SUN, involving the pyrrole moiety, leads possibly to the conjugated imine ring which is further oxidized to the N-oxide form. Lowering of the electron-transfer activation energy by water is assigned in part to release of molecular rigidity but in ITC the major role is assigned to a nucleophilic attack of water already in the activated state.

Síndrome de lisis tumoral en un paciente con cáncer de riñón tratado con sunitinib

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Ezequiel Rodríguez-Reimúndes

2011-04-01

Full Text Available El síndrome de lisis tumoral (SLT es un trastorno metabólico que ocurre como consecuencia de una destrucción celular masiva. Se caracteriza por la presencia de hiperuricemia, hiperfosfatemia, hipocalcemia e hiperkalemia, y predispone al desarrollo de insuficiencia renal aguda. En la mayoría de los casos el SLT ocurre luego de instaurarse un tratamiento antitumoral y es más frecuente en tumores de alto grado de malignidad y alta sensibilidad a la quimioterapia. Presentamos el caso de un paciente con diagnóstico de cáncer de riñón recidivado que presenta un SLT e insuficiencia renal aguda luego de iniciar tratamiento con sunitinib.

Thalidomide increases human keratinocyte migration and proliferation.

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Nasca, M R; O'Toole, E A; Palicharla, P; West, D P; Woodley, D T

1999-11-01

Thalidomide is reported to have therapeutic utility in the treatment of pyoderma gangrenosum, Behçet's disease, aphthous ulcers, and skin wounds. We investigated the effect of thalidomide on human keratinocyte proliferation and migration, two early and critical events in the re-epithelialization of skin wounds. Thalidomide at concentrations less than 1 microM did not affect keratinocyte viability. Using a thymidine incorporation assay, we found that thalidomide, at therapeutic concentrations, induced more than a 2. 5-fold increase in the proliferative potential of the cells. Keratinocyte migration was assessed by two independent motility assays: a colloidal gold assay and an in vitro scratch assay. At optimal concentrations, thalidomide increased keratinocyte migration on a collagen matrix more than 2-fold in the colloidal gold assay and more than 3-fold in the scratch assay over control. Although pro-migratory, thalidomide did not alter the level of metalloproteinase-9 secreted into culture medium. Thalidomide did, however, induce a 2-4-fold increase in keratinocyte-derived interleukin-8, a pro-migratory cellular autocrine factor. Human keratinocyte migration and proliferation are essential for re-epithelialization of skin wounds. Interleukin-8 increases human keratinocyte migration and proliferation and is chemotactic for keratinocytes. Therefore, thalidomide may modulate keratinocyte proliferation and motility by a chemokine-dependent pathway.

Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: an international, multicentre, prospective, randomised, placebo-controlled phase 3 trial (GRID)

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Demetri, George D; Reichardt, Peter; Kang, Yoon-Koo; Blay, Jean-Yves; Rutkowski, Piotr; Gelderblom, Hans; Hohenberger, Peter; Leahy, Michael; von Mehren, Margaret; Joensuu, Heikki; Badalamenti, Giuseppe; Blackstein, Martin; Cesne, Axel Le; Schöffski, Patrick; Maki, Robert G; Bauer, Sebastian; Nguyen, Binh Bui; Xu, Jianming; Nishida, Toshirou; Chung, John; Kappeler, Christian; Kuss, Iris; Laurent, Dirk; Casali, Paolo

2013-01-01

Summary Background To date, only two agents, imatinib and sunitinib, have shown clinical benefit in patients with gastrointestinal stromal tumours (GISTs), but almost all metastatic GISTs eventually develop resistance to these agents, resulting in fatal disease progression. This phase 3 trial assessed efficacy and safety of regorafenib in patients with metastatic and/or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods Patients were randomised 2:1 to receive either regorafenib 160 mg orally daily or placebo, plus best supportive care in both arms, for the first 3 weeks of each 4-week cycle. The primary endpoint was progression-free survival (PFS). Upon disease progression, patients on placebo could cross over to regorafenib. Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR: rate of durable stable disease lasting for ≥12 weeks plus complete or partial responses), and safety. This trial is registered at ClinicalTrials.gov (NCT01271712). Results From January to August 2011, 240 patients were screened at 57 centres in 17 countries, and 199 patients were randomised to receive regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central review was 4·8 months and 0·9 months, respectively (hazard ratio [HR] 0·27, 95% confidence interval [CI] 0·19–0·39; pregorafenib, resulting in no significant difference in OS between study arms (HR 0·77, 95% CI 0·42–1·41; p=0·199). A best response of partial response or stable disease was observed in 101/133 patients (75·9%) on regorafenib and 23/66 patients (34·8%) on placebo. DCR was 52·6% (70/133 patients) and 9·1% (6/66 patients), respectively. Drug-related adverse events were reported in 130 (98·5%) of 132 regorafenib patients and 45 (68·2%) of 66 placebo patients. The most common grade ≥3 regorafenib-related adverse events were hypertension (31/132, 23·5%), hand–foot skin reaction (26

Medical Complications of Tattoos: A Comprehensive Review.

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Islam, Parvez S; Chang, Christopher; Selmi, Carlo; Generali, Elena; Huntley, Arthur; Teuber, Suzanne S; Gershwin, M Eric

2016-04-01

Tattoos are defined as the introduction of exogenous pigments into the dermis in order to produce a permanent design. This process may occur unintentional or may be deliberately administered for cosmetic or medical reasons. Tattoos have been around for over 5000 years and over time have evolved to represent a common cosmetic practice worldwide. Currently, adverse reactions are relatively rare and generally unpredictable and predominantly include immune-mediated reactions and skin infections. Along with better healthcare standards and more stringent public health mandates such as the provision of disposable needles, major infectious complications related to hepatitis and human retroviral infections have decreased significantly. When they do occur, skin infections are most frequently associated with Staphylococcus aureus or Streptococcus pyogenes. The aim of this study is to review the types and rates of medical complications of permanent tattoos. PubMed search and search dates were open ended. Acute local inflammation is the most common complication, but infections, allergic contact dermatitis, and other inflammatory or immune responses that are not well-characterized may occur. As many patients with immune reactions to tattoos do not react on skin or patch testing, it is postulated that the antigens contained in dyes or pigments are such small molecules that they need to be haptenized in order to become immunogenic. Red ink is associated more frequently with long-term reactions, including granulomatous and pseudolymphomatous phenomena or morphea-like lesions and vasculitis. Exacerbation of preexisting psoriasis, atopic dermatitis, and pyoderma gangrenosum may occur after tattooing. There is no well-defined association between cancer and tattoos. The treatment of tattoo-related complications may include local destructive measures (cryotherapy, electro-surgery, dermabrasion, chemical destruction, ablative laser destruction), surgical excision, and thermolysis of the

Cost-Effectiveness of Pazopanib Versus Sunitinib for Renal Cancer in the United States.

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Benedict, Agnes; Ramaswamy, Krishnan; Sandin, Rickard

2015-09-01

We write to comment on a recently published study by Delea et al. in the January 2015 issue of JMCP that evaluated the cost-effectiveness (CE) of sunitinib (SU) versus pazopanib (PAZ) as first-line treatment for metastatic renal cell carcinoma (mRCC) from a U.S. third-party payer perspective.1 This analysis was based on COMPARZ and PISCES, clinical trials that compared SU and PAZ2,3 and led the authors to conclude that PAZ is cost-effective (in fact, dominant, according to the base-case results) compared with SU. Such assessment of economic value is clearly important for deciding between therapies to ensure fair access; therefore, we welcome a comparative evaluation of SU and PAZ. However, we believe that some of the key assumptions and inputs used in the model by Delea et al. render their results and conclusions invalid.  Best practice requires that results from a health economic model should reflect the most likely outcomes based on sound methodology and robust evidence for its inputs, as recommended by the International Society of Pharmacoeconomics and Outcomes Research (ISPOR).4 Here, we focus on 2 key areas (utilities and survival modeling) where, in our view, the analysis by Delea et al. falls short of this standard, and a third area (treatment costs) where the basis for the data derived is unclear.

Systems Level Analysis and Identification of Pathways and Networks Associated with Liver Fibrosis

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2014-11-07

Affymetrix GeneChip Rat Genome 230 2.0 Arrays. In GSE13747, liver fibrosis was produced by bile duct ligation [60]. Six replicates of liver fibrosis...fibrosis produced by bile duct ligation. B) GSE6929 represents sunitinib (SU11248) treatment in liver cirrhosis. doi:10.1371/journal.pone.0112193...respectively. In the study associated with the GSE13747 dataset, liver fibrosis was induced using bile duct ligation. We observed the predicted positive

Comparison of performance of various tumour response criteria in assessment of regorafenib activity in advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib.

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Shinagare, Atul B; Jagannathan, Jyothi P; Kurra, Vikram; Urban, Trinity; Manola, Judith; Choy, Edwin; Demetri, George D; George, Suzanne; Ramaiya, Nikhil H

2014-03-01

To compare performance of various tumour response criteria (TRCs) in assessment of regorafenib activity in patients with advanced gastrointestinal stromal tumour (GIST) with prior failure of imatinib and sunitinib. Twenty participants in a phase II trial received oral regorafenib (median duration 47 weeks; interquartile range (IQR) 24-88) with computed tomography (CT) imaging at baseline and every two months thereafter. Tumour response was prospectively determined on using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, and retrospectively reassessed for comparison per RECIST 1.0, World Health Organization (WHO) and Choi criteria, using the same target lesions. Clinical benefit rate [CBR; complete or partial response (CR or PR) or stable disease (SD)≥16 weeks] and progression-free survival (PFS) were compared between various TRCs using kappa statistics. Performance of TRCs in predicting overall survival (OS) was compared by comparing OS in groups with progression-free intervals less than or greater than 20 weeks by each TRC using c-statistics. PR was more frequent by Choi (90%) than RECIST 1.1, RECIST 1.0 and WHO (20% each), however, CBR was similar between various TRCs (overall CBR 85-90%, 95-100% agreement between all TRC pairs). PFS per RECIST 1.0 was similar to RECIST 1.1 (median 44 weeks versus 58 weeks), and shorter for WHO (median 34 weeks) and Choi (median 24 weeks). With RECIST 1.1, RECIST 1.0 and WHO, there was moderate concordance between PFS and OS (c-statistics 0.596-0.679). Choi criteria had less favourable concordance (c-statistic 0.506). RECIST 1.1 and WHO performed somewhat better than Choi criteria as TRC for response evaluation in patients with advanced GIST after prior failure on imatinib and sunitinib. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of enhanced expression of connexin 43 on sunitinib-induced cytotoxicity in mesothelioma cells

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Miaki Uzu

2015-05-01

Full Text Available Connexin (Cx makes up a type of intercellular channel called gap junction (GJ. GJ plays a regulatory role in cellular physiology. The Cx expression level is often decreased in cancer cells compared to that in healthy ones, and the restoration of its expression has been shown to exert antiproliferative effects. This work aims to evaluate the effect of the restoration of connexin 43 (Cx43 (the most ubiquitous Cx subtype expression on sunitinib (SU-induced cytotoxicity in malignant mesothelioma (MM cells. Increased Cx43 expression in an MM cell line (H28 improved the ability of SU to inhibit receptor tyrosine kinase (RTK signaling. Moreover, higher Cx43 expression promoted SU-induced apoptosis. The cell viability test revealed that Cx43 enhanced the cytotoxic effect of SU in a GJ-independent manner. The effect of Cx43 on a proapoptotic factor, Bax, was then investigated. The interaction between Cx43 and Bax was confirmed by immunoprecipitation. Furthermore, higher Cx43 expression increased the production of a cleaved (active form of Bax during SU-induced apoptosis with no alteration in total Bax expression. These findings indicate that Cx43 most likely increases sensitivity to SU in H28 through direct interaction with Bax. In conclusion, we found that Cx43 overcame the chemoresistance of MM cells.

A PKM2 signature in the failing heart

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Rees, Meredith L.; Subramaniam, Janani; Li, Yuanteng; Hamilton, Dale J.; Frazier, O. Howard; Taegtmeyer, Heinrich

2015-01-01

A salient feature of the failing heart is metabolic remodeling towards predominant glucose metabolism and activation of the fetal gene program. Sunitinib is a multitargeted receptor tyrosine kinase inhibitor used for the treatment of highly vascularized tumors. In diabetic patients, sunitinib significantly decreases blood glucose. However, a considerable proportion of sunitinib-treated patients develop cardiac dysfunction or failure. We asked whether sunitinib treatment results in shift towards glycolysis in the heart. Glucose uptake by the heart was increased fivefold in mice treated with sunitinib. Transcript analysis by qPCR revealed an induction of genes associated with glycolysis and reactivation of the fetal gene program. Additionally, we observed a shift in the enzyme pyruvate kinase from the adult M1 (PKM1) isoform to the fetal M2 (PKM2) isoform, a hallmark of the Warburg Effect. This novel observation led us to examine whether a similar shift occurs in human heart failure. Examination of tissue from patients with heart failure similarly displayed an induction of PKM2. Moreover, this phenomenon was partially reversed following mechanical unloading. We propose that pyruvate kinase isoform switching represents a novel feature of the fetal gene program in the failing heart. PMID:25735978

Granulomatous rosacea: Like leukemid in a patient with acute myeloid leukemia

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Škiljević Dušan

2008-01-01

Full Text Available Introduction. Skin findings in leukemias may be divided into specific lesions (leukemia cutis and non-specific lesions (leukemids which may be found in up to 80% of all patients with leukemias. The leukemids vary clinically and they are usually a manifestation of bone marrow or immunologic impairment, but also Sweet syndrome, pyoderma gangrenosum, erythroderma, maculopapular exanthema, prurigo-like papules, generalized pigmentation, follicular mucinosis, generalized pruritus may be found during the course of leukemia. Case report. We report a 70-year-old male with a 3-month history of erythema, papules and pustules on the face, ears and neck and over a month history of refractory anemia, anorexia, weight loss, malaise, and fever. Physical examination revealed symmetric erythematous, violaceous papules, papulo-nodules and plaques with slate scale and sparse, small pustules on the face, earlobes and neck. Histopathologic findings of involved skin showed diffuse mixed inflammatory cell infiltrate with perifollicular accentuation and focal granulomatous inflammation in the papillary and upper reticular dermis. Extensive checkup revealed the presence of acute myeloid leukemia French- American-British (FAB classification subtype M2, with signs of three-lineage dysplasia. The patient was treated by L6 protocol which led to complete remission, both in bone marrow and skin, but after seven months he had relapse of leukemia with the fatal outcome. Conclusion. This case indicates the importance of skin eruptions in the context of hematological malignancies.

Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma

International Nuclear Information System (INIS)

Yoon, Sam S.; Stangenberg, Lars; Lee, Yoon-Jin; Rothrock, Courtney; Dreyfuss, Jonathan M.; Baek, Kwan-Hyuck; Waterman, Peter R.; Nielsen, G. Petur; Weissleder, Ralph; Mahmood, Umar; Park, Peter J.; Jacks, Tyler

2009-01-01

Purpose: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Methods and Materials: Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. Results: The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm 3 after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. Conclusion: SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.

Commentary on: "Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study." Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Bernard Escudier, Institut Gustave Roussy, Villejuif; Emmanuel Sevin, Centre François Baclesse, Caen; Sylvie Négrier, Leon Berard Cancer Center, Lyon, France; Camillo Porta, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Matteo, Pavia; Cora N Sternberg, San Camillo Forlanini Hospital, Rome; Ugo De Giorgi, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; Petri Bono, Helsinki University Central Hospital, Helsinki, Finland; Thomas Powles, Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London; Tim Eisen, Cambridge University Health Partners, Cambridge; Omi Parikh, Royal Preston Hospital, Lancashire; Robert Hawkins, Christie Cancer Research UK, Manchester; Sadya Khan, Jose Diaz, and Faisal Mehmud, GlaxoSmithKline, Uxbridge, United Kingdom; Jürgen E Gschwend, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany; Suman Redhu, GlaxoSmithKline, Collegeville, PA; David Cella, Northwestern University Feinberg School of Medicine, Chicago, IL.: J Clin Oncol. 2014 May 10;32(14):1412-1418; doi: 10.1200/JCO.2013.50.8267. [Epub 2014 Mar 31].

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Trump, Donald

2016-05-01

Patient-reported outcomes may help inform treatment choice in advanced/metastatic renal cell carcinoma (RCC), particularly between approved targeted therapies with similar efficacy. This double-blind crossover study evaluated patient preference for pazopanib or sunitinib and the influence of health-related quality of life (HRQoL) and safety factors on their stated preference. Patients with metastatic renal cell carcinoma were randomly assigned to pazopanib 800mg per day for 10 weeks, a 2-week washout, and then sunitinib 50mg per day (4 weeks on, 2 weeks off, 4weeks on) for 10 weeks, or the reverse sequence. The primary end point, patient preference for a specific treatment, was assessed by questionnaire at the end of the two treatment periods. Other end points and analyses included reasons for preference, physician preference, safety, and HRQoL. Of 169 randomly assigned patients, 114 met the following prespecified modified intent-to-treat criteria for the primary analysis: exposure to both treatments, no disease progression before cross over, and completion of the preference questionnaire. Significantly more patients preferred pazopanib (70%) over sunitinib (22%); 8% expressed no preference (P<.001). All preplanned sensitivity analyses, including the intent-to-treat population, statistically favored pazopanib. Less fatigue and better overall quality of life were the main reasons for preferring pazopanib, with less diarrhea being the most cited reason for preferring sunitinib. Physicians also preferred pazopanib (61%) over sunitinib (22%); 17% expressed no preference. Adverse events were consistent with each drug׳s known profile. Pazopanib was superior to sunitinib in HRQoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness. This innovative crossover trial demonstrated a significant patient preference for pazopanib over sunitinib, with HRQoL and safety as key influencing factors. Copyright © 2016 Elsevier Inc. All rights reserved.

Intractable Postoperative Wounds Caused by Self-Inflicted Trauma in a Patient with Cutaneous Munchausen Syndrome Presenting as a Pyoderma Gangrenosum-Like Lesion

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Keiko Inui

2016-04-01

Full Text Available A 50-year-old Japanese woman consulted the emergency department of our hospital for bleeding due to an intractable postoperative wound on the lower abdomen; the postoperative wound was owing to a laparoscopic cholecystectomy performed 1 year previously for acute cholecystitis. She presented with a painful ulcer on her right lower abdomen. She also presented with multiple scars, skin grafts on the extremities, and a missing left lower leg, the causes for all of which were unexplained. The results of her blood test were normal, except for the hemoglobin level. Histology of the skin biopsy specimen from the ulcer did not show any specific findings. The previous surgeon who had performed the laparoscopic cholecystectomy revealed that surgical wound dehiscence had occurred during her admission. After a body restraint had been applied, the ulcer improved. Medical records indicated that she had been admitted to the department of plastic surgery at our hospital for skin grafting of a leg ulcer. During that admission, she refused to consult with the department of psychiatry, although the staff suspected mental disorders. Therefore, we diagnosed her with cutaneous Munchausen syndrome. After vacuum-assisted closure (VAC therapy had been performed to prevent her from traumatizing the ulcer again, it rapidly became granulated and reepithelialized. Munchausen syndrome is characterized by feigning physical symptoms to seek attention. Patients self-inflict numerous lesions, keep getting admitted to different hospitals, and feign acute illness, usually spectacular diseases. VAC therapy may be effective for preventing patients with cutaneous Munchausen syndrome from traumatizing their wounds.

Intractable Postoperative Wounds Caused by Self-Inflicted Trauma in a Patient with Cutaneous Munchausen Syndrome Presenting as a Pyoderma Gangrenosum-Like Lesion

OpenAIRE

Inui, Keiko; Hanafusa, Takaaki; Namiki, Takeshi; Ueno, Makiko; Igawa, Ken; Yokozeki, Hiroo

2016-01-01

A 50-year-old Japanese woman consulted the emergency department of our hospital for bleeding due to an intractable postoperative wound on the lower abdomen; the postoperative wound was owing to a laparoscopic cholecystectomy performed 1 year previously for acute cholecystitis. She presented with a painful ulcer on her right lower abdomen. She also presented with multiple scars, skin grafts on the extremities, and a missing left lower leg, the causes for all of which were unexplained. The resu...

Intractable Postoperative Wounds Caused by Self-Inflicted Trauma in a Patient with Cutaneous Munchausen Syndrome Presenting as a Pyoderma Gangrenosum-Like Lesion.

Science.gov (United States)

Inui, Keiko; Hanafusa, Takaaki; Namiki, Takeshi; Ueno, Makiko; Igawa, Ken; Yokozeki, Hiroo

2016-01-01

A 50-year-old Japanese woman consulted the emergency department of our hospital for bleeding due to an intractable postoperative wound on the lower abdomen; the postoperative wound was owing to a laparoscopic cholecystectomy performed 1 year previously for acute cholecystitis. She presented with a painful ulcer on her right lower abdomen. She also presented with multiple scars, skin grafts on the extremities, and a missing left lower leg, the causes for all of which were unexplained. The results of her blood test were normal, except for the hemoglobin level. Histology of the skin biopsy specimen from the ulcer did not show any specific findings. The previous surgeon who had performed the laparoscopic cholecystectomy revealed that surgical wound dehiscence had occurred during her admission. After a body restraint had been applied, the ulcer improved. Medical records indicated that she had been admitted to the department of plastic surgery at our hospital for skin grafting of a leg ulcer. During that admission, she refused to consult with the department of psychiatry, al-though the staff suspected mental disorders. Therefore, we diagnosed her with cutaneous Munchausen syndrome. After vacuum-assisted closure (VAC) therapy had been performed to prevent her from traumatizing the ulcer again, it rapidly became granulated and reepithelialized. Munchausen syndrome is characterized by feigning physical symptoms to seek attention. Patients self-inflict numerous lesions, keep getting admitted to different hospitals, and feign acute illness, usually spectacular diseases. VAC therapy may be effective for preventing patients with cutaneous Munchausen syndrome from traumatizing their wounds.

Metadata: JPST000293 [jPOST repository metadata[Archive

Lifescience Database Archive (English)

Full Text Available JPST000293 PXD007222 Proteomics analyses by iMPAQT in sunitinib resistant cells and its HIF2a knock...ll line, its sunitinib resistant cell, and sunitinib resistant Hif2a knock out cell. partial ... Hirofumi Yoshino Hirofumi Yoshino Kagoshima University

Histopathological aspects of neutrophilic dermatoses: Investigation of 38 cases and review of the literature

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Amir-Hoshang Ehsani

2016-01-01

Full Text Available Introduction: Neutrophilic dermatosis (ND is a heterogeneous group of diseases with various etiologies and clinical presentations. NDs may clinically present as papule, vesiculopustule, plaque, and nodule of the skin, but they all share the common feature of neutrophilic predominance in the skin. Histological examination of patients with suspected ND is a key step for making the proper diagnosis. Patients and Methods: The aim of this article was to investigate histopathological aspects of different NDs. We obtained our data from medical records of patients at Razi dermatology hospital, between 2012 and 2014. Thirty-eight biopsy records coded under the term of any ND, including Sweet's syndrome (SS, pyoderma gangrenosum (PG, skin lesions of Behcet's disease, neutrophilic drug eruption, amicrobial pustulosis of the folds, pustular vasculitis of the hands, and undetermined ND were recruited in our study. The specimens were evaluated regarding inflammatory reaction pattern, epidermal/adnexal changes, and dermal changes. Results: Most common NDs in our study were PG (42.1% followed by SS (21.1%. The most common pattern of inflammatory reaction was superficial perivascular and interstitial dermal inflammation in 44.7% of the patients. Exocytosis of neutrophils into epidermis, hair follicle, and eccrine gland was seen in 71%, 18.5%, and 28.9% of the specimens, respectively. Ulceration was only seen in ten PG specimens. Dermal fibrosis and vascular proliferation were reported in all PG patients. Conclusion: The prevalence of some histopathological findings in different types of ND was significantly different. These features seem helpful in distinguishing between different NDs.

Calciphylaxis and Martorell Hypertensive Ischemic Leg Ulcer: Same Pattern - One Pathophysiology.

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Hafner, Jürg

2016-01-01

This review presents a closer look at four diseases which are probably closely related to one another pathophysiologically: (a) calciphylaxis (distal pattern); (b) calciphylaxis (proximal pattern); (c) Martorell hypertensive ischemic leg ulcer; (d) calciphylaxis with normal renal and parathyroid function (synonym: eutrophication). The four diseases have largely the same risk factors: (1) arterial hypertension, (2) diabetes mellitus (types 1 and 2), (3) secondary or tertiary hyperparathyroidism (in end-stage kidney disease) and (4) oral anticoagulation with vitamin K antagonists. They share the same clinical patterns: necrotizing livedo, skin infarctions at typical locations and acral gangrene in calciphylaxis. They also share the same histopathology: ischemic subcutaneous arteriolosclerosis and small-artery disease and 'miniaturizing' Mönckeberg medial calcinosis. The treatment concept for the acute phase of the diseases is also broadly similar. In addition to an optimized control of the cardiovascular risk factors, a proactive wound approach (necrosectomy, negative pressure wound treatment with vacuum dressings, and early skin grafts supported by systemic antibiotic therapy) leads most rapidly and effectively to a reduction of the initially severe wound pain, and finally to complete healing of the wound. Oral anticoagulation with vitamin K antagonists should be stopped. In extensive cases, the use of intravenous sodium thiosulfate is recommended. All four diagnoses are little known in the medical schools of most countries. The need to improve familiarity with these four closely related disorders is therefore great. In particular, the risk of confusion with pyoderma gangrenosum is a major diagnostic problem which can lead to false and even damaging treatment. © 2016 S. Karger AG, Basel.

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib

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Chris Coppin

2010-04-01

Full Text Available Chris CoppinMedical Oncology, BC Cancer Agency and University of British Columbia, Vancouver, CanadaAbstract: Everolimus (RAD001, Afinitor® Novartis is the first oral inhibitor of mTOR (mammalian target of rapamycin to reach the oncology clinic. Everolimus 10 mg daily achieves complete inhibition of its target at below the maximum tolerable dose for most patients. A phase III randomized placebo-controlled trial has examined the impact of everolimus in patients with clear cell renal cancers and progressive disease on or within 6 months of the VEGFR tyrosine kinase inhibitors sunitinib and/or sorafenib. The primary endpoint of progression-free survival was increased from median 1.9 to 4.9 months (hazard ratio 0.33, P < 0.001 and 25% were still progression-free after 10 months of everolimus therapy. There was a delay in time to decline of performance status and trends to improvement in quality of life, disease-related symptoms, and overall survival despite crossover of the majority of patients assigned to placebo. In 2009, everolimus was approved in the US and Europe as the only validated option for this indication. Toxicities are usually mild to moderate and can be managed with dose reduction or interruption if necessary. Opportunistic infections and non-infectious pneumonitis are seen as a class effect. Management of common practical management issues are discussed. Clinical trials are in progress to examine additional roles for everolimus in renal cancer, alone and in combination with other agents.Keywords: everolimus, drug therapy, advanced renal cancer

Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients

DEFF Research Database (Denmark)

Donskov, Frede; Michaelson, M Dror; Puzanov, Igor

2015-01-01

), neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points. RESULTS: On-treatment neutropenia and hypertension were associated with longer...... PFS (P=0.0276 and Pneutropenia was significantly associated...... with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand-foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63-0.67) for IMDC classification alone and 0.72 (95% CI: 0.70-0.74) when combined with hypertension and neutropenia...

Potential health gains for patients with metastatic renal cell carcinoma in daily clinical practice: A real-world cost-effectiveness analysis of sequential first- and second-line treatments.

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S De Groot

Full Text Available Randomised controlled trials have shown that targeted therapies like sunitinib are effective in metastatic renal cell carcinoma (mRCC. Little is known about the current use of these therapies, and their associated costs and effects in daily clinical practice. We estimated the real-world cost-effectiveness of different treatment strategies comprising one or more sequentially administered drugs.Analyses were performed using patient-level data from a Dutch population-based registry including patients diagnosed with primary mRCC from January 2008 to December 2010 (i.e., treated between 2008 and 2013. The full disease course of these patients was estimated using a patient-level simulation model based on regression analyses of the registry data. A healthcare sector perspective was adopted; total costs included healthcare costs related to mRCC. Cost-effectiveness was expressed in cost per life-year and cost per quality-adjusted life-year (QALY gained. Probabilistic sensitivity analysis was conducted to estimate the overall uncertainty surrounding cost-effectiveness.In current daily practice, 54% (336/621 of all patients was treated with targeted therapies. Most patients (84%; 282/336 received sunitinib as first-line therapy. Of the patients receiving first-line therapy, 30% (101/336 also received second-line therapy; the majority was treated with everolimus (40%, 40/101 or sorafenib (28%, 28/101. Current treatment practice (including patients not receiving targeted therapy led to 0.807 QALYs; mean costs were €58,912. This resulted in an additional €105,011 per QALY gained compared to not using targeted therapy at all. Forty-six percent of all patients received no targeted therapy; of these patients, 24% (69/285 was eligible for sunitinib. If these patients were treated with first-line sunitinib, mean QALYs would improve by 0.062-0.076 (where the range reflects the choice of second-line therapy. This improvement is completely driven by the health

Validation of a short questionnaire to measure symptoms and functional limitations associated with hand-foot syndrome and mucositis in patients with metastatic renal cell carcinoma.

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Lai, Jin-Shei; Beaumont, Jennifer L; Diaz, Jose; Khan, Sadya; Cella, David

2016-01-15

Hand-foot syndrome and mucositis/stomatitis are frequent adverse events (AEs) of treatment with tyrosine kinase inhibitors in cancer therapy. Quality-of-life instruments that measure the functional consequences of these AEs are needed to assess the impact of therapeutic interventions and to guide patient care. The Hand-Foot and Mucositis Symptom and Impact Questionnaire (HAMSIQ [formerly the Supplementary Quality of Life Questionnaire]) was used in the COMPARZ trial (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma [national clinical trial no. NCT00720941]) and the PISCES study (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer [clinicaltrials.gov NCT01064310]) to assess mouth/throat and hand/foot soreness symptoms and subsequent limitations in patients receiving pazopanib or sunitinib for metastatic renal cell carcinoma. The objective of the current analysis was to validate the HAMSIQ using data from the PISCES study. The HAMSIQ was administered in the PISCES study at baseline and every 2 weeks over two 10-week periods to patients who were receiving pazopanib or sunitinib. Data from the first 10-week period were used to assess the feasibility, validity, and responsiveness of the HAMSIQ. In total, ≥85% of 169 patients completed the HAMSIQ (excluding the item concerning days off work). Correlations among items within the same limitation subscale generally were high (Cronbach α ≥ .80). HAMSIQ limitation scores differentiated patients according to their baseline performance status and severity of soreness. Small-to-moderate correlations were observed for the symptoms/limitation scores and for changes from baseline scores between the HAMSIQ and the Functional Assessment of Chronic Illness Therapy fatigue survey. The HAMSIQ demonstrated responsiveness to changes in clinical status and the development of hand-foot syndrome AEs over time. The HAMSIQ is a feasible, valid

Peristomal skin complications: causes, effects, and treatments

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Doctor K

2016-12-01

Full Text Available Kimberly Doctor, Dorin T Colibaseanu Section of Colon and Rectal Surgery, Mayo Clinic, Jacksonville, FL, USA Abstract: Enterostomal formation remains a necessary part of multiple types of surgeries. Stomal difficulties can be a source of frustration for patients; however, a properly functioning stoma in a patient educated in its care can result in a highly functional individual, with a high quality of life, comparable to a person without a stoma. Correct surgical technique is vital to creating a stoma that is sufficiently everted, and in a good anatomical location. Loop ileostomies have a higher chance of complications, thus care in their formation is especially important. Systemic disease (inflammatory conditions, and autoimmune diseases especially as well as local conditions (pyoderma gangrenosum, infections, and fistulas, among others can be the causes for difficult-to-treat peristomal complications. Accurate diagnosis is essential in order to be able to address the underlying disease. Choosing the appropriate products to care for the stoma is often a process of trial and error, and is best done under the guidance of an enterostomal therapist. This is especially true for stomas in overweight individuals or stomas that have become flush with the skin with time and changing body habitus. Inattention to care can result in problems that range from simple mucocutaneous separations (separation of the bowel edge from the surrounding skin to large and difficult-to-heal ulcers. This article provides a systematic review of the most common challenges that patients with stoma are faced with, and offers solutions based on up-to-date review of the literature. Keywords: stoma care, stoma complications, stoma wound

Amelogenin, an extracellular matrix protein, in the treatment of venous leg ulcers and other hard-to-heal wounds: Experimental and clinical evidence  ||FREE PAPER||

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Marco Romanelli

2008-06-01

Full Text Available Marco Romanelli1, Valentina Dini1, Peter Vowden2, Magnus S Ågren31Department of Dermatology, University of Pisa, Pisa, Italy; 2Vascular Unit, Bradford Royal Infirmary, Bradford, United Kingdom; 3Department of Surgery K, Bispebjerg Hospitals, Copenhagen University Hospital, Copenhagen, DenmarkAbstract: Amelogenins are extracellular matrix proteins that, under physiological conditions, self-assemble into globular aggregates up to micron-sizes. Studies with periodontal fibroblasts indicate that attachment to these structures increases the endogenous secretion of multiple growth factors and cell proliferation. Pre-clinical and clinical studies indicate that cutaneous wounds benefit from treatment with amelogenins. A randomized controlled trial (RCT involving patients with hard-to-heal venous leg ulcers (VLUs (ie, ulcers with a surface area ≥10 cm2 and duration of ≥6 months showed that the application of amelogenin (Xelma®, Molnlycke Health Care, Gothenburg, Sweden as an adjunct treatment to compression results in significant reduction in ulcer size, improvement in the state of ulcers, reduced pain, and a larger proportion of ulcers with low levels of exudate, compared with treatment with compression alone. Amelogenin therapy was also shown to be safe to use in that there were no significant differences in adverse events noted between patients treated with amelogenin plus compression and those treated with compression alone. Case study evaluations indicate that the benefits of amelogenin therapy demonstrated in the RCT are being repeated in “real life” situations and that amelogenin therapy may also have a role to play in the treatment of other wound types such as diabetic foot ulcers.Keywords: extracellular matrix, amelogenin, venous leg ulcers, diabetic foot ulcers, pyoderma gangrenosum

Cross-sectional survey on the use and impact of the Danish national antibiotic use guidelines for companion animal practice

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Jessen, Lisbeth Rem; Møller Sørensen, Tina; Lilja, Zenia Littau

2017-01-01

of the Danish Small Animal Veterinary Association in October 2015. The survey was completed by 151 veterinarians. Respondents most frequently consulted the recommendations on skin and urinary tract infections (UTI), and users generally reported a high degree of adherence to the recommendations. Sixty-five per...... cent indicated that the guidelines had influenced their habits in one or more of the areas being investigated, i.e. perioperative use of antibiotics, use of first line antibiotics for the treatment of pyoderma or UTI, and/or use of microbiological diagnostics. Perioperative use of antibiotics for clean...... surgeries was uncommon, irrespective of whether respondents had consulted the relevant recommendations or not. On the contrary, significant differences in the prescribing habits between guideline users and non-users were observed for pyoderma and UTI, suggesting an impact of the guidelines towards more...

Cutaneous manifestations of systemic lupus erythematosus in a tertiary referral center

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Kole Alakes

2009-01-01

.67%, pyoderma gangrenosum in 2 patients (1.34%, erythema multiforme in 10 patients (6.67%, and nail fold infarcts in 2 patients (1.34%; however, mucosal discoid lupus, lichenoid discoid lupus, livedo reticularis, sclerodactyly, etc. were not detected. Patients having lupus-specific skin lesions e.g., malar rash were associated with systemic involvement, whereas those having lupus non-specific skin lesions were associated with disease flare. Conclusions: Skin lesions in patients with SLE are important disease manifestations and proper understanding is essential for diagnosis and efficient management.

Angiogenic Blockade and Radiotherapy in Hepatocellular Carcinoma

International Nuclear Information System (INIS)

Chi, Kwan-Hwa; Liao, Chao-Sheng; Chang, Chih-Chia; Ko, Hui-Ling; Tsang, Yuk-Wah; Yang, Kuo-Ching; Mehta, Minesh P.

2010-01-01

Purpose: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC. Methods and Materials: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial α-fetoprotein (AFP) kinetics, and survival. Results: Of 23 evaluable patients, 60% had ≥2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenance sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had ≥50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had ≥Grade 2 elevation of liver enzymes, and 15 had ≥Grade 2 thrombocytopenia. Conclusions: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.

The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study

International Nuclear Information System (INIS)

Rutkowski, Piotr; Osuch, Czesław; Mierzejewska, Ewa; Wasielewski, Kacper; Woźniak, Agnieszka; Grzesiakowska, Urszula; Nowecki, Zbigniew I; Siedlecki, Janusz A; Limon, Janusz; Bylina, Elżbieta; Klimczak, Anna; Świtaj, Tomasz; Falkowski, Sławomir; Kroc, Jacek; Ługowska, Iwona; Brzeskwiniewicz, Magdalena; Melerowicz, Wojciech

2012-01-01

Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure. We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2 nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes. One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0

JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases.

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Ana Karina Alves de Medeiros

Full Text Available The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs. JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP, cutaneous lupus erythematosus (CLE, atopic dermatitis (AD, pyoderma gangrenosum (PG and alopecia areata (AA versus healthy controls for (pJAK1, (pJAK2, (pJAK3, (pTYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively. This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs.

[Nocardia brasiliensis leg ulcer and nodular lymphangitis in France].

Science.gov (United States)

Hamm, M; Friedel, J; Siré, C; Semon, J

2005-01-01

Nocardia brasiliensis is a very rarely reported cause of chronic phagedenic ulcerations. We report the case of an elderly woman who developed such an infection after falling on her right leg on the road in the Bresse country (an essentially agricultural and bovine-cattle breading region) and developed a chronic phagedenic ulcer secondarily complicated by nodular lymphangitis of the thigh. A 75 year-old woman fell on her right leg on the side of the main road outside her hamlet in the Bresse country and secondarily developed a chronique phagedenic ulceration. We first considered her as suffering from pyoderma gangrenosum. A complete scanning only revealed an autoimmune thyroiditis and a rapidly healing gastric ulceration, and none of the treatments, either local or systemic, helped the skin condition to heal. After 3 weeks of application of a local corticoid ointment, the patient developed fever, general malaise, an exacerbation of her wound and an infiltration of the skin round her knee, together with nodular lymphangitic dissemination. A supplementary bacterial swab disclosed massive proliferation of a slow-growing Gram-positive bacillus, which proved to be Nocardia brasiliensis, together with a methicillino-sensitive Staphylococcus aureus. The treatment with sulfamethoxazole-trimetoprim gave a rash after 12 hours and was changed to amoxicillin and clavulanic acid, which rapidly proved to be permanently effective. The revelation of this particular slow-growing bacteria is difficult and requires bacterial swabs. Nocardia brasiliensis is relatively rare in primary skin ulcerations and we discuss the reasons why an elderly women should find this bacteria on the road outside her hamlet in the French countryside. This particular infectious condition requires general scanning, to make sure that the primary skin condition does not extend to other organs. We review the therapeutical options for patients who exhibit allergic reactions to the classically effective

Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial.

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Komatsu, Yoshito; Doi, Toshihiko; Sawaki, Akira; Kanda, Tatsuo; Yamada, Yasuhide; Kuss, Iris; Demetri, George D; Nishida, Toshirou

2015-10-01

The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs). Seventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively). Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.

Sunitinib

Science.gov (United States)

... grows in the stomach, intestine (bowel), or esophagus (tube that connects the throat with the stomach) in ... magnesium in your blood; problems with your mouth, teeth or gums; or kidney, thyroid, or heart disease. ...

Tyrosine kinase receptor inhibitor-targeted combined chemotherapy for metastatic bladder cancer

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Chia-Lun Wu

2012-04-01

Full Text Available Overexpression of hypoxia-inducible factor-1 alpha is noted during the invasive and metastatic process of transitional cell carcinoma. It will upregulate vascular endothelial growth factor (VEGF and drive proliferation, invasiveness, metastasis, and antiapoptotic ability of cancer cells. We proposed that tyrosine kinase receptor inhibitor, sunitinib malate—(Sutent; Pfizer Inc., Taiwan, combined with chemotherapeutic drug may present synergistic cytotoxic enhancement to transitional cell carcinoma cells with subsequent inhibition of their cellular behaviors, including proliferation, invasiveness, and metastatic activity. The contents of VEGF-A in mouse bladder tumor cells (MBT-2 and culture medium were detected by quantification-polymerase chain reaction and Western blot individually. The inhibitory concentrations of various chemotherapeutic drugs, sunitinib, and their combination treatment in MBT-2 were determined by 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT assay. Microchamber transmembrane migration assay was applied in evaluation of the inhibitory effects of different dosages of sunitinib and combination treatment on tumor cells. The cell cycle and apoptosis were analyzed after combination therapy by flow cytometry. Variation in apoptotic pathway was elucidated by Western blot using specific antibodies with cleaved PARP and caspase-3. Metastatic animal model mimicked by tail vein injection of MBT-2 cells was used to evaluate the treatment efficiency in tumor weight and survival rate. The mRNA and protein level of VEGF-A in MBT-2 cells increased by 70% at 48 hours interval under hypoxia stress condition. In MTT assay, MBT-2 cells had shown the highest sensitivity to epirubicin. Sunitinib combined with epirubicin had shown a synergistic cytotoxic effect to MBT-2 cells. Sunitinib and its combination with epirubicin showed significant inhibition on MBT-2 cells migration in microchambers. G2/M phase arrest and

The Correlation between Individual and Environmental Hygiene and Pioderma Incidence An Analytical Observational Study in Pyoderma Patient in Islamic Sultan Agung Hospital during the Period August to December 2010

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Iis Aisyah Sutisna

2011-06-01

Design and Methods: The study type was analytic observational with case control design. The sample consisted of 30 respondents RSI patients Sultan Agung for case group and 30 persons as control group is the neighbors of patients who have similar characteristics and are not suffering pyoderma. The data used are secondary data from medical records and primary data from questionnaires filled out by respondents, then the data were analyzed with chi-square and to determine the correlation power there was used a contingency coefficient test. Results: It was found that the good and the bad individual hygene for the case group were 3.3% and 66.7% respectively, while for the control group the good and bad individual hygene were 80.0% and 20.0% respectively. Chi-square test resulted in p=0,000 with contingency coefisien of 0.426. It was found that the good and the bad environmental hygene for the case group were 56.7% and 43.3% respectively, while for the control group the good and bad environmental hygene were 83.3% and 16.3% respectively. Chi-square test resulted in p=0,024 with contingency coefisien of 0.27. Conclusion: There was a significant correlation between the personal and environmental hygiene and poderma insicence at the RSI Sultan Agung with a moderate relationship between individual hygiene and weak relationship between environmental hygene (Sains Medika, 3(1:24-30.

Ovatodiolide Targets β-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma

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Jar-Yi Ho

2013-01-01

Full Text Available Dysregulated β-catenin signaling is intricately involved in renal cell carcinoma (RCC carcinogenesis and progression. Determining potential β-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β-catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound of Anisomeles indica, inhibited β-catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β-catenin (S552 that inhibited β-catenin nuclear translocation. Moreover, ovatodiolide decreased β-catenin stability and impaired the association of β-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.

The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST after imatinib failure - one institution study

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Rutkowski Piotr

2012-03-01

Full Text Available Abstract Background Gastrointestinal stromal tumors (GIST mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM or sunitinib (SU. Arterial hypertension (AH is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+ GIST patients after IM failure. Methods We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment. Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs of VEGFA and VEGFR2 genes. Results One year progression-free survival (PFS; calculated from the start of SU rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks in 55 patients with AH vs. 22% (median 17 weeks in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively. We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism

Clinical profile of HIV infection

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Khopkar Uday

1992-01-01

Full Text Available HIV seropositivity rate of 14 percent was observed amongst STD cases. Heterosexual contact with prostitutes was the main risk factor. Fever, anorexia, weight loss, lymphadenopathy and tuberculosis were useful clinical leads. Genital ulcers, especially chancroid, were common in seropositivies. Alopecia of unknown cause, atypical pyoderma, seborrhea, zoster, eruptive mollusca and sulfa-induced erythema multiforme were viewed with suspicion in high risk groups. Purpura fulminans, fulminant chancroid, vegetating pyoderma and angioedema with purpura were unique features noted in this study.

Serum detection of IgG antibodies against Demodex canis by western blot in healthy dogs and dogs with juvenile generalized demodicosis.

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Ravera, Ivan; Ferreira, Diana; Gallego, Laia Solano; Bardagí, Mar; Ferrer, Lluís

2015-08-01

The aim of this study was to investigate the presence of canine immunoglobulins (Ig) G against Demodex proteins in the sera of healthy dogs and of dogs with juvenile generalized demodicosis (CanJGD) with or without secondary pyoderma. Demodex mites were collected from dogs with CanJGD. Protein concentration was measured and a western blot technique was performed. Pooled sera from healthy dogs reacted mainly with antigen bands ranging from 55 to 72 kDa. Pooled sera from dogs with CanJGD without secondary pyoderma reacted either with 10 kDa antigen band or 55 to 72 kDa bands. Pooled sera from dogs with CanJGD with secondary pyoderma reacted only with a 10 kDa antigen band. The results of this study suggest that both healthy dogs and dogs with CanJGD develop a humoral response against different proteins of Demodex canis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Postvaccination wounds associated predominantly with Arcanobacterium phocae in mink (Neovison vison) at three mink farms.

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Molenaar, Robert J; Buter, Rianne; Sroka, Agnieszka

2017-04-01

The emerging skin disease fur animal epidemic necrotic pyoderma (FENP) has been attributed to infection with Arcanobacterium phocae (ABP). The exact pathogenesis and risk factors of FENP have yet to be elucidated. Three mink from each of three different mink farms (A-C) with postvaccination skin wounds at the vaccination site and six mink from an unaffected mink farm (D) that had used the same vaccine batch and vaccination site (hind leg). All mink from farms A-C had severe necrotizing to necropurulent dermatitis where they were vaccinated intramuscularly in the hind leg. ABP was the sole bacterium cultured from six of nine wounds. Using 16S-23S rDNA intergenic spacer region and BOX-PCR, the ABP isolates from these wounds were indistinguishable from isolates originating from several cases of FENP. This is the first report of FENP-like lesions at the site of vaccination, in the days following the procedure, associated with ABP. At farms with FENP vaccination, procedures should be considered carefully. © 2016 ESVD and ACVD.

Examining the bleeding incidences associated with targeted therapies used in metastatic renal cell carcinoma.

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Crist, MacKenzie; Hansen, Elizabeth; Chablani, Lipika; Guancial, Elizabeth

2017-12-01

A systematic review was conducted to illustrate the bleeding risks associated with targeted therapies used in the treatment of metastatic renal cell carcinoma (mRCC). Eligible studies included phase II, III, or IV clinical trials using pazopanib, sunitinib, cabozantinib, lenvatinib, everolimus, temsirolimus, bevacizumab, axitinib, and/or sorafenib in the setting of mRCC. Types of bleeding event(s), bleeding event frequency, and incidence of thrombocytopenia were collected from the relevant articles. ClinicalTrials.gov was also searched for incidence of "Serious bleeding adverse effects" reported in these trials. The incidences of bleeding events ranged from 1 to 36%, and incidences of thrombocytopenia ranged from 2 to 78%. Available serious bleeding adverse events ranged from 1 to 7%. The highest percentage of bleeding incidences were seen with bevacizumab, while the lowest percentage of bleeding incidences were seen with axitinib. All of the included trials were of high quality per Jadad scoring. Copyright © 2017 Elsevier B.V. All rights reserved.

A split-body, randomized, blinded study to evaluate the efficacy of a topical spray composed of essential oils and essential fatty acids from plant extracts with antimicrobial properties.

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Bensignor, Emmanuel; Fabriès, Lionel; Bailleux, Lucie

2016-12-01

Bacterial pyoderma is a frequent presentation in dogs. Despite the widespread availability of effective systemic and topical antimicrobial products, good clinical practice currently recommends avoidance of long-term use to mitigate the development of bacterial resistance. To evaluate the speed of resolution of clinical signs of bacterial pyoderma in dogs treated with a systemic antimicrobial agent with or without the use of an adjunctive spray with antimicrobial properties. Twelve dogs with superficial bacterial pyoderma. In this controlled and blinded study, all dogs were treated with oral cefalexin and a topical spray (PYOClean Spray) for 4 weeks. The spray was applied to one half of each dog's body, whereas a placebo spray was applied to the other half. Twelve dogs completed the study. Mean clinical scores were significantly reduced on spray-treated sites, for test product and placebo (respectively), by 47% and 34% at Week 1, 83% and 60% at Week 2, 95% and 82% at Week 3, and 100% and 96% at Week 4. Fifty percent of treated sites were considered clinically and cytologically cured at Week 2, 83% at Week 3, and 100% at Week 4 compared to 8%, 50% and 83% for the placebo sites, respectively. These results demonstrate that use of a topical spray which contains plant-derived essential oils and fatty acids, and compounds with antimicrobial properties (Manuka oil and N-acetyl cysteine) may help to speed resolution of pyoderma and may allow for shorter antimicrobial treatment time. © 2016 ESVD and ACVD.

Blastomycosis-like pyoderma

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Vijay Kumar

1990-01-01

Full Text Available Seven cases of blastomycosis like pyo4erma without, any systemic were treated with a combination of antibiotics and corticosteroids, with good results. The number of lesions from one to ten and were present on the extremities. All the patients were having eosinophilia with an increased ESR, Staphylococcus aureus was the commonest micro-organism isolated there was no underlying medical problem in any patient.

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

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Li, Jing-Yun; Ren, Yu-Peng; Yuan, Yin; Ji, Shuang-Min; Zhou, Shu-Pei; Wang, Li-Jie; Mou, Zhen-Zhen; Li, Liang; Lu, Wei; Zhou, Tian-Yan

2016-07-01

Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research. The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

Emergency surgery due to complications during molecular targeted therapy in advanced gastrointestinal stromal tumors (GIST)

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Rutkowski, P.; Nowecki, Z. I.; Dziewirski, W.; Ruka, W.; Siedlecki, J. A.; Grzesiakowska, U.

2010-01-01

Aim. The aim of the study was to assess the frequency and results of disease/treatment-related emergency operations during molecular targeted therapy of advanced gastrointestinal stromal tumors (GISTs). Methods. We analyzed emergency operations in patients with metastatic/inoperable GISTs treated with 1 st -line imatinib - IM (group I: 232 patients; median follow-up time 31 months) and 2 nd -line sunitinib - SU (group II: 43 patients; median follow-up 13 months; 35 patients in trial A6181036) enrolled into the Polish Clinical GIST Registry. Results. In group I 3 patients (1.3%) underwent emergency surgery due to disease/treatment related complications: one due to bleeding from a ruptured liver tumor (1 month after IM onset) and two due to bowel perforation on the tumor with subsequent intraperitoneal abscess (both 2 months after IM onset). IM was restarted 5-8 days after surgery and no complications in wound healing were observed. In group II 4 patients (9.5%) underwent emergency operations due to disease/treatment related complications: three due to bowel perforations on the tumor (2 days, 20 days and 10 months after SU onset; 1 subsequent death) and one due to intraperitoneal bleeding from ruptured, necrotic tumor (3.5 months after SU start). SU was restarted 12-18 days after surgery and no complications in wound healing were observed. Conclusions. Emergency operations associated with disease or therapy during imatinib treatment of advanced GISTs are rare. The frequency of emergency operations during sunitinib therapy is considered to be higher than during first line therapy with imatinib which may be associated with more advanced and more resistant disease or to the direct mechanism of sunitinib action, i.e. combining cytotoxic and antiangiogenic activity and thus leading to dramatic tumor response. Molecular targeted therapy in GISTs should always be conducted in cooperation with an experienced surgeon. (authors)

Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline.

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Claret, Laurent; Zheng, Jenny; Mercier, Francois; Chanu, Pascal; Chen, Ying; Rosbrook, Brad; Yazdi, Pithavala; Milligan, Peter A; Bruno, Rene

2016-09-01

To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data. Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated. A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79]. A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.

CCR 20th Anniversary Commentary: Determining a Pharmacokinetic/Pharmacodynamic Relationship for Sunitinib—A Look Back.

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Mendel, Dirk B; Cherrington, Julie M; Laird, A Douglas

2015-06-01

The article by Mendel and colleagues, published in the January 1, 2003, issue of Clinical Cancer Research, described their novel preclinical approach to developing a thorough understanding of the exposure-activity relationship for sunitinib, a multitargeted receptor tyrosine kinase inhibitor being developed for oncology therapy. This work successfully set exposure guidelines to identify a biologically active dose in early clinical trials. ©2015 American Association for Cancer Research.

Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy.

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Moyle, Louise A; Blanc, Eric; Jaka, Oihane; Prueller, Johanna; Banerji, Christopher Rs; Tedesco, Francesco Saverio; Harridge, Stephen Dr; Knight, Robert D; Zammit, Peter S

2016-11-14

Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, we over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD. RET is dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of either RET9 or RET51 increased myoblast proliferation, whereas siRNA-mediated knockdown of Ret induced myogenic differentiation. Suppressing RET activity using Sunitinib, a clinically-approved tyrosine kinase inhibitor, rescued differentiation in both DUX4-expressing murine myoblasts and in FSHD patient-derived myoblasts. Importantly, Sunitinib also increased engraftment and differentiation of FSHD myoblasts in regenerating mouse muscle. Thus, DUX4-mediated activation of Ret prevents myogenic differentiation and could contribute to FSHD pathology by preventing satellite cell-mediated repair. Rescue of DUX4-induced pathology by Sunitinib highlights the therapeutic potential of tyrosine kinase inhibitors for treatment of FSHD.

Angiogenesis and Tissue Engineering Research

Science.gov (United States)

2010-08-01

Model with the Angiogenesis Inhibitor Sunitinib. American Pediatric Surgical Association – 40th Annual Meeting, Fajardo, Puerto Rico, May 2009...Res 149(1):115-9. 14 5. Ray NF, Denton WG, Thamer M, Henderson SC, Perry S (1998) Abdominal adhesiolysis: inpatient care and expenditures in the...nude mice (n¼ 9). Mice were injected with near- infrared agents and imaged using intravital fluorescence microscope at 0, 7, and 35 days to validate in

Ekstraintestinale manifestationer ved inflammatorisk tarmsygdom

DEFF Research Database (Denmark)

Larsen, Signe; Bendtzen, Klaus; Nielsen, Ole Haagen

2009-01-01

dermatological manifestations, while episcleritis, iridocyclitis and uveitis are common ophthalmological complications. Conventional drugs and biologicals have proven effective in the treatment of several of the manifestations, including peripheral arthritis, pyoderma gangraenosum and episcleritis...

[Management of side effects of targeted therapies in renal cancer: iatrogenic side effects].

Science.gov (United States)

Massard, Christophe; Patard, Jean-Jacques; Hermine, Olivier; Ravaud, Alain

2011-01-01

Since premedication of patients with an H1 antihistamine is recommended before the start of the intravenous infusion of temsirolimus, temsirolimus is to be used with caution in cases where there is a history of hypersensitivity to this class of antihistamines, or medical contra-indication for treatment with antihistamines. Comorbidities and co-medications must be taken into account in the prescription of targeted therapies. For sunitinib, sorafenib, and pazopanib: potential drug interactions are possible with inducers/inhibitors of CYP3A4, anti-hypertensive drugs, antidiabetic drugs, thyroid hormones, and anticoagulant treatments. The combination of bevacizumab and sunitinib is very toxic (microangiopathic haemolytic anaemia), and is contra-indicated unless part of a clinical trial. Screening, equilibration or treatment of hypothyroidism, anaemia, undernutrition, hypophosphatemia, hypomagnesaemia, sleep disorders, depression or other comorbidities, which may contribute to asthenia is recommended. In patients treated with sunitinib or pazopanib, a thyroid function test is recommended at the treatment centre as well as regular TSH assays. Copyright © 2011 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma

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Busch, Jonas; Grünwald, Viktor; Seidel, Christoph; Weikert, Steffen; Wolff, Ingmar; Kempkensteffen, Carsten; Weinkauf, Lisa; Hinz, Stefan; Magheli, Ahmed; Miller, Kurt

2011-01-01

Data on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague. We retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy. Thirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4). Intrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients

Ekstraintestinale manifestationer ved inflammatorisk tarmsygdom

DEFF Research Database (Denmark)

Larsen, Signe; Bendtzen, Klaus; Nielsen, Ole Haagen

2009-01-01

Extraintestinal manifestations are relatively common in chronic inflammatory bowel disease and affect joints, skin, eyes and bile ducts. The most frequent rheumatologic manifestations are peripheral arthritis and axial arthropathies. Erythema nodosum and pyoderma gangraenosum are common...

Regorafenib: A Review of Its Use in Patients with Advanced Gastrointestinal Stromal Tumours.

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Shirley, Matt; Keating, Gillian M

2015-06-01

Regorafenib (Stivarga(®)) is an orally administered small molecule inhibitor of multiple protein kinases, including kinases involved in oncogenesis and tumour angiogenesis. It was initially approved for use in patients with previously treated metastatic colorectal cancer. Based on the findings of the phase III GRID clinical trial, approval for regorafenib has been expanded to include the treatment of advanced gastrointestinal stromal tumours (GISTs) following the failure of imatinib and sunitinib. In the GRID trial, regorafenib significantly improved progression-free survival and was associated with a significantly higher disease control rate than placebo. No significant between-group difference was observed in overall survival (OS) in the trial; however, the high proportion of patients who crossed over from placebo to regorafenib likely impacted the OS analysis. Regorafenib has an acceptable tolerability profile, with most adverse events being manageable with dose modification and/or supportive measures. The most commonly reported drug-related adverse events among patients receiving regorafenib in the GRID trial were hand-foot skin reaction, hypertension, diarrhoea and fatigue. In conclusion, regorafenib presents a valuable new tool in the treatment of patients with advanced GISTs following the failure of imatinib and sunitinib.

Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

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Kiersten Marie Miles

Full Text Available The Notch ligand Delta-like 4 (Dll4 is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC.Severe combined immunodeficiency (SCID mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36-62% that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38-54% and ziv-aflibercept (46%. Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72-80% growth inhibition, including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.

Investigating the effect of independent, blinded digital image assessment on the STOP GAP trial.

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Patsko, Emily; Godolphin, Peter J; Thomas, Kim S; Hepburn, Trish; Mitchell, Eleanor J; Craig, Fiona E; Bath, Philip M; Montgomery, Alan A

2017-02-02

Blinding is the process of keeping treatment assignment hidden and is used to minimise the possibility of bias. Trials at high risk of bias have been shown to report larger treatment effects than low-risk studies. In dermatology, one popular method of blinding is to have independent outcome assessors who are unaware of treatment allocation assessing the endpoint using digital photographs. However, this can be complex, expensive and time-consuming. The objective of this study was to compare the effect of blinded and unblinded outcome assessment on the results of the STOP GAP trial. The STOP GAP trial compared prednisolone to ciclosporin in treating pyoderma gangrenosum. Participants' lesions were measured at baseline and at 6 weeks to calculate the primary outcome, speed of healing. Independent blinded assessors obtained measurements from digital photographs using specialist software. In addition, unblinded treating clinicians estimated lesion area by measuring length and width. The primary outcome was determined using blinded measurements where available, otherwise unblinded measurements were used (method referred to as trial measurements). In this study, agreement between the trial and unblinded measurements was determined using the intraclass correlation coefficient (ICC). The STOP GAP trial's primary analysis was repeated using unblinded measurements only. We introduced differential and nondifferential error in unblinded measurements and investigated the effect on the STOP GAP trial's primary analysis. Eighty-six (80%) of the 108 patients were assessed using digital images. Agreement between trial and unblinded measurements was excellent (ICC = 0.92 at baseline; 0.83 at 6 weeks). There was no evidence that the results of the trial primary analysis differed according to how the primary outcome was assessed (p value for homogeneity = 1.00). Blinded digital image assessment in the STOP GAP trial did not meaningfully alter trial conclusions compared with

Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1

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Moehler, Markus; Sieben, Maike; Roth, Susanne; Springsguth, Franziska; Leuchs, Barbara; Zeidler, Maja; Dinsart, Christiane; Rommelaere, Jean; Galle, Peter R

2011-01-01

Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV. Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC). H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone. In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine

Lucilia eximia (Diptera: Calliphoridae, a new alternative for maggot therapy. Case series report Lucilia eximia (Diptera: Calliphoridae, una nueva alternativa para la terapia larval

Directory of Open Access Journals (Sweden)

Silvia Emelia Herrera Higuita

2010-05-01

Full Text Available

Larval therapy is used in the treatment of infected chronic wounds by allowing the removal of necrotic tissue, which induces the formation of granular tissue and the growth of healthy skin.

Considering the increasing prevalence of antibiotic resistance, this type of therapy may be an effective alternative in the management of infected chronic wounds. In this article we report the use of maggot therapy using the Lucilia eximia species in 42 patients with chronic skin wounds associated to different pathologies including: venous and arterial ulcers, diabetic foot, sickle cell disease, vasculopathy, elephantiasis, Berger disease, pyoderma gangrenosum (PG, traumatic wounds, erysipelas, and hospital acquired infections. Four cases are depicted photographically.

La terapia larval es utilizada desde los años 30 del siglo pasado para la remoción del tejido necrótico en el tratamiento de úlceras crónicas infectadas logrando con ello promover la formación de tejido granuloso para el crecimiento de piel sana; especialmente a partir de la aparición de la resistencia a los antibioticos se la reconoce

The world of targeted therapies in kidney cancers: pitfalls, tips and tricks

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Vallard A

2017-03-01

Full Text Available Alexis Vallard, Jane-Chloé Trone, Julien Langrand-Escure, Sophie Espenel, Jean-Baptiste Guy, Chloé Rancoule, Yaoxiong Xia, Anis El Meddeb Hamrouni, Majed Ben Mrad, Nicolas Magné Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez, France Abstract: In the past few years, metastatic renal cell carcinoma prognosis was improved by the development of molecular targeted therapies (TTs. At the metastatic stage, the tolerance to treatment is a major concern, not only because of the challenge of the efficacy/toxicity ratio improvement but also because of the importance of an optimal adherence to oral treatments. The present case series relates the issues of dealing with uncommon and sometimes never described side effects of sunitinib and sorafenib. The first case report deals with grade 3 vomiting during hemodialysis with concurrent administration of sunitinib. The second case is an iterative gout attack induced by sunitinib. The third case presents a grade 3 scalp dysesthesia with sorafenib. The fourth case includes an astonishing efficacy of metronomic (ie, low doses during a long period of time bevacizumab in monotherapy. Multidisciplinary management and systematic reporting of unexpected efficacies and toxicities are needed to better understand TTs real therapeutic index. Although TTs revolutionized metastatic renal cell cancer prognosis, they also brought about previously unknown side effects. Identification and management of these off-target effects may be tricky, and therefore, comedication must be wisely chosen. As the physiopathology of these side effects is still unclear, multidisciplinary management and systematic reporting of toxicities are essential. Keywords: renal cell carcinoma, bevacizumab, sunitinib, sorafenib, toxicity, efficacy

Gastrointestinal stromal tumors

International Nuclear Information System (INIS)

Sufliarsky, J.

2011-01-01

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the digestive tract. Better understanding of the molecular characteristics of GISTs led to the clinical development of imatinib for treating patients with this disease. New immuno markers and mechanisms of primary and secondary resistance were discovered. Adjuvant imatinib in intermediate or high risk GIST has improved the recurrence-free survival. Sunitinib in patients with intolerance or progression on imatinib demonstrated significant improvements in progression-free and overall survival versus placebo. Second-generation tyrosine kinase inhibitors, such as sorafenib, dasatinib, and nilotinib, have shown activity in patients with imatinib- and sunitinib-resistant GIST. (author)

A study of an effective sunitinib–chemotherapeutic combination regimen for bladder cancer treatment using a mouse model

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Dah-Shyong Yu

2014-06-01

Conclusion: Combination of the tyrosine kinase receptor inhibitor sunitinib with gemcitabine chemotherapy synergistically enhances tumor cytotoxicity and may provide a new treatment modality for advanced bladder cancer.

Clinical efficacy of second-generation tyrosine kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors: a meta-analysis of recent clinical trials

Directory of Open Access Journals (Sweden)

Wu L

2014-10-01

Full Text Available Lile Wu, Zhongqiang Zhang, Hongliang Yao, Kuijie Liu, Yu Wen, Li Xiong Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China Background: Primary and secondary resistance to imatinib, a selective receptor tyrosine kinase inhibitor (TKI, is a serious clinical problem in the control of advanced gastrointestinal stromal tumors (GIST. Here we report on a meta-analysis we performed to evaluate the efficacy of second-generation TKIs in the treatment of patients with imatinib-resistant GIST.Methods: Randomized controlled trials evaluating the clinical efficacy of second-generation TKIs were identified by searching PubMed and EMBASE from 2000 to February 2014. Outcomes subjected to analysis were progression-free survival and overall survival. Statistical analyses were performed using Review Manager version 5.1.0 (Cochrane Collaboration, Oxford, UK. Weighted hazard ratios (HR with 95% confidence intervals (CIs were calculated for the outcomes. Fixed-effects or random-effects models were used, depending on the degree of heterogeneity across the selected studies.Results: Three randomized controlled trials were selected for meta-analysis. Among imatinib-resistant or imatinib-intolerant patients, 541 received second-generation TKIs (sunitinib, nilotinib, or regorafenib and 267 controls received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.38; 95% CI 0.24–0.59; P<0.0001. No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71–1.03; P=0.09. In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib improved progression-free survival (HR 0.40; 95% CI 0.19–0.84; P=0.02 but not overall survival (HR 0.83; 95% CI 0.63–1.08; P=0.17. Regorafenib was shown to be

prevalence of head lice infestation in primary school children in port ...

African Journals Online (AJOL)

2013-08-01

Aug 1, 2013 ... Excoriation and secondary pyoderma, following trauma due to scratching, may result in matting together of the hair, cervical and occipital lymphadenopathy. Severe cases may result in group A Streptococcal impetigo with the risk of developing rheumatic heart disease and glomerulonephritis (14). Head lice.

Identification of cellular targets involved in cardiac failure caused by PKI in oncology: an approach combining pharmacovigilance and pharmacodynamics.

Science.gov (United States)

Patras de Campaigno, Emilie; Bondon-Guitton, Emmanuelle; Laurent, Guy; Montastruc, Francois; Montastruc, Jean-Louis; Lapeyre-Mestre, Maryse; Despas, Fabien

2017-07-01

The aims of the present study were to evaluate the risk of cardiac failure (CF) associated with 15 anticancer protein kinase inhibitors (PKIs) through a case/noncase analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. In order to evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the World Health Organization safety report database (VigiBase®). We realised a literature review to identify 21 protein kinases (PKs) that were possibly involved in CF caused by PKIs. Pearson correlation coefficients (r) between aRORs and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely to be involved in PKI-induced CF. A total of 141 601 individual case safety reports (ICSRs) were extracted from VigiBase® for the following PKIs: afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib and vandetanib. Among them, 2594 ICSRs concerned CF. The disproportionality analysis revealed that, for dasatinib, imatinib, bosutinib, sunitinib and nilotinib, disproportionality for CF was significantly higher than for other PKIs, with aRORs of 2.52 [95% CI 2.26, 2.82], 1.79 (95% CI 1.57, 2.03), 1.73 (95% CI 1.18, 2.54), 1.67 (95% CI 1.51, 1.84) and 1.38 (95% CI 1.18, 1.61), respectively. Significant values for correlation coefficients between the product of dissociation constant (pKd) and aROR were observed for two non-receptor protein kinases: ABL1 (non-phosphorylated and phosphorylated forms) and ABL2 protein kinases, with values of r = 0.83 (P = 0.0001), r = 0.75 (P = 0.0014) and r = 0.78 (P = 0.0006), respectively. We observed a higher disproportionality for CF with dasatinib, imatinib, bosutinib, sunitinib and nilotinib than with other PKIs. In addition, the study highlighted the role of ABL tyrosine kinases in CF caused by anticancer PKIs. © 2017 The British

Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.

Science.gov (United States)

Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Carducci, Michael; Chen, Ronald C; Frame, James N; Garrels, Kristina; Hotte, Sebastien; Kattan, Michael W; Raghavan, Derek; Saad, Fred; Taplin, Mary-Ellen; Walker-Dilks, Cindy; Williams, James; Winquist, Eric; Bennett, Charles L; Wootton, Ted; Rumble, R Bryan; Dusetzina, Stacie B; Virgo, Katherine S

2014-10-20

To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or

Prostate cancer revealed by skin metastasis: A case report in black ...

African Journals Online (AJOL)

K. Tengue

2016-11-23

Nov 23, 2016 ... ter Joseph's nodule, basal cell carcinoma, pyoderma, morphea, and more, resulting in poor recognition [9]. The diagnosis is easier if there is a history of prostatic cancer with known disseminated dis- ease. Our patient had no complaints of urinary symptoms and the diagnosis was determined by prostate ...

A Biodegradable Microneedle Cuff for Comparison of Drug Effects through Perivascular Delivery to Balloon-Injured Arteries

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Dae-Hyun Kim

2017-02-01

Full Text Available Restenosis at a vascular anastomosis site is a major cause of graft failure and is difficult to prevent by conventional treatment. Perivascular drug delivery has advantages as drugs can be diffused to tunica media and subintima while minimizing the direct effect on endothelium. This in vivo study investigated the comparative effectiveness of paclitaxel, sirolimus, and sunitinib using a perivascular biodegradable microneedle cuff. A total of 31 New Zealand white rabbits were used. Rhodamine was used to visualize drug distribution (n = 3. Sirolimus- (n = 7, sunitinib- (n = 7, and paclitaxel-loaded (n = 7 microneedle cuffs were placed at balloon-injured abdominal aortae and compared to drug-free cuffs (n = 7. Basic histological structures were not affected by microneedle devices, and vascular wall thickness of the device-only group was similar to that of normal artery. Quantitative analysis revealed significantly decreased neointima formation in all drug-treated groups (p < 0.001. However, the tunica media layer of the paclitaxel-treated group was significantly thinner than that of other groups and also showed the highest apoptotic ratio (p < 0.001. Proliferating cell nuclear antigen (PCNA-positive cells were significantly reduced in all drug-treated groups. Sirolimus or sunitinib appeared to be more appropriate for microneedle devices capable of slow drug release because vascular wall thickness was minimally affected.

Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis

International Nuclear Information System (INIS)

Capdevila, Jaume; Sevilla, Isabel; Alonso, Vicente; Antón Aparicio, Luís; Jiménez Fonseca, Paula; Grande, Enrique; Reina, Juan José; Manzano, José Luís; Alonso Lájara, Juan Domingo; Barriuso, Jorge; Castellano, Daniel; Medina, Javier; López, Carlos; Segura, Ángel; Carrera, Sergio; Crespo, Guillermo; Fuster, José; Munarriz, Javier; García Alfonso, Pilar

2015-01-01

Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. Of the 133 patients, with a median age of 59.4 (16–83) years, 70 (52.6 %) patients were male, 64 (48.1 %) had pancreatic NET, 23 (17.3 %) had ECOG PS ≥2, 41 (30.8 %) had functioning tumours, 63 (47.7 %) underwent surgery of the primary tumour, 45 (33.8 %) had received prior chemotherapy, and 115 (86.5 %) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5 % (6 months), 68.6 % (12 months) and 57.0 % (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3 % (6 months), 73.0 % (12 months), and 67.4 % (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95 % CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely

Atypical presentation of post infectious glomerulonephritis as malignant hypertension and thrombotic microangiopathy

Directory of Open Access Journals (Sweden)

M Vankalakunti

2014-01-01

Full Text Available Infection-related glomerulonephritis presents commonly as acute nephritic illness, hypertension, hypocomplementinemia following an episode of pharyngitis or pyoderma. Atypical features like thrombotic microangiopathy (TMA, produced by neuraminidase antigen targeting endothelium have been described rarely. We report a case of TMA secondary to malignant hypertension, coexisting with post infectious glomerulonephritis.

Localization of immunoglobulins and complement by the peroxidase antiperoxidase method in autoimmune and non-autoimmune canine dermatopathies.

Science.gov (United States)

Moore, F M; White, S D; Carpenter, J L; Torchon, E

1987-01-01

Formalin-fixed, paraffin embedded skin biopsy specimens from 44 dogs with various dermatopathies were examined for the presence of immunoglobulins (IgG, IgM, IgA) and complement (C3) by the peroxidase antiperoxidase method (PAP). Final diagnoses of the skin diseases were determined by clinical findings, fungal and bacterial cultures, skin scrapings, serum endocrinologic tests, and histologic features of cutaneous biopsies. The dermatopathies included examples of pyoderma (folliculitis/furunculosis), demodecosis, sarcoptic mange, dermatophytosis, endocrine dermatopathy, and autoimmune skin disease (AISD). In the latter category, 7 cases of pemphigus foliaceus, 1 pemphigus vulgaris, 4 discoid lupus erythematosus (DLE) and 4 examples of indeterminate AISD were examined. Immunoglobulins, C3, or both, were localized in tissue sections from AISD (15/16), pyoderma (7/11), demodecosis (4/8) sarcoptic mange (3/3), and dermatomycosis (2/3). Endocrine dermatopathy biopsies were consistently negative for Ig and C3 (0/3). The pattern of localization was most often intercellular (31/44 positive biopsies) with basement membrane immunoreactivity in 4 cases of DLE, and 1 case of indeterminate AISD. There was no consistent correlation between histologic features of hematoxylin and eosin-stained biopsies and the presence of Ig and C3. Clinical outcome was similar in both Ig and C3 positive and negative cases of non-AISD dermatitis. The high percentage (95%) of positive results in AISD biopsies indicates the usefulness and sensitivity of the PAP method for the localization of Ig and C3. Because of the high percentage of Ig localization in pyoderma (73%), biopsy specimens with extensive inflammatory skin disease are not suitable for diagnosis of AISD. The PAP method is useful in the diagnosis of AISD in biopsy specimens with minimal inflammation. Caution is warranted in the interpretation of immunoreactivity independent of clinical and histologic information.

Antibiotic treatments of a methicillin-resistant Staphylococcus pseudintermedius infection in a dog: a case presentation.

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Decristophoris, P; Mauri, F; Albanese, F; Carnelli, A; Vanzetti, T; Zinsstag, J

2011-09-01

We report the antibiotic treatments administered to a female dog with mastitis and successive pyoderma. Microbiological investigations allowed the identification of Staphylococcus pseudintermedius after 54 days of various antibiotic treatments. The isolate carried the mecA gene and was resistant to 9 of 15 tested antibiotics. Consistent antibiotic treatment of the infection was possible only after accurate microbiological diagnosis.

A study on the cutaneous manifestations of diabetes mellitus

Directory of Open Access Journals (Sweden)

Neerja Puri

2012-04-01

Full Text Available The cutaneous manifestations of diabetes mellitus are varied. We conducted a study of fifty patients having diabetes mellitus coming from the department of dermatology and medicine. The commonest cutaneous feature of diabetes were pyodermas seen in 40% patients, dermatophytosis seen in 36% patients, pruritis diabetic thick skin seen in 20 % patients, diabetic dermopathy seen in 16% patients, diabetic bulla and rubeosis seen in 8% patients each and meralgia paraesthetica and diabetic foot seen in 4% patients each. About the associations of diabetes mellitus, achrchordons were seen in 8% patients, vitiligo and perforating dermatoses were seen in 6% patients each, granuloma annulare, eruptive xanthomas, acanthosis nigricans, necrobiosis lipoidica and oral lichen planus were seen in 4 % patients each and xanthelasma was seen in 2% patients.

A Continuation Study Using Sunitinib Malate For Patients Leaving Treatment On A Previous Sunitinib Study.

Science.gov (United States)

2015-10-07

Metastatic Breast Cancer [F]; Advanced Breast Cancer; Metastatic Castration Resistant Prostate Cancer; Metastatic Renal Cell Cancer; Non-Small Cell Lung Cancer; Thyroid Cancer; Advanced/Metastatic Non-Small Cell Lung Cancer; Advanced Gastric Cancer; Gastrointestinal Stromal Tumor; Hepatocellular Carcinoma; Pancreatic Islet Cell Carcinoma; Pancreatic Neuroendocrine Tumor

Role of everolimus in the treatment of renal cell carcinoma

Directory of Open Access Journals (Sweden)

Saby George

2009-08-01

Full Text Available Saby George1, Ronald M Bukowski21University of Texas Health Sciences Center, MC-8221, Division of Hematology and Oncology, San Antonio, Texas, USA; 2CCF Lerner College of Medicine Division of Hematology and Oncology, Cleveland, Ohio, USAAbstract: The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC. Everolimus (RAD 001 is an oral inhibitor of the mammalian target of rapamycin (mTOR pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1 conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P ≤ 0 0.001. Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.Keywords: mTOR inhibitor, mammalian target of rapamycin inhibitor, signal transduction inhibitor, renal cell carcinoma, targeted therapy

Embolization biomaterial reinforced with nanotechnology for an in-situ release of anti-angiogenic agent in the treatment of hyper-vascularized tumors and arteriovenous malformations.

Science.gov (United States)

Jubeli, E; Yagoubi, N; Pascale, F; Bédouet, L; Slimani, K; Labarre, D; Saint-Maurice, J P; Laurent, A; Moine, L

2015-10-01

A polymer based material was developed to act as an embolic agent and drug reservoir for the treatment of arteriovenous malformations (AVM) and hyper vascularized solid tumors. The aim was to combine the blocking of blood supply to the target region and the inhibition of the embolization-stimulated angiogenesis. The material is composed of an ethanolic solution of a linear acrylate based copolymer and acrylate calibrated microparticles containing nanospheres loaded with sunitinib, an anti-angiogenic agent. The precipitation of the linear copolymer in aqueous environment after injection through microcatheter results in the formation of an in-situ embolization gel whereas the microparticles serve to increase the cohesive properties of the embolization agent and to form a reservoir from which the sunitinib-loaded nanospheres are released post-embolization. The swollen state of the microparticles in contact with aqueous medium results in the release of the nanospheres out of microparticles macromolecular structure. After the synthesis, the formulation and the characterization of the different components of the material, anti-angiogenic activity was evaluated in vitro using endothelial cells and in vivo using corneal neovascularization model in rabbit. The efficiency of the arterial embolization was tested in vivo in a sheep model. Results proved the feasibility of this new system for vascular embolization in association with an in situ delivery of anti-angiogenic drug. This combination is a promising strategy for the management of arteriovenous malformations and solid tumors. Copyright © 2015 Elsevier B.V. All rights reserved.

Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets

DEFF Research Database (Denmark)

Swanton, C.; Larkin, J.M.; Gerlinger, M.

2010-01-01

-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway...

Cost utility analysis of everolimus in the treatment of metastatic renal cell cancer in the Netherlands

NARCIS (Netherlands)

Mihajlović, J.; Minović, I.; Bruinsma, A.; Postma, M.J.

2013-01-01

Objectives: Metastatic renal cell cancer (mRCC) is becoming an important part of Dutch health care expenditure due to expensive pharmaceutical options for disease control and lack of adequate prevention methods. New targeted therapeutics, such as sunitinib, sorafenib and everolimus, have recently

Durable clinical activity of single-agent bevacizumab in a nonagenarian patient with metastatic alveolar soft part sarcoma.

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Mir, Olivier; Boudou-Rouquette, Pascaline; Larousserie, Frédérique; Blanchet, Benoit; Babinet, Antoine; Anract, Philippe; Goldwasser, François

2012-08-01

Alveolar soft part sarcoma is a rare malignancy usually considered resistant to conventional chemotherapy, but recent data suggest that the multikinase inhibitors sunitinib and cediranib could be active in this setting. A 90-year-old lady with alveolar soft part sarcoma of the leg and lung metastases was started on sunitinib 37.5 mg daily. The treatment was poorly tolerated with grade 3 hypertension and grade 3 thrombocytopenia, which persisted after dose reduction to 25 mg daily. The patient was subsequently started on bevacizumab 10 mg/kg every 2 weeks, resulting in a marked improvement in pain and a partial response on lung metastases for 16 months and ongoing. Agents targeting the vascular endothelial growth factor-signalling pathway seem to exert clinically relevant and prolonged activity against alveolar soft part sarcoma and deserve further evaluation in the treatment of this rare soft tissue sarcoma.

Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.

Science.gov (United States)

Faes, Seraina; Uldry, Emilie; Planche, Anne; Santoro, Tania; Pythoud, Catherine; Demartines, Nicolas; Dormond, Olivier

2016-12-27

Anti-angiogenic treatments targeting the vascular endothelial growth factor or its receptors have shown clinical benefits. However, impact on long-term survival remains limited. Solid tumors display an acidic microenvironment that profoundly influences their biology. Consequences of acidity on endothelial cells and anti-angiogenic therapies remain poorly characterized and hence are the focus of this study. We found that exposing endothelial cells to acidic extracellular pH resulted in reduced cell proliferation and migration. Also, whereas VEGF increased endothelial cell proliferation and survival at pH 7.4, it had no effect at pH 6.4. Furthermore, in acidic conditions, stimulation of endothelial cells with VEGF did not result in activation of downstream signaling pathways such as AKT. At a molecular level, acidity significantly decreased the expression of VEGFR-2 by endothelial cells. Consequently, anti-angiogenic therapies that target VEGFR-2 such as sunitinib and sorafenib failed to block endothelial cell proliferation in acidic conditions. In vivo, neutralizing tumor acidity with sodium bicarbonate increased the percentage of endothelial cells expressing VEGFR-2 in tumor xenografts. Furthermore, combining sodium bicarbonate with sunitinib provided stronger anti-cancer activity than either treatment alone. Histological analysis showed that sunitinib had a stronger anti-angiogenic effect when combined with sodium bicarbonate. Overall, our results show that endothelial cells prosper independently of VEGF in acidic conditions partly as a consequence of decreased VEGFR-2 expression. They further suggest that strategies aiming to raise intratumoral pH can improve the efficacy of anti-VEGF treatments.

Brazilian data of renal cell carcinoma in a public university hospital.

Science.gov (United States)

Aguiar, Pedro; Padua, Tiago Costa; Guimaraes, Daiane Pereira

2016-01-01

Among renal malignancies, renal cell carcinoma (RCC) accounts for 85% of cases. Stage is a relevant prognostic factor; 5-year survival ranges from 81% to 8% according to the stage of disease. The treatment is based on surgery and molecularly targeted therapy has emerged as a choice for metastatic disease. Retrospective study by reviewing the medical records of patients with RCC treated in the last 10 years at UNIFESP. The primary end point of this trial was to evaluate the overall survival (OS) of the patients. The secondary end point was to evaluate the progression-free survival (PFS) after nephrectomy. 118 patients with RCC were included. The mean age was 58.3 years, 61.9% men; nephrectomy was performed in 90.7%, clear cell was the histology in 85.6%, 44 patients were classified as stage IV at diagnosis. Among these, 34 had already distant metastasis. 29 patients were treated with sunitinib. The median OS among all patients was 55.8 months. The median PFS after nephrectomy was 79.1 months. Sarcomatoid differentiation HR29.74 (95% CI, 4.31-205.26), clinical stage IV HR1.94 (95% CI, 1.37-2.75) and nephrectomy HR0.32 (95% CI, 0.15-0.67) were OS prognostic factors. Sunitinib had clinical activity. Patients treated in our hospital achieved median OS compatible with literature. Nevertheless, this study has shown a high number of patients with advanced disease. For patients with advanced disease, treatment with sunitinib achieved median OS of 28.7 months, consistent with the literature.

Regorafenib-associated hand–foot skin reaction: practical advice on diagnosis, prevention, and management

Science.gov (United States)

McLellan, B.; Ciardiello, F.; Lacouture, M. E.; Segaert, S.; Van Cutsem, E.

2015-01-01

Background Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand–foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible. Design This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients. Results Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand–foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and

Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management.

Science.gov (United States)

McLellan, B; Ciardiello, F; Lacouture, M E; Segaert, S; Van Cutsem, E

2015-10-01

Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand-foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible. This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients. Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand-foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and tried-and-tested empirical

Antiangiogenic therapy for breast cancer

DEFF Research Database (Denmark)

Nielsen, D.L.; Andersson, M.; Andersen, Jon Alexander Lykkegaard

2010-01-01

tyrosine kinase activity, such as sorafenib, appear promising. While, the role of sunitinib and inhibitors of mammalian target of rapamycin (mTOR) in breast cancer has to be defined. Several unanswered questions remain, such as choice of drug(s), optimal duration of therapy and patient selection criteria...

Acute Liver Failure Due to Regorafenib May Be Caused by Impaired Liver Blood Flow: A Case Report.

Science.gov (United States)

Akamine, Takaki; Ando, Koji; Oki, Eiji; Saeki, Hiroshi; Nakashima, Yuichiro; Imamura, Y U; Ohgaki, Kippei; Maehara, Yoshihiko

2015-07-01

Regorafenib has been approved for treatment of patients with unresectable or recurrent gastrointestinal stromal tumors resistant to imatinib or sunitinib. However, regorafenib has severe side-effects, including acute liver failure. We describe the case of a patient with multiple liver metastases of a small intestinal stromal tumor who experienced acute liver failure while being treated with regorafenib. A 50-year-old patient with an unresectable small intestinal stromal tumor resistant to prior treatment with imatinib and sunitinib was started on regorafenib, but experienced acute liver failure 10 days later. Plasma exchange and steroid pulse treatment improved her liver function. During liver failure, abdominal ultrasonography showed to-and-fro flow in the portal vein. Lactate dehydrogenase concentration was markedly elevated to 1633 U/l. These findings indicate that liver failure in this patient was due to impaired liver blood flow. Regorafenib may impair liver blood flow, inducing acute liver failure. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Targeting gastrointestinal stromal tumors: the role of regorafenib

Directory of Open Access Journals (Sweden)

Schroeder B

2016-05-01

Full Text Available Brett Schroeder,1 Zula Li,2,3 Lee D Cranmer,2,3 Robin L Jones,4 Seth M Pollack2,3 1College of Human Medicine, Michigan State University, Grand Rapids, MI, 2Division of Medical Oncology, University of Washington, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 4Royal Marsden Hospital, Institute of Cancer Research, London, UK Abstract: Gastrointestinal stromal tumor (GIST is a devastating disease in the metastatic setting, but its natural history has been dramatically altered by the development of small molecule tyrosine kinase inhibitors, most notably imatinib. Although patients with advanced GIST live much longer today than they did in the past, imatinib-refractory disease remains a tremendous problem. For disease that is refractory to imatinib and sunitinib, regorafenib is an excellent option. In this review, we discuss the biology and clinical work establishing regorafenib as the standard of care for advanced GIST refractory to both imatinib and sunitinib. Keywords: regorafenib, GIST, refractory, imatinib

Downsizing Treatment with Tyrosine Kinase Inhibitors in Patients with Advanced Gastrointestinal Stromal Tumors Improved Resectability

Science.gov (United States)

Sjölund, Katarina; Andersson, Anna; Nilsson, Erik; Nilsson, Ola; Ahlman, Håkan

2010-01-01

Background Gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT. Most GISTs have mutations in the KIT or PDGFRA gene, causing activation of tyrosine kinase. Imatinib, a tyrosine kinase inhibitor (TKI), is the first-line palliative treatment for advanced GISTs. Sunitinib was introduced for patients with mutations not responsive to imatinib. The aim was to compare the survival of patients with high-risk resected GISTs treated with TKI prior to surgery with historical controls and to determine if organ-preserving surgery was facilitated. Methods Ten high-risk GIST-patients had downsizing/adjuvant TKI treatment: nine with imatinib and one with sunitinib. The patients were matched with historical controls (n = 89) treated with surgery alone, from our population-based series (n = 259). Mutational analysis of KIT and PDGFRA was performed in all cases. The progression-free survival was calculated. Results The primary tumors decreased in mean diameter from 20.4 cm to 10.5 cm on downsizing imatinib. Four patients with R0 resection and a period of adjuvant imatinib had no recurrences versus 67% in the historical control group. Four patients with residual liver metastases have stable disease on continuous imatinib treatment after surgery. One patient has undergone reoperation with liver resection. The downsizing treatment led to organ-preserving surgery in nine patients and improved preoperative nutritional status in one patient. Conclusions Downsizing TKI is recommended for patients with bulky tumors with invasion of adjacent organs. Sunitinib can be used for patients in case of imatinib resistance (e.g., wild-type GISTs), underlining the importance of mutational analysis for optimal surgical planning. PMID:20512492

Posterior Reversible Leukoencephalopathy Syndrome Associated with Pazopanib

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Robert Foerster

2013-04-01

Full Text Available A 62-year-old female patient with metastatic renal cell carcinoma under third-line treatment with pazopanib for 8 weeks suddenly developed severe headaches, grand mal seizures and paresis of the left arm in combination with gait instability as well as nausea and vomiting during her vacation abroad. The emergency physician measured systolic blood pressure values over 300 mm Hg and suspected a stroke. The CT imaging without contrast agent in a local hospital did not show any pathologic findings despite bone metastases. The colleagues suspected cerebral metastases or meningeosis carcinomatosa and referred the patient to our department for further diagnostics and treatment planning. An MRI scan ruled out the suspected cerebral metastases or meningeosis carcinomatosa, but showed signs of reversible posterior leukoencephalopathy syndrome (RPLS in the form of band-like hyperintensities as a sign of cytotoxic edema in the gray and white matter of the left parietal lobe. The patient then reported that similar blood pressure values had been measured shortly after the start of a first-line therapy with sunitinib, so that we discontinued the current treatment with pazopanib. Within 6 days the neurologic symptoms vanished and the patient was discharged. An intermittent hypertension persisted. A follow-up MRI 3 weeks later showed an RPLS-typical cortical infarction in the affected area. RPLS should be considered as the actual reason for neurologic findings in hypertensive patients with known metastatic cancers under tyrosine kinase inhibitor therapy.

[Immunotherapy for renal cell carcinoma - current status].

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Grimm, Marc-Oliver; Foller, Susan

2018-04-01

Systemic treatment of metastatic renal cell carcinoma (mRCC) has substantially changed during the last 2 years due to approval of the immune-checkpoint inhibitor Nivolumab (Opdivo ® ) and new multikinase inhibitors (Cabozantinib, Lenvatinib, Tivozanib). The german kidney tumor guideline strongly recommends Nivolumab and Cabozantinib as 2nd line treatments after prior VEGF targeted therapy. CheckMate 025, the prospective randomized trial which led to approval of Nivolumab demonstrated improved overall survival (26 month vs. 19.7 month; hazard ratio 0.73; p = 0.0006) and response rate (26 % vs. 5 %) as well as a favorable toxicity profile compared with Everolimus. Currently, numerous combinations with PD-1/PD-L1 inhibitors are compared to Sunitinib as first line treatment of mRCC. Out of these CheckMate 214, a randomized phase-3 trial is the first to demonstrate a significant higher objective response rate (42 % vs. 27 %, p < 0.0001) and overall survival (Sunitinib 26.0 month, median for Nivo + Ipi has been not yet reached (28.2 - NR); Hazard ratio 0.63) for the combination of Nivolumab and the CTLA-4 antibody Ipilimumab in IMDC intermediate and high risk patients. Furthermore, CheckMate 214 shows better side effect profile and quality of life in patients receiving Nivolumab and Ipilimumab compared with Sunitinib. However, a considerable increase of immune related adverse events is associated with the immune combination therapy. Another randomized trial demonstrates improved progression-free survival for the combination of the PD-L1 inhibitor Atezolizumab and the VEGF antibody Bevacizumab in patients with PD-L1 positive tumors; this was found in all IMDC risk groups. Further phase-3 trials with "new" VEGFR-TKIs (Axitinib, Cabozantinib, Lenvatinib) and PD-1/PD-L1 inhibitor combinations are ongoing.In conclusion, the PD-1 immune checkpoint inhibitor Nivolumab will remain a standard treatment for patients with metastatic renal cell carcinoma

Cross-sectional survey on the use and impact of the Danish national antibiotic use guidelines for companion animal practice

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Jessen, Lisbeth Rem; Møller Sørensen, Tina; Lilja, Zenia Littau

2017-01-01

Background: The Danish antibiotic use guidelines for companion animal practice were published by the Danish Veterinary Association in 2012. Since then, national surveillance data indicate a 10% reduction in the total use of antibiotics for companion animals, particularly a marked reduction...... in the use of third generation cephalosporins. The aim of the study was to assess if and how the guidelines have impacted diagnostic and antibiotic prescription habits of the users, and to identify user perceived barriers to implementation. Results: An online questionnaire was sent to all 882 members...... cent indicated that the guidelines had influenced their habits in one or more of the areas being investigated, i.e. perioperative use of antibiotics, use of first line antibiotics for the treatment of pyoderma or UTI, and/or use of microbiological diagnostics. Perioperative use of antibiotics for clean...

[Complications of cosmetic skin bleaching in Africa].

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Morand, J J; Ly, F; Lightburn, E; Mahé, A

2007-12-01

Use of cosmetic products to bleach or lighten the skin is common among dark-skinned women in some sub-Saharan African countries. Long-term use of some pharmacologic compounds (e.g. hydroquinone, glucocorticoids and mercury) can cause adverse effects including dermatologic disorders such as dyschromia, exogenous ochronosis, acne and hypertrichosis, prominent striae, tinea corporis, pyoderma, erysipelas, scabies, and contact dermatitis and systemic complications such as hypertension, hypercorticism or surrenal deficiency, and mercurial nephropathy.

The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia.

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Saleh, Langeza; Verdonk, Koen; Visser, Willy; van den Meiracker, Anton H; Danser, A H Jan

2016-10-01

Pre-eclampsia (PE) is the most frequently encountered medical complication during pregnancy. It is characterized by a rise in systemic vascular resistance with a relatively low cardiac output and hypovolemia, combined with severe proteinuria. Despite the hypovolemia, renin-angiotensin system (RAS) activity is suppressed and aldosterone levels are decreased to the same degree as renin. This suggests that the RAS is not the cause of the hypertension in PE, but rather that its suppression is the consequence of the rise in blood pressure. Abnormal placentation early in pregnancy is widely assumed to be an important initial event in the onset of PE. Eventually, this results in the release of anti-angiogenic factors [in particular, soluble Fms-like tyrosine kinase-1 (sFlt-1)] and cytokines, leading to generalized vascular dysfunction. Elevated sFlt-1 levels bind and inactivate vascular endothelial growth factor (VEGF). Of interest, VEGF inhibition with drugs like sunitinib, applied in cancer patients, results in a PE-like syndrome, characterized by hypertension, proteinuria and renal toxicity. Both in cancer patients treated with sunitinib and in pregnant women with PE, significant rises in endothelin-1 occur. Multiple regression analysis revealed that endothelin-1 is an independent determinant of the hypertension and proteinuria in PE, and additionally a renin suppressor. Moreover, studies in animal models representative of PE, have shown that endothelin receptor blockers prevent the development of this disease. Similarly, endothelin receptor blockers are protective during sunitinib treatment. Taken together, activation of the endothelin system emerges as an important pathway causing the clinical manifestations of PE. This paper critically addresses this concept, taking into consideration both clinical and preclinical data, and simultaneously discusses the therapeutic consequences of this observation. © The Author(s), 2016.

Response-predictive gene expression profiling of glioma progenitor cells in vitro.

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Sylvia Moeckel

Full Text Available High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist.In this study, we used serum-free short-term treated in vitro cell cultures to predict treatment response in vitro. This approach allowed us (a to enrich specimens for brain tumor initiating cells and (b to confront cells with a therapeutic agent before expression profiling.As a proof of principle we analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed to predict therapy-induced impairment of proliferation in vitro.For the tyrosine kinase inhibitor Sunitinib used in this dataset, the approach revealed additional predictive information in comparison to the evaluation of classical signaling analysis.

Treatment Of Sunitinib-Induced Hypertension In Solid Tumors By Nitric Oxid Donors

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Luís A. Leon

2015-08-01

Hypertension (HT is one of the most common adverse effects of angiogenesis inhibitors. Hypertension observed in clinical trials appears to correlate with the potency of VEGF kinase inhibitor against VEGFR-2: agents with higher potency are associated with a higher incidence of hypertension. Although the exact mechanism by TKIs induce hypertension has not yet been completely clarified, two key hypotheses have been postulated. First, some studies have pointed to a VEGF inhibitors-induced decrease in nitric oxide synthase (NOS and nitric oxide (NO production, that can result in vasoconstriction and increased blood pressure. VEGF, mediated by PI3K/Akt and MAPK pathway, upregulates the endothelial nitric oxide synthase enzyme leading to up-regulation of NO production. So inhibition of signaling through the VEGF pathway would lead to a decrease in NO production, resulting in an increase in vascular resistance and blood pressure. Secondly a decrease in the number of microvascular endothelial cells and subsequent depletion of normal microvessel density (rarefaction occurs upon VEGF signaling inhibition.

Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF).

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Lebellec, Loïc; Chauffert, Bruno; Blay, Jean-Yves; Le Cesne, Axel; Chevreau, Christine; Bompas, Emmanuelle; Bertucci, François; Cupissol, Didier; Fabbro, Michel; Saada-Bouzid, Esma; Duffaud, Florence; Feuvret, Loïc; Bonneville-Levard, Alice; Bay, Jacques-Olivier; Vauleon, Elodie; Vinceneux, Armelle; Noel, Georges; Penel, Nicolas; Mir, Olivier

2017-07-01

To assess the role of first-line Molecular Targeted Therapies (MTTs) in Advanced chordoma (AC) patients. Retrospective study of 80 patients treated between January 2004 and December 2015 at 15 major French Sarcoma or Neurooncology Centres. The sex ratio M/F was 46/34. The median age was 59 (6-86) years. The primary sites were the sacrum (50, 62.5%), mobile spine (12, 15.0%), and skull base (18, 22.5%). Metastases were present in 28 patients (36.0%). The first line of MTTs consisted of imatinib (62, 77.5%), sorafenib (11, 13.7%), erlotinib (5, 6.3%), sunitinib (1, 1.2%) and temsirolimus (1, 1.2%). The reported responses were: partial response (5, 6.3%), stable disease (58, 72.5%), or progressive disease (10, 12.5%). Symptomatic improvement was seen in 28/66 assessable patients (42.4%) and was associated with an objective response occurrence (p = 0.005), imatinib (p = 0.020) or erlotinib use (p = 0.028). The median progression-free survival (PFS) was 9.4°months (95% CI, [6.8-16.1]). Two independent factors of poor prognosis for PFS were identified: a skull-based primary location (HR = 2.5, p = 0.019), and the interval between diagnosis and MTT of guide treatment decisions and design further clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sunitinib Malate in Treating HIV-Positive Patients With Cancer Receiving Antiretroviral Therapy

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2014-03-14

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Langerhans Cell Histiocytosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Aggressive NK-cell Leukemia; AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Malignancies; AIDS-related Small Noncleaved Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV Infection; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Light Chain Deposition Disease; Mast Cell Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Osteolytic Lesions of Multiple Myeloma; Peripheral T-cell Lymphoma; Plasma Cell Neoplasm; Polycythemia Vera; Post

Síndromes autoinflamatórias hereditárias na faixa etária pediátrica Pediatric hereditary autoinflammatory syndromes

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Adriana Almeida Jesus

2010-10-01

from the PubMed and SciELO was carried out using the keywords autoinflammatory syndromes and child. SUMMARY OF THE FINDINGS: The hereditary autoinflammatory syndromes are caused by monogenic defects of innate immunity and are classified as primary immunodeficiencies. These syndromes are characterized by recurrent or persistent systemic inflammatory symptoms and must be distinguished from infectious diseases, autoimmune diseases, and other primary immunodeficiencies. This review describes the epidemiological, clinical and laboratory features, prognosis, and treatment of the main autoinflammatory syndromes, namely: familial Mediterranean fever; TNF receptor associated periodic syndrome; the cryopyrinopathies; mevalonate kinase deficiency; pediatric granulomatous arthritis; pyogenic arthritis, pyoderma gangrenosum and acne syndrome; Majeed syndrome; and deficiency of interleukin 1 receptor antagonist. The cryopyrinopathies discussed include neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic, cutaneous and articular syndrome Muckle-Wells syndrome, and familial cold autoinflammatory syndrome. CONCLUSIONS: Pediatricians must recognize the clinical features of the most prevalent autoinflammatory syndromes. Early referral to a pediatric rheumatologist may allow early diagnosis and institution of treatment, with improvement in the quality of life of these patients.

Medikamentöse Therapie des metastasierten Nierenzellkarzinoms

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Schmidinger M

2013-01-01

Full Text Available Einleitung: Zum Zeitpunkt der Diagnose eines Nierenzellkarzinoms befinden sich 60 % der Patienten in einem metastasierten Stadium. Screening-Verfahren zur Früherkennung existieren nicht. In den vergangenen 6 Jahren nach jahrzehntelanger Interferon-alpha-Therapie wurde diese Ära mit der Zulassung von neuen, zielgerichteten Therapien revolutioniert. Damit wurden das Gesamt- und das progressionsfreie Überleben dieser Erkrankung erheblich verbessert. Die palliative Nephrektomie stellt jedoch auch in dieser Ära der neuen Therapien den Goldstandard dar. Ergebnisse: In den ersten Studien wurden Patienten nach Versagen von Interferon-alpha eingeschlossen. In diesem Setting gibt es positive Daten zu Sunitinib, Sorafenib und Pazopanib. Später, nach der Zulassung der ersten Tyrosinkinaseinhibitoren, wurden die Studien als richtige Erstlinienstudien ohne Interferon-alpha-Vorbehandlung konzipiert. Die optimale Therapieabfolge sollte nach dem Risikoprofil stratifiziert werden, nämlich vorrangig nach dem so genannten „Memorial Sloan Kettering Cancer Center“- (MSKCC- Risikoscore. Abhängig davon, welcher der 3 Risikogruppen („good“, „intermediate“ oder „poor“ der Patient angehört, empfehlen die Guidelines unterschiedliche Substanzen. In der Erstlinie für „Good“- oder „Intermediate-risk“-Patienten sind Sunitinib, Bevacizumab + Interferon-alpha und Pazopanib eine Standardoption. Sie unterscheiden sich vor allem in ihrem Nebenwirkungsprofil. Daher sollten bei der Wahl der Erstlinie neben dem Risikoscore immer auch die Begleiterkrankungen mit einbezogen werden. Für so genannte „Poor-risk“-Patienten gibt es Daten zu Temsirolimus und Sunitinib. In der Zweitlinie sind Everolimus und Axitinib zur Behandlung zugelassen. Zusammenfassung: Die Behandlung des metastasierten Nierenzellkarzinoms wurde durch die Zulassung von einigen neuen, zielgerichteten Substanzen in den letzten Jahren bereichert. Die optimale Therapieabfolge zur Verbesserung des

Hypertension in Patients with Cancer

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Souza, Vinicius Barbosa de; Silva, Eduardo Nani; Ribeiro, Mario Luiz; Martins, Wolney de Andrade, E-mail: wolney@cardiol.br [Curso de Pós-Graduação em Ciências Cardiovasculares da Universidade Federal Fluminense, Niterói, RJ (Brazil)

2015-03-15

There is a known association between chemotherapy and radiotherapy for treatment of cancer patients and development or worsening of hypertension. The aim of this article is to review this association. A literature search was conducted for articles reporting this association on the databases PubMed, SciELO and LILACS between 1993 and 2013. There was a high coprevalence of hypertension and cancer, since both diseases share the same risk factors, such as sedentary lifestyle, obesity, smoking, unhealthy diet and alcohol abuse. The use of chemotherapy and adjuvant drugs effective in the treatment of cancer increased the survival rate of these patients and, consequently, increased the incidence of hypertension. We described the association between the use of angiogenesis inhibitors (bevacizumab, sorafenib and sunitinib), corticosteroids, erythropoietin and non-steroidal anti-inflammatory drugs with the development of hypertension. We also described the relationship between hypertension and carotid baroreceptor injury secondary to cervical radiotherapy. Morbidity and mortality increased in patients with cancer and hypertension without proper antihypertensive treatment. We concluded that there is need for early diagnosis, effective monitoring and treatment strategies for hypertension in cancer patients in order to reduce cardiovascular morbidity and mortality.

Hypertension in Patients with Cancer

International Nuclear Information System (INIS)

Souza, Vinicius Barbosa de; Silva, Eduardo Nani; Ribeiro, Mario Luiz; Martins, Wolney de Andrade

2015-01-01

There is a known association between chemotherapy and radiotherapy for treatment of cancer patients and development or worsening of hypertension. The aim of this article is to review this association. A literature search was conducted for articles reporting this association on the databases PubMed, SciELO and LILACS between 1993 and 2013. There was a high coprevalence of hypertension and cancer, since both diseases share the same risk factors, such as sedentary lifestyle, obesity, smoking, unhealthy diet and alcohol abuse. The use of chemotherapy and adjuvant drugs effective in the treatment of cancer increased the survival rate of these patients and, consequently, increased the incidence of hypertension. We described the association between the use of angiogenesis inhibitors (bevacizumab, sorafenib and sunitinib), corticosteroids, erythropoietin and non-steroidal anti-inflammatory drugs with the development of hypertension. We also described the relationship between hypertension and carotid baroreceptor injury secondary to cervical radiotherapy. Morbidity and mortality increased in patients with cancer and hypertension without proper antihypertensive treatment. We concluded that there is need for early diagnosis, effective monitoring and treatment strategies for hypertension in cancer patients in order to reduce cardiovascular morbidity and mortality

Facial botryomycosis-like pyoderma in an HIV-infected patient: remission after initiation of darunavir and raltegravir

Directory of Open Access Journals (Sweden)

Walter de Araujo Eyer-Silva

Full Text Available Abstract Botryomycosis is an uncommon, chronic, suppurative, bacterial infection that primarily affects the skin and subcutaneous tissues. It has long been associated with defects of cellular immunity. We report a 28-year-old woman who presented with a chronic, ulcerated lesion with draining sinuses in the right malar region. Predisposing factors were HIV infection with poor immunological control, alcoholism, and a previous trauma to the right cheek. Several courses of antimicrobial therapy provided only partial and temporary remission. Complete clinical remission was only achieved 5 years later when a novel antiretroviral regimen composed of darunavir and raltegravir was initiated.

Impact insertion of transfer-molded microneedle for localized and minimally invasive ocular drug delivery.

Science.gov (United States)

Song, Hyun Beom; Lee, Kang Ju; Seo, Il Ho; Lee, Ji Yong; Lee, Sang-Mok; Kim, Jin Hyoung; Kim, Jeong Hun; Ryu, WonHyoung

2015-07-10

It has been challenging for microneedles to deliver drugs effectively to thin tissues with little background support such as the cornea. Herein, we designed a microneedle pen system, a single microneedle with a spring-loaded microneedle applicator to provide impact insertion. To firmly attach solid microneedles with 140 μm in height at the end of macro-scale applicators, a transfer molding process was employed. The fabricated microneedle pens were then applied to mouse corneas. The microneedle pens successfully delivered rhodamine dye deep enough to reach the stromal layer of the cornea with small entry only about 1000 μm(2). When compared with syringes or 30 G needle tips, microneedle pens could achieve more localized and minimally invasive delivery without any chances of perforation. To investigate the efficacy of microneedle pens as a way of drug delivery, sunitinib malate proven to inhibit in vitro angiogenesis, was delivered to suture-induced angiogenesis model. When compared with delivery by a 30 G needle tip dipped with sunitinib malate, only delivery by microneedle pens could effectively inhibit corneal neovascularization in vivo. Microneedle pens could effectively deliver drugs to thin tissues without impairing merits of using microneedles: localized and minimally invasive delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Exploring the novel heterocyclic derivatives as lead molecules for design and development of potent anticancer agents.

Science.gov (United States)

Azad, Iqbal; Nasibullah, Malik; Khan, Tahmeena; Hassan, Firoj; Akhter, Yusuf

2018-05-01

This paper deals with in silico evaluation of newly proposed heterocyclic derivatives in search of potential anticancer activity. Best possible drug candidates have been proposed using a rational approach employing a pipeline of computational techniques namely MetaPrint2D prediction, molinspiration, cheminformatics, Osiris Data warrior, AutoDock and iGEMDOCK. Lazar toxicity prediction, AdmetSAR predictions, and targeted docking studies were also performed. 27 heterocyclic derivatives were selected for bioactivity prediction and drug likeness score on the basis of Lipinski's rule, Viber rule, Ghose filter, leadlikeness and Pan Assay Interference Compounds (PAINS) rule. Bufuralol, Sunitinib, and Doxorubicin were selected as reference standard drug for the comparison of molecular descriptors and docking. Bufuralol is a known non-selective adreno-receptor blocking agent. Studies showed that beta blockers are also used against different types of cancers. Sunitinib is well known Food and Drug administration (FDA) approved pyrrole containing tyrosine kinase inhibitor and our proposed molecules possess similarities with both drug and doxorubicin is another moiety having anticancer activity. All heterocyclic derivatives were found to obey the drug filters except standard drug Doxorubicin. Bioactivity score of the compounds was predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G protein-coupled receptor (GPCR) ligands and ion channel modulators. Absorption, distribution, metabolism and toxicity (ADMET) prediction of all proposed compound showed good Blood-brain barrier (BBB) penetration, Human intestinal absorption (HIA), Caco-2 cell permeability except compound-11 and was found to have no AdmetSAR toxicity as well as carcinogenic effect. Compounds 1-9 were slightly mutagenic while compound 2, 11, 20 and 21 showed carcinogenic effect according to Lazar toxicity prediction. Rests of the compounds were predicted to have no side effect

Longitudinal monitoring of tumor antiangiogenic therapy with near-infrared fluorophore-labeled agents targeted to integrin α{sub v}β{sub 3} and vascular endothelial growth factor

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Sun, Xianlei; Ma, Teng; Liu, Hao; Yu, Xinhe; Wu, Yue; Jia, Bing; Wang, Fan; Liu, Zhaofei [Peking University, Medical Isotopes Research Center, Beijing (China); Peking University, Department of Radiation Medicine, School of Basic Medical Sciences, Beijing (China); Shi, Jiyun; Zhao, Huiyun [Peking University, Medical Isotopes Research Center, Beijing (China); Peking University, Medical and Healthy Analytical Center, Beijing (China)

2014-07-15

Optical imaging is emerging as a powerful tool for the noninvasive imaging of the biological processes in living subjects. This study aimed to investigate whether optical imaging of integrin α{sub v}β{sub 3} and vascular endothelial growth factor (VEGF) expression can serve as sensitive biomarkers for tumor early response to antiangiogenic therapy. We synthesized two near-infrared fluorescence (NIRF) imaging agents, CF680R-3PRGD2 and CF750-BevF(ab'){sub 2}, which were designed to specifically bind to integrin α{sub v}β{sub 3} and VEGF, respectively. The ability of optical imaging using the two imaging agents for early monitoring the antiangiogenic effect of sunitinib was evaluated. CF680R-3PRGD2 and CF750-BevF(ab'){sub 2} specifically bound to their respective targets in vitro and in HT-29 tumor-bearing nude mice. Sunitinib treatment led to significantly decreased tumor uptake of CF680R-3PRGD2 (e.g., 7.47 ± 1.62 % vs. 4.24 ± 0.16 % on day 4; P < 0.05) and CF750-BevF(ab'){sub 2} (e.g., 7.43 ± 2.43 % vs. 4.04 ± 1.39 % on day 2; P < 0.05) in vivo. Immunofluorescence staining and an enzyme-linked immunosorbent assay confirmed that sunitinib-induced changes in tumor uptake of CF680R-3PRGD2 and CF750-BevF(ab'){sub 2} were correlated with changes in the levels of integrin α{sub v}β{sub 3} and VEGF. Radiobiodistribution of {sup 99m}Tc-3PRGD2 and {sup 125}I-BevF(ab'){sub 2}, the radiocounterparts of CF680R-3PRGD2 and CF750-BevF(ab'){sub 2}, respectively, also validated optical imaging results. Longitudinal monitoring of tumor integrin α{sub v}β{sub 3} and VEGF expression could be used as early biomarkers for tumor response to antiangiogenic therapy. This strategy may facilitate the development of new antiangiogenic drugs, and be used for elucidation of the underlying mechanisms of therapies involving the integrin and the VEGF signaling pathway. (orig.)

Identification of mast cells in buffy coat preparations from dogs with inflammatory skin diseases.

Science.gov (United States)

Cayatte, S M; McManus, P M; Miller, W H; Scott, D W

1995-02-01

In 100 dogs with 4 inflammatory dermatologic diseases, buffy coat preparations from EDTA-treated blood samples were examined cytologically. Fifty-four dogs had atopy, 26 had flea-bite hypersensitivity, 17 had sarcoptic mange, and 3 had food allergy. Twenty-eight dogs had 2 or more concurrent skin diseases; most of these had secondary pyoderma. Dogs did not have mast cell tumors. Thirteen samples contained 1 or more mast cells/4 slides reviewed. This study revealed that dogs with inflammatory skin diseases can have a few to many mast cells evident on cytologic examination of buffy coat preparations.

Variation in use of targeted therapies for metastatic renal cell carcinoma: Results from a Dutch population-based registry

International Nuclear Information System (INIS)

De Groot, S.; Sleijfer, S.; Redekop, W. K.; Oosterwijk, E.; Haanen, J. B. A. G.; Kiemeney, L. A. L. M.; Uyl-de Groot, C. A.

2016-01-01

For patients with metastatic renal cell carcinoma (mRCC), targeted therapies have entered the market since 2006. The aims of this study were to evaluate the uptake and use of targeted therapies for mRCC in The Netherlands, examine factors associated with the prescription of targeted therapies in daily clinical practice and study their effectiveness in terms of overall survival (OS). Two cohorts from PERCEPTION, a population-based registry of mRCC patients, were used: a 2008–2010 Cohort (n = 645) and a 2011–2013 Cohort (n = 233). Chi-squared tests for trend were used to study time trends in the use of targeted therapy. Patients were grouped based on the eligibility criteria of the SUTENT trial, the trial that led to sunitinib becoming standard of care, to investigate the use of targeted therapies amongst patients fulfilling those criteria. Multi-level logistic regression was used to identify patient subgroups that are less likely to receive targeted therapies. Approximately one-third of patients fulfilling SUTENT trial eligibility criteria did not receive any targeted therapy (29 % in the 2008–2010 Cohort; 35 % in the 2011–2013 Cohort). Patients aged 65+ years were less likely to receive targeted therapy in both cohorts and different risk groups (odds ratios range between 0.84–0.92); other factors like number of metastatic sites were of influence in some subgroups. Amongst treated patients, there was a decreasing trend in sunitinib use over time (p = 0.0061), and an increasing trend in pazopanib use (p = 0.0005). Targeted therapies have largely replaced interferon-alfa as first-line standard of care. Nevertheless, many eligible patients in Dutch daily practice did not receive targeted therapies despite their ability to improve survival. Reasons for their apparent underutilisation should be examined more carefully. The online version of this article (doi:10.1186/s12885-016-2395-x) contains supplementary material, which is available to authorized users

Analyses of Potential Predictive Markers and Response to Targeted Therapy in Patients with Advanced Clear-cell Renal Cell Carcinoma

Directory of Open Access Journals (Sweden)

Yan Song

2015-01-01

Full Text Available Background: Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC, but biomarkers of activity are lacking. The aim of this study was to investigate the association of Von Hippel-Lindau (VHL gene status, vascular endothelial growth factor receptor (VEGFR or stem cell factor receptor (KIT expression, and their relationships with characteristics and clinical outcome of advanced ccRCC. Methods: A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute, Chinese Academy of Medical Sciences between January 2010 and November 2012. Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry. Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS and overall survival (OS were calculated and then compared based on expression status. The Chi-square test, the Kaplan-Meier method, and the Lon-rank test were used for statistical analyses. Results: Of 59 patients, objective responses were observed in 28 patients (47.5%. The median PFS was 13.8 months and median OS was 39.9 months. There was an improved PFS in patients with the following clinical features: Male gender, number of metastatic sites 2 or less, VEGFR-2 positive or KIT positive. Eleven patients (18.6% had evidence of VHL mutation, with an objective response rate of 45.5%, which showed no difference with patients with no VHL mutation (47.9%. VHL mutation status did not correlate with either overall response rate (P = 0.938 or PFS (P = 0.277. The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients, respectively, which was significantly longer than that of VEGFR-2 or KIT negative patients (P = 0.026 and P = 0.043. Conclusion

The safety of regorafenib for the treatment of gastrointestinal stromal tumors.

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Rutkowski, Piotr; Stępniak, Joanna

2016-01-01

The management of gastrointestinal stromal tumors (GIST) evolved due to effective molecularly targeted therapy with imatinib and sunitinib which are used first- and second-line, respectively. However, due to the development of resistance to those drugs in the majority of patients, the need for third-line therapy arose. Regorafenib, an oral multitargeted inhibitor with activity against multiple kinases including KIT, RET, RAF1, BRAF, angiogenesis (VEGFR, TIE-2) and those involved in tumor microenvironment (PDGFR and FGFR) was introduced after the successful Phase III GRID (GIST - Regorafenib In progressive Disease) clinical trial. This study showed significant improvement in progression-free survival for patients receiving regorafenib compared to placebo (4.8 months vs 0.9 months). The treatment was reasonably well tolerated, with arterial hypertension, hand-foot syndrome, diarrhea being the most common grade ≥3 adverse events, which could be managed by dose reduction and supportive treatment. The aim of this paper is to describe, assess and advise on the safety of regorafenib as third-line therapy in GIST. Regorafenib has demonstrated clinical benefit in GIST patients after progression on prior treatment with at least imatinib/sunitinib and currently it is the approved standard third-line option in therapy of advanced GIST. The safety profile is similar to other multikinase inhibitors with anti-VEGFR activity and is manageable.

Ultrasound assisted dispersive micro solid-phase extraction of four tyrosine kinase inhibitors from serum and cerebrospinal fluid by using magnetic nanoparticles coated with nickel-doped silica as an adsorbent

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Ghazaghi, Mehri; Mousavi, Hassan Zavvar; Shirkhanloo, Hamid; Rashidi, Alimorad

2016-01-01

Nanoparticles (NPs) consisting of a magnetic Fe 3 O 4 core and a nickel(II)-doped silica shell were prepared and are shown to be viable materials for selective magnetic extraction of trace quantities of the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, erlotinib and sunitinib. The NPs were characterized by scanning electron microscopy, transmission electron microscopy, DLS and XRD analysis, and the results revealed a uniform in size (with a typical diameter of 40 nm) and a core-shell structure. The magnetic nanoadsorbent displays good affinity of the TKIs, probably because of the affinity between the Ni(II) ions of the NPs with the nitrogen atoms in the TKIs. The magnetism of the NPs enables them to be quickly separated from serum and cerebrospinal fluid samples. Imidazole, with its higher affinity for Ni(II) than that of the TKIs, was used for desorption of the TKIs from the NPs prior to their quantification by HPLC with UV detection. The detection limits are as low as 200, 480, 130, and 250 ng·L -1 for imatinib, sunitinib, erlotinib, and nilotinib, respectively. The intra-day precisions (RSDs) were lower than 4.0 %. The method displays a wide linear range. It was applied to the determination of TKIs in (spiked) human serum and cerebrospinal fluid and gave recoveries in the range from 94.6 to 98.6 %. (author)

Severe paraneoplastic hypereosinophilia in metastatic renal cell carcinoma

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Todenhöfer Tilman

2012-03-01

Full Text Available Abstract Background Renal cell carcinoma can cause various paraneoplastic syndromes including metabolic and hematologic disturbances. Paraneoplastic hypereosinophilia has been reported in a variety of hematologic and solid tumors. We present the first case in the literature of severe paraneoplastic hypereosinophilia in a patient with renal cell carcinoma. Case presentation A 46 year-old patient patient with a history of significant weight loss, reduced general state of health and coughing underwent radical nephrectomy for metastasized renal cell carcinoma. Three weeks after surgery, the patient presented with excessive peripheral hypereosinophilia leading to profound neurological symptoms due to cerebral microinfarction. Systemic treatment with prednisolone, hydroxyurea, vincristine, cytarabine, temsirolimus and sunitinib led to reduction of peripheral eosinophils but could not prevent rapid disease progression of the patient. At time of severe leukocytosis, a considerable increase of cytokines associated with hypereosinophilia was measurable. Conclusions Paraneoplastic hypereosinophilia in patients with renal cell carcinoma might indicate poor prognosis and rapid disease progression. Myelosuppressive therapy is required in symptomatic patients.

Antimicrobial susceptibility of methicillin-resistant Staphylococcus pseudintermedius isolated from veterinary clinical cases in the UK.

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Maluping, R P; Paul, N C; Moodley, A

2014-01-01

Staphylococcus pseudintermedius is a leading aetiologic agent of pyoderma and other body tissue infections in dogs and cats. In recent years, an increased prevalence of methicillin-resistant S. pseudintermedius (MRSP) has been reported. Isolation of MRSP in serious infections poses a major therapeutic challenge as strains are often resistant to all forms of systemic antibiotic used to treat S. pseudintermedius -related infections. This study investigates the occurrence of MRSP from a total of 7183 clinical samples submitted to the authors' laboratories over a 15-month period. Identification was based on standard microbiological identification methods, and by S. pseudintermedius-specific nuc polymerase chain reaction (PCR). Methicillin resistance was confirmed by PBP2a latex agglutination and mecA PCR. Susceptibility against non-beta-lactam antibiotics was carried out using a disc-diffusion method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. In addition, susceptibility to pradofloxacin--a new veterinary fluoroquinolone--was also investigated. SCCmec types were determined by multiplex PCR. Staphylococcus pseudintermedius was isolated from 391 (5%) samples and 20 were confirmed as MRSP from cases of pyoderma, otitis, wound infections, urinary tract infection and mastitis in dogs only. All 20 isolates were resistant to clindamycin and sulphamethoxazole/trimethoprim. Nineteen were resistant to chloramphenicol, enrofloxacin, gentamicin, marbofloxacin and pradofloxacin; additionally, seven isolates were resistant to tetracycline. Fifteen isolates carried SCCmec type II-III, four isolates had type V and one harboured type IV. To date, only a few scientific papers on clinical MRSP strains isolated from the UK have been published, thus the results from this study would provide additional baseline data for further investigations.

Dynamic Contrast-Enhanced Computed Tomography-Derived Blood Volume and Blood Flow Correlate With Patient Outcome in Metastatic Renal Cell Carcinoma.

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Mains, Jill Rachel; Donskov, Frede; Pedersen, Erik Morre; Madsen, Hans Henrik Torp; Rasmussen, Finn

2017-02-01

The aim was to explore the potential for using dynamic contrast-enhanced computed tomography as a noninvasive functional imaging biomarker before and during the early treatment of metastatic renal cell carcinoma (mRCC). Dynamic contrast-enhanced computed tomography scans were performed at baseline and after 5 and 10 weeks' treatment in 69 prospectively included mRCC patients receiving treatment with interferon alpha and interleukin 2 (n = 26); interferon alpha, interleukin 2, and bevacizumab (n = 24); sunitinib (n = 7); pazopanib (n = 5); or temsirolimus (n = 7). Using a prototype software program (Advanced Perfusion and Permeability Application, Philips Healthcare, Best, the Netherlands), blood volume (BV), blood flow (BF), and permeability surface area product (PS) were calculated for each tumor at baseline, week 5, and week 10. These parameters as well as relative changes between baseline and weeks 5 and 10 were tested for associations with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. Using the 25th percentile as the cutoff, baseline BV for all patients independent of subsequent treatment was statistically significantly associated with PFS (10.8 vs 5.3 months, P = 0.007) and OS (35.2 vs 13.3 months, P = 0.001), and baseline BF was significantly associated with OS (31.7 vs 14.6 months, P = 0.024) with high values for both parameters being associated with significantly longer PFS and OS. Baseline PS was not associated with PFS or OS.In patients treated with angiogenesis inhibitors (bevacizumab, sunitinib, pazopanib, or temsirolimus), the relative change in BV from baseline to week 5 using 25th percentile as the cutoff was associated with PFS (5.6 vs 24.8 months, P = 0.001) and OS (19.1 months vs not reached, P = 0.008) and from baseline to week 10 with PFS (8.1 vs 16.4 months, P = 0.014) and OS (15.5 months vs not reached, P = 0.002). The relative change in BF from baseline to week 5 using medians as the

Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors

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Dabora Sandra L

2010-02-01

Full Text Available Abstract Background Tuberous Sclerosis Complex (TSC is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC. Methods In cohorts of Tsc2+/- mice, we compared kidney cystadenoma severity in A/J and C57BL/6 mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A/J Tsc2+/- mice. In addition, we used nude mice bearing Tsc2-/- subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizumab, vincristine, and asparaginase. Results TSC related kidney disease severity is 5-10 fold higher in A/J Tsc2+/- mice compared with C57BL/6 Tsc2+/- mice. Similar to kidney angiomyolipomas associated with TSC, the severity of kidney cystadenomas increases with age in A/J Tsc2+/- mice. When rapamycin dosing schedules were compared in A/J Tsc2+/- cohorts, we observed a 66% reduction in kidney tumor burden in mice treated daily for 4 weeks, an 82% reduction in mice treated daily for 4 weeks followed by weekly for 8 weeks, and an 81% reduction in mice treated weekly for 12 weeks. In the Tsc2-/- subcutaneous tumor mouse model, vincristine is not effective, but angiogenesis inhibitors (sunitinib and bevacizumab and asparaginase are effective as single agents. However, these drugs are not as effective as rapamycin in that they increased median survival only by 24-27%, while rapamycin increased median survival by 173%. Conclusions Our results indicate that the A/J Tsc2+/- mouse model is an improved, higher through-put mouse model for future TSC

HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients.

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Wang, Jiajun; Liu, Li; Qu, Yang; Xi, Wei; Xia, Yu; Bai, Qi; Xiong, Ying; Long, Qilai; Xu, Jiejie; Guo, Jianming

2018-01-01

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients. A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort. In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

A case of treatment in a patient with synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands: Clinical observation

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V. R. Latypov

2014-11-01

Full Text Available Synchronous bilateral renal cell carcinoma occurs in 1.4 % of cases. The probability of bilateral adrenal metastases from renal cell carcinoma is less than 0.5 %. The clinical observation presents a case of synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands. A 55‑year-old male patient was adm tted with the signs of hematuria and anemia to the Unit of Urology, Clinic of General Surgery, Siberian State Medical University. He was found to have synchronous bilateral renal cell carcinoma and simultaneous bilateral adrenal involvement. Sequential surgical treatment – radical nephrectomy (with adrenal gland removal on the right side and, after 3 months, adrenalectomy and kidney resection on the left side were performed. All the organs removed displayed tumors that proved to be renal cell carcinomas (a clear cell variant. There were lymph node metastases in the right-sided renal portal. Postoperatively, the investigators performed hormone replacement therapy for adrenal insufficiency, an immunotherapy cycle, three cycles of targeted therapy withsorafenib and sunitinib (at an interval of 0.5–2 years, and insulin therapy for new-onset diabetes mellitus. The duration of a follow-up was 6.2 years. When describing the case, the patient was alive and showed a generalized tumorous process with extensive tumor involvement of the solitary kidney. Sunitinib therapy was used.

A case of treatment in a patient with synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands: Clinical observation

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V. R. Latypov

2014-01-01

Full Text Available Synchronous bilateral renal cell carcinoma occurs in 1.4 % of cases. The probability of bilateral adrenal metastases from renal cell carcinoma is less than 0.5 %. The clinical observation presents a case of synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands. A 55‑year-old male patient was adm tted with the signs of hematuria and anemia to the Unit of Urology, Clinic of General Surgery, Siberian State Medical University. He was found to have synchronous bilateral renal cell carcinoma and simultaneous bilateral adrenal involvement. Sequential surgical treatment – radical nephrectomy (with adrenal gland removal on the right side and, after 3 months, adrenalectomy and kidney resection on the left side were performed. All the organs removed displayed tumors that proved to be renal cell carcinomas (a clear cell variant. There were lymph node metastases in the right-sided renal portal. Postoperatively, the investigators performed hormone replacement therapy for adrenal insufficiency, an immunotherapy cycle, three cycles of targeted therapy withsorafenib and sunitinib (at an interval of 0.5–2 years, and insulin therapy for new-onset diabetes mellitus. The duration of a follow-up was 6.2 years. When describing the case, the patient was alive and showed a generalized tumorous process with extensive tumor involvement of the solitary kidney. Sunitinib therapy was used.

Molecular Imaging to Predict Response to Targeted Therapies in Renal Cell Carcinoma

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Ingrid Leguerney

2017-01-01

Full Text Available Molecular magnetic resonance imaging targeted to an endothelial integrin involved in neoangiogenesis was compared to DCE-US and immunochemistry to assess the early response of three different therapeutic agents in renal cell carcinoma. Human A498 renal cells carcinoma was subcutaneously inoculated into 24 nude mice. Mice received either phosphate-buffered saline solution, sunitinib, everolimus, or bevacizumab during 4 days. DCE-US and molecular MRI targeting αvβ3 were performed at baseline and 4 days after treatment initiation. PI, AUC, relaxation rate variations ΔR2⁎, and percentage of vessels area quantified on CD31-stained microvessels were compared. Significant decreases were observed for PI and AUC parameters measured by DCE-US for bevacizumab group as early as 4 days, whereas molecular αvβ3-targeted MRI was able to detect significant changes in both bevacizumab and everolimus groups. Percentage of CD31-stained microvessels was significantly correlated with DCE-US parameters, PI (R=0.87, p=0.0003 and AUC (R=0.81, p=0.0013. The percentage of vessel tissue area was significantly reduced (p<0.01 in both sunitinib and bevacizumab groups. We report an early detection of neoangiogenesis modification after induction of targeted therapies, using DCE-US or αvβ3-targeted MRI. We consider these outcomes should encourage clinical trial developments to further evaluate the potential of this molecular MRI technique.

Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight.

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Purohit, Rituraj

2014-01-01

KIT receptor is the prime target in gastrointestinal stromal tumor (GISTs) therapy. Second generation inhibitor, Sunitinib, binds to an inactivated conformation of KIT receptor and stabilizes it in order to prevent tumor formation. Here, we investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805-850) by conducting molecular dynamics simulation (∼100 ns). We analyzed different properties such as root mean square cutoff or deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, hydrogen bonding network analysis, and essential dynamics. Apart from this, clustering and cross-correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of KIT receptor. Molecular dynamics analysis indicated that mutation (D816H) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region. Moreover, flexible secondary elements, specially, coil and turns were dominated in EAL region of mutant KIT receptor during simulation. This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation. Our atomic investigation of mutant KIT receptor which emphasized on EAL region provided a better insight into the understanding of Sunitinib resistance mechanism of KIT receptor and would help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.

Determination of staphylococcal exotoxins, SCCmec types, and genetic relatedness of Staphylococcus intermedius group isolates from veterinary staff, companion animals, and hospital environments in Korea

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Youn, Jung-Ho; Ahn, Kuk Ju; Lim, Suk-Kyung

2011-01-01

The Staphylococcus (S.) intermedius group (SIG) has been a main research subject in recent years. S. pseudintermedius causes pyoderma and otitis in companion animals as well as foodborne diseases. To prevent SIG-associated infection and disease outbreaks, identification of both staphylococcal exotoxins and staphylococcal cassette chromosome mec (SCCmec) types among SIG isolates may be helpful. In this study, it was found that a single isolate (one out of 178 SIG isolates examined) harbored the canine enterotoxin SEC gene. However, the S. intermedius exfoliative toxin gene was found in 166 SIG isolates although the S. aureus-derived exfoliative toxin genes, such as eta, etb and etd, were not detected. SCCmec typing resulted in classifying one isolate as SCCmec type IV, 41 isolates as type V (including three S. intermedius isolates), and 10 isolates as non-classifiable. Genetic relatedness of all S. pseudintermedius isolates recovered from veterinary staff, companion animals, and hospital environments was determined by pulsed-field gel electrophoresis. Strains having the same band patterns were detected in S. pseudintermedius isolates collected at 13 and 18 months, suggesting possible colonization and/or expansion of a specific S. pseudintermedius strain in a veterinary hospital. PMID:21897094

Dermatological consequences of the Cs-137 radiological accident in Goiania, Goias State, Brazil; Repercussoes dermatologicas no acidente radioativo com o Cesio 137 em Goiania

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Castro, Lia Candida Miranda de

1996-07-01

The objective of the present study was to analyse the occurrence of dermatosis in individuals that had been exposed to cesium{sup 137} during the radioactive accident in Goiania, in 1987 and detect pre-cancerous dermatosis or those predictive of low immunity. The groups were evaluated according to the intensity of radiation they had been exposed to and then compared to a control group of people not exposed to radiation. The population exposed to the cesium{sup 137} was comprised of 109 people, who were divided into Groups I and II, according to the CNEN norms. In group I, 54 people with {<=} 20 rads exposure and/or radio lesion were included; in group II, 55 people with > 20 rads exposure were included, along with the children of group I individuals. This was a historic cohort study, that is, a retrospective study that lasted 9 years, extending from September of 1987 to August, 1996. The presence of the oncoprotein p-53 was studied in the radio lesions of 10 patients. There is no evidence of an increase in the incidence of dermatosis in the exposed groups, excepts for pyoderma in patients with radio lesions. The most frequent dermatosis were: pyoderma, pityriasis versicolor, scabies, dermatophytosis and seborrhoeic dermatitis. The results obtained were not statistically significant for the evaluation of dermatosis predictive of low immunity or precancerous lesions. The oncoprotein p-53 in individuals with radio lesion showed a 80% positivity rate and risk factor estimated in 8 times, for the test. It has proved to be useful because it represents one more option in terms of propaedeutic evaluation and suggests that one should pay close and continuous attention in order to better control the evolution of these individuals. (author)

Dermatological consequences of the Cs-137 radiological accident in Goiania, Goias State, Brazil

International Nuclear Information System (INIS)

Castro, Lia Candida Miranda de

1996-01-01

The objective of the present study was to analyse the occurrence of dermatosis in individuals that had been exposed to cesium 137 during the radioactive accident in Goiania, in 1987 and detect pre-cancerous dermatosis or those predictive of low immunity. The groups were evaluated according to the intensity of radiation they had been exposed to and then compared to a control group of people not exposed to radiation. The population exposed to the cesium 137 was comprised of 109 people, who were divided into Groups I and II, according to the CNEN norms. In group I, 54 people with ≤ 20 rads exposure and/or radio lesion were included; in group II, 55 people with > 20 rads exposure were included, along with the children of group I individuals. This was a historic cohort study, that is, a retrospective study that lasted 9 years, extending from September of 1987 to August, 1996. The presence of the oncoprotein p-53 was studied in the radio lesions of 10 patients. There is no evidence of an increase in the incidence of dermatosis in the exposed groups, excepts for pyoderma in patients with radio lesions. The most frequent dermatosis were: pyoderma, pityriasis versicolor, scabies, dermatophytosis and seborrhoeic dermatitis. The results obtained were not statistically significant for the evaluation of dermatosis predictive of low immunity or precancerous lesions. The oncoprotein p-53 in individuals with radio lesion showed a 80% positivity rate and risk factor estimated in 8 times, for the test. It has proved to be useful because it represents one more option in terms of propaedeutic evaluation and suggests that one should pay close and continuous attention in order to better control the evolution of these individuals. (author)

Innovative Therapeutic Strategies in the Treatment of Brain Metastases

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Francesco Tomasello

2013-01-01

Full Text Available Brain metastases (BM are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature.

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Massey, Paul R; Okman, Jonathan S; Wilkerson, Julia; Cowen, Edward W

2015-06-01

Inhibition of the vascular endothelial growth factor receptor (VEGFR) with tyrosine kinase inhibitors (TKIs) is associated with cutaneous adverse effects that increase patient morbidity. Our objective was to examine the skin toxicity profile of anti-VEGFR TKIs and determine the changing incidence in clinical trials. PubMed was queried for phase II or III trials of anti-VEGFR TKIs between 2000 and 2013 involving ≥50 patients. Adverse events were abstracted, with results presented in both fixed and random effects models. Odds ratios (OR) and 95 % confidence intervals (CIs) were estimated for studies with at least two arms. Across 82 included studies, all grades rash (OR, 2.68; 95 % CI, 2.45-2.94), hand-foot skin reaction (HFSR) (OR, 2.70; 95 % CI, 2.43-3.00), and pruritus (OR, 1.25; 95 % CI, 1.12-1.39) were associated with anti-VEGFR TKIs. Vandetanib had the highest incidence of rash (41 %), while sorafenib was most commonly associated with HFSR (37 %) and pruritus (14 %). The incidence of HFSR from 2000 to 2013 showed an upward trend (r (2) = 0.042, p = 0.10) and in sunitinib therapy increased significantly (r (2) = 0.237, p = 0.04). The incidence of HFSR, rash, and pruritus varies considerably by drug. Our data suggest a continued need to address skin toxicities and improve reporting strategies.

Piodermite profunda por Staphylococcus intermedius em eqüino Deep pyoderma by Staphylococcus intermedius in equine

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Fábio Cordeiro Oliveira Santos

2008-12-01

Full Text Available Neste trabalho descreve-se um caso de piodermite, com tempo de evolução de um mês, de um eqüino de oito anos de idade, sem raça definida, com áreas alopécicas, crostas na pálpebra superior, nos membros torácicos e pélvicos, na região do prepúcio e, principalmente, na região do pescoço e escápula. O prurido era discreto. O exame histopatológico revelou dermatite piogranulomatosa perivascular e perianexial associada à hiperplasia epidérmica, além de orto e paraceratose e crostas. O epitélio folicular exibiu focos de espongiose e exocitose de neutrófilos, predominando aspectos de inflamação crônica. A cultura bacteriana identificou o Staphylococcus intermedius a partir das suas características morfo-tintoriais e bioquímicas, com resultados positivos aos testes de catalase, coagulase, glicose e produção ácida aeróbica a partir do manitol. O eqüino foi tratado diariamente com dimetilsulfóxido, gentamicina e dexametasona por via tópica. Mesmo que algumas das lesões apresentaram rápida regressão (sete dias, as localizadas na região do pescoço e escápula demoraram 13 meses para a completa cicatrização.A case of one month of evolution, of an 8-year-old equine of undefined breed, presenting alopecic areas, crusts on the upper eyelid, forelimbs, hindlimbs, preputial region and mainly, on the neck and scapula is reported. Pruritus was discrete. The histological analysis revealed pyogranulomatous dermatitis round blood vessels and adnexa, associated with epidermal hyperplasia, as well as orthokeratosis, parakeratosis and crusts. The follicular epithelium exhibited foci of spongiosis and exocytosis of neutrophils, with predominant chronic inflammation changes. Bacterial culture identified Staphylococcus intermedius, based on morphology, staining and biochemical tests positive for catalase, coagulase, glucose and aerobic acid production from mannitol. The equine was treated with dimethylsulfoxide, gentamicine and

Metastatic renal cell carcinoma management

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Flavio L. Heldwein

2009-06-01

Full Text Available PURPOSE: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. MATERIAL AND METHODS: The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. RESULTS: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. CONCLUSIONS: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

Patients with advanced and metastatic renal cell carcinoma treated with targeted therapy in the Czech Republic: twenty cancer centres, six agents, one database.

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Poprach, Alexandr; Bortlíček, Zbyněk; Büchler, Tomáš; Melichar, Bohuslav; Lakomý, Radek; Vyzula, Rostislav; Brabec, Petr; Svoboda, Marek; Dušek, Ladislav; Gregor, Jakub

2012-12-01

The incidence and mortality of renal cell carcinoma (RCC) in the Czech Republic are among the highest in the world. Several targeted agents have been recently approved for the treatment of advanced/metastatic RCC. Presentation of a national clinical database for monitoring and assessment of patients with advanced/metastatic RCC treated with targeted therapy. The RenIS (RENal Information System, http://renis.registry.cz ) registry is a non-interventional post-registration database of epidemiological and clinical data of patients with RCC treated with targeted therapies in the Czech Republic. Twenty cancer centres eligible for targeted therapy administration participate in the project. As of November 2011, six agents were approved and reimbursed from public health insurance, including bevacizumab, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus. As of 10 October 2011, 1,541 patients with valid records were entered into the database. Comparison with population-based data from the Czech National Cancer Registry revealed that RCC patients treated with targeted therapy are significantly younger (median age at diagnosis 59 vs. 66 years). Most RenIS registry patients were treated with sorafenib and sunitinib, many patients sequentially with both agents. Over 10 % of patients were also treated with everolimus in the second or third line. Progression-free survival times achieved were comparable to phase III clinical trials. The RenIS registry has become an important tool and source of information for the management of cancer care and clinical practice, providing comprehensive data on monitoring and assessment of RCC targeted therapy on a national level.

Aspects of surgical treatment for gastro-intestinal stromal tumors; Chirurgische Therapieaspekte gastrointestinaler Stromatumoren

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Hohenberger, P. [Medizinische Fakultaet Mannheim, Universitaet Heidelberg, Sektion Chirurgische Onkologie und Thoraxchirurgie, Chirurgische Universitaetsklinik, Mannheim (Germany)

2009-12-15

Gastro-intestinal stromal tumors (GIST) form the commonest subgroup of soft tissue sarcomas. They arise in the muscular layer of the esophagus, stomach, small intestines and rectum. Characteristic and important for the assessment of the extent of tumors is the peripheral rim vascularization of primary tumors and metastases. Indications for resection are given for tumors larger than 2 cm in size. Locally advanced GISTs can be advantageously treated with imatinib/sunitinib as neoadjuvant and it is often possible to select a low level of resection for this size of tumor and when the rim area is not hypervascularized. Even in the metastizing stage surgical treatment can be used for elimination of resistant metastases or for removal of residual tumor tissue in an attempt to counteract secondary tumor progression. The effect of this treatment is currently being tested in a randomized phase III study. (orig.) [German] Gastrointestinale Stromatumoren (GIST) stellen die haeufigste Subgruppe von Weichgewebesarkomen dar. Sie entstehen in der Muskularisschicht von Oesophagus, Magen, Duenndarm und Rektum. Charakteristisch und wichtig fuer die Einschaetzung des Tumorausmasses ist die Randvaskularisation von Primaertumoren und Metastasen. Die Indikation zur Resektion gilt fuer Tumoren ab 2 cm Groesse. Lokal fortgeschrittene GIST koennen sehr vorteilhaft mit Imatinib/Sunitinib neoadjuvant vorbehandelt werden, und es ist oft moeglich, bei der Tumorgroesse und wenn keine hypervaskularisierten Randbereiche vorliegen, ein geringeres Resektionsausmass zu waehlen. Auch im metastasierten Stadium hat die chirurgische Therapie einen Platz zur Eliminierung resistenter Metastasen bzw. zur Entfernung von Residualtumorgewebe als Versuch, einer sekundaeren Tumorprogression zu begegnen. Dieser Behandlungseffekt wird derzeit in einer randomisierten Phase-III-Studie ueberprueft. (orig.)

Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

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Helen B. Stone

2016-02-01

Full Text Available BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY, thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials.

Testicular Metastasis from Renal Cell Carcinoma: A Case Report and Review of the Literature

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Keren Rouvinov

2017-04-01

Full Text Available Testicular metastases from renal cell carcinoma (RCC are extremely rare. To the best of our knowledge, only 33 cases have been described in the literature. Most of the reported cases are of unilateral testicular metastasis from RCC. We report a case of metachronous ipsilateral testicular metastasis from RCC in a 78-year-old man 6 years after nephrectomy. Scrotal ultrasonography showed a 4 × 5 cm mass in the right testis. Right inguinal orchiectomy was performed for diagnosis. Computed tomography revealed liver and lung metastases. First-line therapy with sunitinib was started in November 2016 for metastatic RCC.

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP 4 and breast cancer resistance protein (BCRP

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Rhiannon N. Hardwick

2016-12-01

Full Text Available Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI and aurora (AKI kinase inhibitors are anti-cancer agents specifically designed to target such signaling pathways through TKI/AKI binding to the ATP-binding pocket of kinases thereby leading to diminished kinase activity. Some TKIs have been identified as inhibitors of ATP-binding cassette (ABC transporters such as P-glycoprotein and breast cancer resistance protein (BCRP, which are commonly upregulated in malignant cells. TKI/AKIs have been investigated as ABC transporter inhibitors in order to facilitate the accumulation of concomitantly administered chemo-therapeutics within cancer cells. However, ABC transporters are prominently expressed in the liver and other eliminating organs, and their inhibition has been linked to intracellular accumulation of drugs, altered disposition, and toxicity. The potential for TKIs/AKIs to inhibit other important hepatic efflux transporters, particularly multidrug resistance-associated proteins (MRPs, remains unknown. The aim of the current study was to compare the inhibitory potency of 20 selected TKI/AKIs against MRP4 and BCRP through the use of inverted membrane vesicle assays. Relative IC50 values were estimated by determining TKI/AKI inhibition of MRP4-mediated [3H]-dehydroepiandrosterone sulfate uptake and BCRP-mediated [3H]-estrone sulfate uptake. To provide insight to the clinical relevance of TKI/AKI inhibition of ABC efflux transporters, the ratio of the steady-state maximum total plasma concentration (Css to the IC50 for each compound was calculated with Css/IC50 ratio >0.1 deemed potentially clinically relevant. Such analysis identified several potentially clinically relevant inhibitors of MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of

Transient thrombocytosis with megathrombocytes in a case of acute myeloblastic leukemia

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Kotru Mrinalini

2009-01-01

Full Text Available Thrombocytosis is commonly seen in reactive conditions and certain neoplastic states, such as chronic myeloproliferative disorders. It is rarely seen in acute leukemia. A 12-year-old girl with acute myeloblastic leukemia (FAB M2 in remission presented with pyoderma. Her hemogram revealed anemia (Hb-6.4g/dl, leucopenia (TLC - 1.2 x 109/L and thrombocytosis (platelet count- 580 x 109/L. A peripheral blood film showed numerous abnormally large platelets with few atypical cells. The thrombocytosis subsided with the clearance of infection but atypical cells persisted. One month later, she relapsed. Cytogenetic analysis revealed variable results (trisomy 9 and deletion 3. This case has been presented because thrombocytosis is rare in AML and its appearance calls for a close follow-up.

Differential inhibition of ex-vivo tumor kinase activity by vemurafenib in BRAF(V600E and BRAF wild-type metastatic malignant melanoma.

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Andliena Tahiri

Full Text Available Treatment of metastatic malignant melanoma patients harboring BRAF(V600E has improved drastically after the discovery of the BRAF inhibitor, vemurafenib. However, drug resistance is a recurring problem, and prognoses are still very bad for patients harboring BRAF wild-type. Better markers for targeted therapy are therefore urgently needed.In this study, we assessed the individual kinase activity profiles in 26 tumor samples obtained from patients with metastatic malignant melanoma using peptide arrays with 144 kinase substrates. In addition, we studied the overall ex-vivo inhibitory effects of vemurafenib and sunitinib on kinase activity status.Overall kinase activity was significantly higher in lysates from melanoma tumors compared to normal skin tissue. Furthermore, ex-vivo incubation with both vemurafenib and sunitinib caused significant decrease in phosphorylation of kinase substrates, i.e kinase activity. While basal phosphorylation profiles were similar in BRAF wild-type and BRAF(V600E tumors, analysis with ex-vivo vemurafenib treatment identified a subset of 40 kinase substrates showing stronger inhibition in BRAF(V600E tumor lysates, distinguishing the BRAF wild-type and BRAF(V600E tumors. Interestingly, a few BRAF wild-type tumors showed inhibition profiles similar to BRAF(V600E tumors. The kinase inhibitory effect of vemurafenib was subsequently analyzed in cell lines harboring different BRAF mutational status with various vemurafenib sensitivity in-vitro.Our findings suggest that multiplex kinase substrate array analysis give valuable information about overall tumor kinase activity. Furthermore, intra-assay exposure to kinase inhibiting drugs may provide a useful tool to study mechanisms of resistance, as well as to identify predictive markers.

Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors for Patients with Advanced Gastrointestinal Stromal Tumors.

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Nerich, Virginie; Fleck, Camille; Chaigneau, Loïc; Isambert, Nicolas; Borg, Christophe; Kalbacher, Elsa; Jary, Marine; Simon, Pauline; Pivot, Xavier; Blay, Jean-Yves; Limat, Samuel

2017-01-01

The management of advanced gastrointestinal stromal tumors (GISTs) has been modified considerably by the availability of costly tyrosine kinase inhibitors (TKIs); however, the best therapeutic sequence in terms of cost and effectiveness remains unknown. The aim of this study was to compare four potential strategies (reflecting the potential daily practice), each including imatinib 400 mg/day, as first-line treatment: S1 (imatinib 400 /best supportive care [BSC]); S2 (imatinib 400 /imatinib 800 /BSC); S3 (imatinib 400 /sunitinib/BSC); and S4 (imatinib 400 /imatinib 800 /sunitinib/BSC). A Markov model was developed with a hypothetical cohort of patients and a lifetime horizon. Transition probabilities were estimated from the results of clinical trials. The analysis was performed from the French payer perspective, and only direct medical costs were included. Clinical and economic parameters were discounted, and the robustness of results was assessed. The least costly and effective strategy was S1, at a cost of €65,744 for 32.9 life months (reference). S3 was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of €48,277/life-year saved (LYS). S2 was dominated, and S4 yielded an ICER of €363,320/LYS compared with S3. Sensitivity analyses confirmed the robustness of these results; however, when taking into account a price reduction of 80 % for imatinib, S2 and S4 become the most cost-effective strategies. Our approach is innovative to the extent that our analysis takes into account the sequential application of TKIs. The results suggest that the S1 strategy is the best cost-effective strategy, but a price reduction of imatinib impacts on the results. This approach must continue, including new drugs and their impact on the quality of life of patients with advanced GISTs.

Are predictions of cancer response to targeted drugs, based on effects in unrelated tissues, the 'Black Swan' events?

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Kurbel, Beatrica; Golem, Ante Zvonimir; Kurbel, Sven

2015-01-01

Adverse effects of targeted drugs on normal tissues can predict the cancer response. Rash correlates with efficacy of erlotinib, cetuximab and gefitinib and onset of arterial hypertension with response to bevacizumab, sunitinib, axitinib and sorafenib, possible examples of 'Black Swan' events, unexpected scientific observations, as described by Karl Popper in 1935. The proposition is that our patients have individual intrinsic variants of cell growth control, important for tumor response and adverse effects on tumor-unrelated tissue. This means that the lack of predictive side effects in healthy tissue is linked with poor results of tumor therapy when tumor resistance is caused by mechanisms that protect all cells of that patient from the targeted drug effects.

Adverse drug reaction and toxicity caused by commonly used antimicrobials in canine practice

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K. Arunvikram

2014-05-01

Full Text Available An adverse drug reaction (ADR is a serious concern for practicing veterinarians and other health professionals, and refers to an unintended, undesired and unexpected response to a drug that negatively affects the patient's health. It may be iatrogenic or genetically induced, and may result in death of the affected animal. The ADRs are often complicated and unexpected due to myriad clinical symptoms and multiple mechanisms of drug-host interaction. Toxicity due to commonly used drugs is not uncommon when they are used injudiciously or for a prolonged period. Licosamides, exclusively prescribed against anaerobic pyoderma, often ends with diarrhoea and vomiting in canines. Treatment with Penicillin and β-lactam antibiotics induces onset of pemphigious vulgare, drug allergy or hypersensitivity. Chloroamphenicol and aminoglycosides causes Gray's baby syndrome and ototoxicity in puppies, respectively. Aminoglycosides are very often associated with nephrotoxicity, ototoxicity and neuromuscular blockage. Injudicious use of fluroquinones induces the onset of arthropathy in pups at the weight bearing joints. The most effective therapeutic measure in managing ADR is to treat the causative mediators, followed by supportive and symptomatic treatment. So, in this prospective review, we attempt to bring forth the commonly occurring adverse drug reactions, their classification, underlying mechanism, epidemiology, treatment and management as gleaned from the literature available till date and the different clinical cases observed by the authors.

Canine eosinophilic folliculitis and furunculosis in three cases.

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Curtis, C F; Bond, R; Blunden, A S; Thomson, D G; McNeil, P E; Whitbread, T W

1995-03-01

The historical, clinical and histopathological features of three dogs with eosinophilic folliculitis and furunculosis are described. The disease was characterised by the rapid development of pruritic, papular, pustular and ulcerative lesions on the dorsum of the muzzle. Skin lesions were confined to the face in two cases. The third dog had more generalised pustular lesions. Skin biopsy specimens showed marked eosinophil infiltration particularly centred on pilosebaceous units. Dermal collagen necrosis was evident in two cases. Similar facial lesions have previously been described as 'nasal pyoderma'. The three dogs failed to respond to initial antibacterial therapy but showed a rapid clinical response when prednisolone was given orally at doses ranging from 1 to 2.2 mg/kg, in addition to the antibacterial therapy, suggesting that glucocorticoids are indicated for the treatment of eosinophilic folliculitis and furunculosis. The aetiology of the disease was not determined.

Optimizing Treatment Outcomes With Regorafenib: Personalized Dosing and Other Strategies to Support Patient Care

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van Cutsem, Eric; Blay, Jean-Yves; Sobrero, Alberto; Demetri, George D.

2014-01-01

Regorafenib is an oral multikinase inhibitor that inhibits several kinases relevant to tumor biology in several cancers, including colorectal carcinoma (CRC) and gastrointestinal stromal tumor (GIST). In phase III trials, regorafenib significantly improved overall survival versus placebo in patients with metastatic CRC progressing after all available standard therapies, and significantly prolonged progression-free survival in patients with advanced GIST in whom at least imatinib and sunitinib had failed. Thus, this agent holds promise as a new standard of care for CRC and GIST patients after disease progression following all other approved therapies. The clinical trials reported to date show that this new treatment has a consistent adverse event profile that is quite different from that of traditional cytotoxic chemotherapies. The most common adverse events of regorafenib include dermatologic and mucosal toxicities (especially hand-foot skin reaction, rash, and oral mucositis), constitutional symptoms (e.g., fatigue, nausea, and weight loss), vascular effects (especially hypertension), and gastrointestinal symptoms (e.g., diarrhea). To help health care professionals anticipate and manage the adverse events associated with regorafenib, we describe our experiences in clinical trials and show that such toxicities can be effectively managed with close observation of patients from initiation of dosing, along with prompt appropriate interventions, including dose modifications, if necessary. PMID:24821824

Targeted therapies in the treatment of urothelial cancers.

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Aragon-Ching, Jeanny B; Trump, Donald L

2017-07-01

Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

Renal cell carcinoma: evolving approaches to advanced non-clear cell carcinoma

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Daniel Y.C. Heng

2011-12-01

Full Text Available The treatment of metastatic renal cell carcinoma (RCC has changed dramatically with the introduction of targeted therapies including sunitinib, sorafenib, and temsirolimus. Because patients with conventional clear cell histology account for 75- 80% of all patients with RCC, there has been little accumulated evidence on the treatment of patients with non-clear cell histologies. Most clinical trials have excluded them from enrolment, except for randomized studies investigating temsirolimus. Many retrospective studies on the use of all three of these targeted therapies in patients with non-clear cell histology have demonstrated response rates ranging from 3.7%–16%. Although response rates may not be as high compared to patients with clear cell histologies, targeted therapy does provide a clinically meaningful response.

Picrotoxane sesquiterpenoids from the stems of Dendrobium nobile and their absolute configurations and angiogenesis effect.

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Meng, Chun-Wang; He, Yu-Lin; Peng, Cheng; Ding, Xing-Jie; Guo, Li; Xiong, Liang

2017-09-01

Five picrotoxane sesquiterpenoids belonging to the unusual dendrobine-type (1 and 4) and the picrotoxinin-type (2, 3, and 5) were isolated from the stems of Dendrobium nobile Lindl. Their structures were established by spectroscopic analyses and physical properties. Compound 1 was a new dendrobine analogue. Although the planar structure of 2 and 3 had been reported, their absolute configurations were first determined by single-crystal X-ray diffraction and circular dichroism. Compound 2 exhibited angiogenesis effect against sunitinib-induced damage on intersegmental blood vessels in Tg (flk1: EGFP) and Tg (fli1: nEGFP) transgenic zebrafish at concentrations of 3.13, 6.25, 12.50, and 25.00μM. Copyright © 2017. Published by Elsevier B.V.

The 'holi' dermatoses: annual spate of skin diseases following the spring festival in India.

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Ghosh, Sudip Kumar; Bandyopadhyay, Debabrata; Chatterjee, Gobinda; Saha, Debabrata

2009-07-01

'Holi' is an annual spring festival celebrated all over India. The central ritual of Holi involves throwing of colors on one another. Playing with toxic industrial dyes often results in various dermatological complaints in a significant number of people immediately following the celebration. To describe patterns of various skin manifestations directly or indirectly related to the use of different colors in the celebration of Holi. Observational clinical study on consecutive patients presenting to a teaching hospital in Kolkata, India. Forty-two patients with a mean age of 24.2 years were studied. Itching was the commonest symptom (25, 59.5%), followed by burning sensation, pain, oozing, and scaling. Eleven patients' symptoms were attributed to activities related to preparation of colors and the removal of colors from the skin surface. Eczematous lesions were the most common pattern (24, 57.1%) followed by erosions, xerosis and scaling, erythema, urticaria, acute nail-fold inflammation, and abrasions. Thirteen (30.9%) patients reported aggravation of preexisting dermatoses (acne, eczema, and paronychia). Secondary pyoderma occurred in 3 (7.1%). Face was the commonest site affected (24, 57.1%), followed by dorsum of the hands, scalp, forearm, palms, arms, and trunk. Ocular complaints in the form of redness, watering, and grittiness occurred in 7 (16.7%) patients. Various forms of cutaneous manifestations, often associated with ocular complaints, occur commonly due to Holi colors. Public awareness and regulatory actions are needed to avoid these preventable conditions.

The ′Holi′ dermatoses : Annual spate of skin diseases following the spring festival in India

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Ghosh Sudip

2009-01-01

Full Text Available Background : ′Holi′ is an annual spring festival celebrated all over India. The central ritual of Holi involves throwing of colors on one another. Playing with toxic industrial dyes often results in various dermatological complaints in a significant number of people immediately following the celebration. Aims : To describe patterns of various skin manifestations directly or indirectly related to the use of different colors in the celebration of Holi. Methods : Observational clinical study on consecutive patients presenting to a teaching hospital in Kolkata, India. Results : Forty-two patients with a mean age of 24.2 years were studied. Itching was the commonest symptom (25, 59.5%, followed by burning sensation, pain, oozing, and scaling. Eleven patients′ symptoms were attributed to activities related to preparation of colors and the removal of colors from the skin surface. Eczematous lesions were the most common pattern (24, 57.1% followed by erosions, xerosis and scaling, erythema, urticaria, acute nail-fold inflammation, and abrasions. Thirteen (30.9% patients reported aggravation of preexisting dermatoses (acne, eczema, and paronychia. Secondary pyoderma occurred in 3 (7.1%. Face was the commonest site affected (24, 57.1%, followed by dorsum of the hands, scalp, forearm, palms, arms, and trunk. Ocular complaints in the form of redness, watering, and grittiness occurred in 7 (16.7% patients. Conclusion : Various forms of cutaneous manifestations, often associated with ocular complaints, occur commonly due to Holi colors. Public awareness and regulatory actions are needed to avoid these preventable conditions.

THE ‘HOLI’ DERMATOSES: ANNUAL SPATE OF SKIN DISEASES FOLLOWING THE SPRING FESTIVAL IN INDIA

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Ghosh, Sudip Kumar; Bandyopadhyay, Debabrata; Chatterjee, Gobinda; Saha, Debabrata

2009-01-01

Background: ‘Holi’ is an annual spring festival celebrated all over India. The central ritual of Holi involves throwing of colors on one another. Playing with toxic industrial dyes often results in various dermatological complaints in a significant number of people immediately following the celebration. Aims: To describe patterns of various skin manifestations directly or indirectly related to the use of different colors in the celebration of Holi. Methods: Observational clinical study on consecutive patients presenting to a teaching hospital in Kolkata, India. Results: Forty-two patients with a mean age of 24.2 years were studied. Itching was the commonest symptom (25, 59.5%), followed by burning sensation, pain, oozing, and scaling. Eleven patients’ symptoms were attributed to activities related to preparation of colors and the removal of colors from the skin surface. Eczematous lesions were the most common pattern (24, 57.1%) followed by erosions, xerosis and scaling, erythema, urticaria, acute nail-fold inflammation, and abrasions. Thirteen (30.9%) patients reported aggravation of preexisting dermatoses (acne, eczema, and paronychia). Secondary pyoderma occurred in 3 (7.1%). Face was the commonest site affected (24, 57.1%), followed by dorsum of the hands, scalp, forearm, palms, arms, and trunk. Ocular complaints in the form of redness, watering, and grittiness occurred in 7 (16.7%) patients. Conclusion: Various forms of cutaneous manifestations, often associated with ocular complaints, occur commonly due to Holi colors. Public awareness and regulatory actions are needed to avoid these preventable conditions. PMID:20161854

Cutaneous manifestations of Nocardia brasiliensis infection in Taiwan during 2002-2012-clinical studies and molecular typing of pathogen by gyrB and 16S gene sequencing.

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Chen, Kuo-Wei; Lu, Chun-Wei; Huang, Ting-Chi; Lu, Chin-Fang; Liau, Yea-Ling; Lin, Jeng-Fong; Li, Shu-Ying

2013-09-01

To observe the clinicopathologic and resistance profiles of the Nocardia brasiliensis causing cutaneous nocardiosis in Taiwan, 12 N. brasiliensis isolates were prospectively collected from patients with cutaneous nocardiosis in a hospital during 2002-2012. Clinicopathologic data were obtained, and isolates were identified by biochemical methods and 16S rRNA sequencing. Susceptibilities to 14 antimicrobial compounds were tested. Isolates were further genotyped by sequencing of 16S rRNA, secA1, hsp65, and gyrB genes. The nodulopustular pyoderma associated with sporotrichoid spreading was the most common skin presentations caused by N. brasiliensis. All of the isolates were susceptible to amikacin, gentamicin, tobramycin, piperacillin/tazobactam, and trimethoprim/sulfamethoxazole and resistant to kanamycin, erythromycin, and oxacillin, while susceptibilities to imipenem, vancomycin, penicillin-G, tetracycline, clindamycin, and ciprofloxacin varied among the 12 isolates. GyrB genotyping delineated the 12 isolates into 2 major groups, which was coincident with different single nucleotide substitutions at position 160 (G versus T) of 16S rRNA, different levels of imipenem minimum inhibition concentration (4-32 versus 0.25-0.75 mg/L), and prevalence of lymphadenitis (66.7 versus 16.7%). We have noted that tiny pustular lesions can be the first sign of cutaneous nocardiosis, which we believe has not been previously emphasized. No resistance to trimethoprim and sulfamethoxazole was found; therefore, sulphonamide drugs remain effective for treatment of cutaneous nocardiosis in Taiwan. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluating the safety and efficacy of axitinib in the treatment of advanced renal cell carcinoma

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Gunnarsson O

2015-02-01

Full Text Available Orvar Gunnarsson,1 Nicklas R Pfanzelter,2 Roger B Cohen,1 Stephen M Keefe1 1Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, 2Department of Medicine, Division of Hematology and Oncology, Rush University Medical Center, Chicago, IL, USA Abstract: Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor-α, and c-kit. Phase I studies demonstrated 5 mg twice daily as the recommended starting dose with notable effects seen in renal cell carcinoma, an observation confirmed in Phase II trials. The trial of comparative effectivess of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS was an international randomized Phase III study designed for registration purposes, compared axitinib to sunitinib. This trial randomized 723 patients with metastatic kidney cancer to axitinib or sunitinib in the second-line setting and demonstrated a median progression-free survival of 6.7 months for axitinib versus 4.7 months for sorafenib (P<0.0001. Clinical benefit was detected regardless of prior therapy, but no overall survival benefit has been observed. Axitinib is well tolerated without a significant effect on quality of life. The most common grade 3 toxicities are hypertension (16%, diarrhea (11%, and fatigue (11%, with other notable side effects being anorexia, nausea, hand–foot syndrome, and rash. Patients who developed diastolic blood pressure >90 mmHg were noted to have significantly longer median overall survival and overall response rates when compared to normotensive patients. Therefore, the manufacturer recommends escalating the twice-daily dose to 7 mg and 10 mg, as tolerated, if there is no significant increase in blood pressure on treatment. Currently, axitinib is approved for use in the second-line setting for patients with metastatic renal cell carcinoma. Research is ongoing in other disease

Triiodothyronine regulates cell growth and survival in renal cell cancer.

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Czarnecka, Anna M; Matak, Damian; Szymanski, Lukasz; Czarnecka, Karolina H; Lewicki, Slawomir; Zdanowski, Robert; Brzezianska-Lasota, Ewa; Szczylik, Cezary

2016-10-01

Triiodothyronine plays an important role in the regulation of kidney cell growth, differentiation and metabolism. Patients with renal cell cancer who develop hypothyreosis during tyrosine kinase inhibitor (TKI) treatment have statistically longer survival. In this study, we developed cell based model of triiodothyronine (T3) analysis in RCC and we show the different effects of T3 on renal cell cancer (RCC) cell growth response and expression of the thyroid hormone receptor in human renal cell cancer cell lines from primary and metastatic tumors along with human kidney cancer stem cells. Wild-type thyroid hormone receptor is ubiquitously expressed in human renal cancer cell lines, but normalized against healthy renal proximal tube cell expression its level is upregulated in Caki-2, RCC6, SKRC-42, SKRC-45 cell lines. On the contrary the mRNA level in the 769-P, ACHN, HKCSC, and HEK293 cells is significantly decreased. The TRβ protein was abundant in the cytoplasm of the 786-O, Caki-2, RCC6, and SKRC-45 cells and in the nucleus of SKRC-42, ACHN, 769-P and cancer stem cells. T3 has promoting effect on the cell proliferation of HKCSC, Caki-2, ASE, ACHN, SK-RC-42, SMKT-R2, Caki-1, 786-0, and SK-RC-45 cells. Tyrosine kinase inhibitor, sunitinib, directly inhibits proliferation of RCC cells, while thyroid hormone receptor antagonist 1-850 (CAS 251310‑57-3) has less significant inhibitory impact. T3 stimulation does not abrogate inhibitory effect of sunitinib. Renal cancer tumor cells hypostimulated with T3 may be more responsive to tyrosine kinase inhibition. Moreover, some tumors may be considered as T3-independent and present aggressive phenotype with thyroid hormone receptor activated independently from the ligand. On the contrary proliferation induced by deregulated VHL and or c-Met pathways may transgress normal T3 mediated regulation of the cell cycle.

A Rare Case of Metastasis to the Thyroid Gland from Renal Clear Cell Carcinoma 11 Years after Nephrectomy and Concurrent Primary Esophageal Carcinoma

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Mohammad Saud Khan

2018-01-01

Full Text Available Renal cell carcinoma is known to cause metastasis to unusual sites, which can be both synchronous or metachronous. Thyroid gland is a rare site for metastasis, but when it occurs, renal cell carcinoma is the most common primary neoplasm. We report the case of a 81-year-old female patient who had a significant medical history of right clear cell renal carcinoma with adrenal metastasis. She underwent right radical nephrectomy and adrenalectomy followed by radiofrequency ablation of left adrenal metastasis and systemic chemotherapy with sunitinib. Eleven years later, she presented with dysphagia and was found to have distal esophageal adenocarcinoma. On imaging, there was incidental detection of a left renal mass lesion and a right thyroid nodule, which on histopathology and immunohistochemistry were confirmed to be clear cell carcinoma of renal origin.

Antiangiogenic therapy for breast cancer

DEFF Research Database (Denmark)

Nielsen, D.L.; Andersson, M.; Andersen, Jon Alexander Lykkegaard

2010-01-01

and optimal use of these agents for the treatment of breast cancer. Currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Small molecular inhibitors of VEGF...... tyrosine kinase activity, such as sorafenib, appear promising. While, the role of sunitinib and inhibitors of mammalian target of rapamycin (mTOR) in breast cancer has to be defined. Several unanswered questions remain, such as choice of drug(s), optimal duration of therapy and patient selection criteria......ABSTRACT: Angiogenesis is an important component of cancer growth, invasion and metastasis. Therefore, inhibition of angiogenesis is an attractive strategy for treatment of cancer. We describe existing clinical trials of antiangiogenic agents and the challenges facing the clinical development...

Perinatal HIV-infection in Sankt Petersburg and Modern Therapy Concomitant Viral Infections

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V. N. Timchenko

2016-01-01

Full Text Available The study included 338 HIV-infected children (B-23 and 350 children with perinatal contact HIV infection (R-75, consisting on the dispensary in the department of maternal and child the St. Petersburg City AIDS Center. In 32 persons (9.5% diagnosed with secondary infections. In the structure of viral opportunistic infections (herpesvirus, SARS amounted to 39.8%, bacterial (bronchitis, tonsillitis, pyoderma, tuberculosis — 34.8%, fungal and parasitic (candidiasis of the oral mucosa, PCP — 25.4 %. Combined therapy (causal, pathogenetic, symptomatic SARS in children with B-23 and R-75, allows you to get in early (6th d. Treatment regress the main symptoms of acute respiratory diseases. Modern therapy of congenital cytomegalovirus infection (VTSMI in children with B-23 and R-75 of the first year of life with antitsitomegalovirusnogo immunoglobulin and preparation of human recombinant interferon alfa-2b in the form of rectal suppositories — VIFERON, causes persistent normalization of clinical and laboratory parameters.

Diagnosis of Churg-Strauss Syndrome Presented With Neuroendocrine Carcinoma: A Case Report.

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Park, Dayun; Lee, Ho Jun; Lee, Kwang Hoon; Kwon, Bum Sun; Park, Jin-Woo; Nam, Ki Yeun; Lee, Kyoung Hwan

2017-06-01

Churg-Strauss syndrome (CSS) is a rare systemic vasculitis that affect small and medium-sized blood vessels and is accompanied by asthma, eosinophilia, and peripheral neuropathy. This report describes a case of a 52-year-old man who had a history of sinusitis, asthma, and thymus cancer and who had complained of bilateral lower extremity paresthesia and weakness for a month. Peripheral neuropathy was detected by electrodiagnostic studies. Resection of a mediastinal mass, which was diagnosed as thymic neuroendocrine carcinoma, was performed five months before his visit. After thymectomy, peripheral blood tests revealed a gradual increase in eosinophils. Two months after surgery, he was admitted to the hospital for dyspnea, and nodules of focal consolidation were found in his chest X-ray. One month later, pyoderma occurred in the right shin, and the skin biopsy showed extravascular eosinophilic infiltration. He was diagnosed with CSS after thymectomy, and we report a very rare case of CSS presented with thymic neuroendocrine carcinoma.

Primary seborrhoea in English springer spaniels: a retrospective study of 14 cases.

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Scott, D W; Miller, W H

1996-04-01

Primary seborrhoea was diagnosed in 14 English springer spaniels over a 17-year period. Seven of the dogs developed clinical signs by two years of age. The dermatosis began as a generalised non-pruritic dry scaling which gradually worsened. Some dogs remained in this dry (seborrhoea sicca) stage, but in most cases the dermatosis became greasy and inflamed (seborrhoea oleosa and seborrhoeic dermatitis). Eight of the dogs suffered from recurrent episodes of superficial or deep bacterial pyoderma. Histological findings in skin biopsy specimens included marked orthokeratotic hyperkeratosis of surface and infundibular epithelium, papillomatosis, parakeratotic capping of the papillae, and superficial perivascular dermatitis in which lymphocytes and mast cells were prominent. The dogs with seborrhoea sicca responded more satisfactorily to therapy with topical emollient-humectant agents or oral omega-3/omega-6 fatty acid supplementation. Dogs with seborrhoea oleosa and seborrhoeic dermatitis did not respond satisfactorily to topical therapy. One dog, however, responded well to etretinate and omega-3/omega-6 fatty acid administration. No dog was cured.

Pattern of skin diseases among civil population and armed forces personnel at Pune

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Sayal S

1997-01-01

Full Text Available The pattern of skin disorders among 11393 civil and 8123 defence service personnel who attended out-patient department (OPD from January 1989 to December 1994 is presented. Infective dermatoses were more common in civil population (41.2% as compared to defence service personnel (36.3%. Fungal infection was common in both groups (15.1% and 17.2% whereas parasitic infestations and pyoderma were more common in civil population (12.8% and 6.1% as compared to service personnel (7.8% and 3.6%. Among non-infective dermatoses eczemas were more common in civil population (17.3% as compared to Armed Forces personnel (11.7%, whereas papulosquamous disorders, pigmentary disorders, acne and alopecia were more common in Armed Forces personnel (13.5%, 13.4% 8.7% and 6.2% as compared to civil population (10.8%, 10.1%, 6.4% and 4.1%. The incidence of other skin disorders did not differ much between the two groups.

Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis.

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Takagi, Satoshi; Takemoto, Ai; Takami, Miho; Oh-Hara, Tomoko; Fujita, Naoya

2014-08-01

The interactions of tumor cells with platelets contribute to the progression of tumor malignancy, and the expression levels of platelet aggregation-inducing factors positively correlate with the metastatic potential of osteosarcoma cells. However, it is unclear how tumor-platelet interaction contributes to the proliferation of osteosarcomas. We report here that osteosarcoma-platelet interactions induce the release of platelet-derived growth factor (PDGF) from platelets, which promotes the proliferation of osteosarcomas. Co-culture of platelets with MG63 or HOS osteosarcoma cells, which could induce platelet aggregation, enhanced the proliferation of each cell line in vitro. Analysis of phospho-antibody arrays revealed that co-culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor (PDGFR) and Akt. The addition of supernatants of osteosarcoma-platelet reactants also increased the growth of MG63 and HOS cells as well as the level of phosphorylated-PDGFR and -Akt. Sunitinib or LY294002, but not erlotinib, significantly inhibited the platelet-induced proliferation of osteosarcoma cells, indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the PDGFR and then Akt. Our results suggest that inhibitors that specifically target osteosarcoma-platelet interactions may eradicate osteosarcomas. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Epithelioid Sarcoma: Opportunities for Biology-Driven Targeted Therapy.

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Noujaim, Jonathan; Thway, Khin; Bajwa, Zia; Bajwa, Ayeza; Maki, Robert G; Jones, Robin L; Keller, Charles

2015-01-01

Epithelioid sarcoma (ES) is a soft tissue sarcoma of children and young adults for which the preferred treatment for localized disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review, we will summarize clinically relevant biomarkers (e.g., SMARCB1, CA125, dysadherin, and others) with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR, and polykinase inhibitors (e.g., sunitinib) in the management of local and disseminated disease. Toward building a consortium of pharmaceutical, academic, and non-profit collaborators, we will discuss the state of resources for investigating ES with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed toward effective biology-driven therapies.

Uso da oxigenoterapia hiperbárica em pacientes de um serviço de reumatologia pediátrica Hyperbaric oxygen therapy in patients of a pediatric rheumatology service

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Juliana Figueira M. R. Rossi

2005-04-01

ça, Hospital das Clínicas, Faculty of Medicine, São Paulo University, between 1996 and 2002, were submitted to hyperbaric oxygen therapy. This therapy was indicated by the presence of chronic osteomyelitis and tissue ulcer (vasculitis or infection not responsive to the usual treatment. Two patients presented cutaneous polyarteritis, two presented chronic recurrent multifocal osteomyelitis, one presented diffuse cutaneous sclerodema and one presented pyoderma gangrenosum. Five patients were girls (age range from 6 to 13.2 years-old. The sessions of hyperbaric oxygen therapy were performed under pressures that ranged from 2.4 to 2.8 absolute atmospheres and their duration were two hours. The lowest number of sessions was 18 and the highest was 80. Five patients presented complete resolution of the injuries. The patient with cutaneous sclerodema suspended the treatment after the 18th session, because she went back to her birthplace with partial improvement of the cutaneous injuries. The main adverse event during the sessions was ear pain after the first sessions, which disappeared with reduction of the pressure inside the chamber and the duration of the session. Spandrel perforation or other adverse events were not observed. The hyperbaric oxygen therapy was efficient and well tolerated by patients with rheumatic diseases and ulcerated injuries by vasculitis, infected injuries or chronic osteomyelitis.

A CONTROVERSIAL ON THE DIAGNOSIS OF CHRONIC BULLOUS TYPE MUCOCUTANEOUS DISEASE INVOLVING ORAL MUCOSA (A CASE REPORT

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Isadora Gracia

2006-04-01

Full Text Available A case of chronic bullous type mucocutaneous disease involving oral mucosa was reported from a 56 years old man with never healing oral ulcers and wound on the perianal skin for three years. There were also red and black spots on the limb and back skin and a lesion on nail. Painful oral lesion consisted of mucous erosion, desquamative gingivitis, and sloughing area on palate and tongue. The patient is diabetic. The first perianal skin diagnosis was granulomatous candidasis with differential diagnosis pemphigus vegetates and acuminarum condiloma. However the histopathologic examination did not support these diagnosis. After several histopathologic examinations, the latest perianal skin diagnosis was lichen planus with differential diagnosis granulomatous vasculitis, bowenoid papulosis and pyodema gangrenosum. Other skin diagnosis was erythema multiforme. Oral diagnosis was mucous membrane pemphigoid with differential diagnosis lichen planus, Behçet's syndrome and erythema multiforme. Oral histopathologic examinations showed a sub-epithelial blister, which supported mucous membrane pemphigoid. A lip balm, prednisone 5 mg oral rinse and multivitamins were given but oral improvement started after blood sugar level was controlled. Conclusion: It is not yet known whether skin and oral mucous lesions are from the same disease or not.

RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis.

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Yang, Lin; Alyasova, Anna; Ye, Dingwei; Ridolfi, Antonia; Dezzani, Luca; Motzer, Robert J

2018-02-17

RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients. RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014. Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were < 65 years of age. All (100%) Asian patients were of Chinese ethnicity. Median duration of exposure was 5.5 mo for Asian and 6.0 mo for non-Asian patients. Among Asian versus non-Asian patients, median progression-free survival (months) was 7.4 versus 7.8 overall, 7.4 versus 4.0 with prior sunitinib, and 5.7 versus 9.2 with prior other anti-VEGFs. Clinical benefit rate was similar between populations: 74.5% (95% CI 61.0-85.3) for Asian patients and 74.7% (95% CI 63.6-83.8) for non-Asian patients. Most patients achieved stable disease as best overall response (Asian, 63.6%; non-Asian, 69.6%). Overall rate of grade 3/4 adverse events appeared similar for Asian (58%) and non-Asian patients (54%). This RECORD-4 subanalysis demonstrated comparable efficacy and adverse event profiles of second-line everolimus in Asian and non-Asian patients. Efficacy and safety outcomes by prior therapy should be interpreted with caution because of small

Silica Nanofibers with Immobilized Tetracycline for Wound Dressing

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Irena Lovětinská-Šlamborová

2016-01-01

Full Text Available Local antibiotic treatment has its justification for superficial infections. The advantage of this treatment is that the antibiotic has effects on bacterial agent directly at the application site. Skin infections which are intended for the local antibiotic treatment are superficial pyoderma, some festering wounds, burns of second and third degree, infected leg ulcers, or decubitus of second and third degree. Tetracyclines are available topical antibiotics with a broad bacterial spectrum. At present, ointments containing tetracycline are also used for the treatment, which rarely can lead to skin sensitization. In this paper, a development of novel nanofibrous material with immobilized tetracycline is presented. Two different methods of immobilized tetracycline quantification onto silica nanofibers are employed. It was proven that the prevailing part of tetracycline was bound weakly by physisorption forces, while the minor part was covalently bound by NH2 groups formed by the preceding functionalization. The silica nanofibers with immobilized tetracycline are promising material for wound dressing applications due to its antibacterial activity; it was proved by tests.

Adult-onset demodicosis in two dogs due to Demodex canis and a short-tailed demodectic mite.

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Saridomichelakis, M; Koutinas, A; Papadogiannakis, E; Papazachariadou, M; Liapi, M; Trakas, D

1999-11-01

Infestation with a short-tailed demodectic mite and Demodex canis was diagnosed in both a six-and-a-half-year-old and a four-year-old dog. The clinical picture was compatible with generalised demodicosis complicated by staphylococcal pyoderma (case 1), or localised demodicosis (case 2). In both cases, the short-tailed demodectic mite outnumbered D canis in superficial skin scrapings. The laboratory findings (lymphopenia, eosinopenia, increased serum alkaline phosphatase and alanine aminotransferase activities, diluted urine and proteinuria) and the results of a low dose dexamethasone suppression test were suggestive of underlying hyperadrenocorticism in the first case. Hypothyroidism was considered a possibility in the second case, owing to the sustained bradycardia and the extremely low basal total thyroxine value. Systemic treatment with ivermectin and cephalexin (case 1), or topical application of an amitraz solution in mineral oil, along with sodium levothyroxine replacement therapy (case 2), resulted in a complete resolution of the skin lesions and the disappearance of both types of demodectic mite after two and one and a half months, respectively.

Epithelioid Sarcoma: Opportunities for Biology-driven Targeted Therapy

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Jonathan eNoujaim

2015-08-01

Full Text Available Epithelioid sarcoma is a soft tissue sarcoma of children and young adults for which the preferred treatment for localised disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review we will summarize clinically-relevant biomarkers (e.g., SMARCB1, CA125, dysadherin and others with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR and polykinase inhibitors (e.g., sunitinib in the management of local and disseminated disease. Towards building a consortium of pharmaceutical, academic and non-profit collaborators, we will discuss the state of resources for investigating epithelioid sarcoma with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed towards effective biology-driven therapies.

More than 10 years survival with sequential therapy in a patient with advanced renal cell carcinoma: a case report

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Yuan, J.L.; Wang, F.L.; Yi, X.M.; Qin, W.J.; Wu, G.J. [Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi' an, Shaanxi (China); Huan, Y. [Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi' an, Shaanxi (China); Yang, L.J.; Zhang, G.; Yu, L.; Zhang, Y.T.; Qin, R.L.; Tian, C.J. [Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi' an, Shaanxi (China)

2014-10-31

Although radical nephrectomy alone is widely accepted as the standard of care in localized treatment for renal cell carcinoma (RCC), it is not sufficient for the treatment of metastatic RCC (mRCC), which invariably leads to an unfavorable outcome despite the use of multiple therapies. Currently, sequential targeted agents are recommended for the management of mRCC, but the optimal drug sequence is still debated. This case was a 57-year-old man with clear-cell mRCC who received multiple therapies following his first operation in 2003 and has survived for over 10 years with a satisfactory quality of life. The treatments given included several surgeries, immunotherapy, and sequentially administered sorafenib, sunitinib, and everolimus regimens. In the course of mRCC treatment, well-planned surgeries, effective sequential targeted therapies and close follow-up are all of great importance for optimal management and a satisfactory outcome.

Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

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Laura Pisarsky

2016-05-01

Full Text Available Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.

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Naito, Sei; Makhov, Peter; Astsaturov, Igor; Golovine, Konstantin; Tulin, Alexei; Kutikov, Alexander; Uzzo, Robert G; Kolenko, Vladimir M

2017-04-25

Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs. We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib. The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet. The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.

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Bellmunt, Joaquim; Calvo, Emiliano; Castellano, Daniel; Climent, Miguel Angel; Esteban, Emilio; García del Muro, Xavier; González-Larriba, José Luis; Maroto, Pablo; Trigo, José Manuel

2009-03-01

For almost the last two decades, interleukin-2 and interferon-alpha have been the only systemic treatment options available for metastatic renal cell carcinoma. However, in recent years, five new targeted therapies namely sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab have demonstrated clinical activity in these patients. With the availability of new targeted agents that are active in this disease, there is a need to continuously update the treatment algorithm of the disease. Due to the important advances obtained, the Spanish Oncology Genitourinary Group (SOGUG) has considered it would be useful to review the current status of the disease, including the genetic and molecular biology factors involved, the current predicting models for development of metastases as well as the role of surgery, radiotherapy and systemic therapies in the early- or late management of the disease. Based on this previous work, a treatment algorithm was developed.

The Role of Biomarkers in Decreasing Risk of Cardiac Toxicity after Cancer Therapy

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Christine Henri

2016-01-01

Full Text Available With the improvement of cancer therapy, survival related to malignancy has improved, but the prevalence of long-term cardiotoxicity has also increased. Cancer therapies with known cardiac toxicity include anthracyclines, biologic agents (trastuzumab, and multikinase inhibitors (sunitinib. The most frequent presentation of cardiac toxicity is dilated cardiomyopathy associated with poorest prognosis. Monitoring of cardiac toxicity is commonly performed by assessment of left ventricular (LV ejection fraction, which requires a significant amount of myocardial damage to allow detection of cardiac toxicity. Accordingly, this creates the impetus to search for more sensitive and reproducible biomarkers of cardiac toxicity after cancer therapy. Different biomarkers have been proposed to that end, the most studied ones included troponin release resulting from cardiomyocyte damage and natriuretic peptides reflecting elevation in LV filling pressure and wall stress. Increase in the levels of troponin and natriuretic peptides have been correlated with cumulative dose of anthracycline and the degree of LV dysfunction. Troponin is recognized as a highly efficient predictor of early and chronic cardiac toxicity, but there remains some debate regarding the clinical usefulness of the measurement of natriuretic peptides because of divergent results. Preliminary data are available for other biomarkers targeting inflammation, endothelial dysfunction, myocardial ischemia, and neuregulin-1. The purpose of this article is to review the available data to determine the role of biomarkers in decreasing the risk of cardiac toxicity after cancer therapy.

A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC).

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Atchison, Elizabeth; Eklund, John; Martone, Brenda; Wang, Lili; Gidron, Adi; Macvicar, Gary; Rademaker, Alfred; Goolsby, Charles; Marszalek, Laura; Kozlowski, James; Smith, Norm; Kuzel, Timothy M

2010-09-01

High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.

Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib

NARCIS (Netherlands)

van der Veldt, A.A.M.; de Boer, M.P.; Boven, E.; Eringa, E.C.; van den Eertwegh, A.J.M.; van Hinsbergh, V.W.M.; Smulders, Y.M.; Serné, E.H.

2010-01-01

Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural

The Role of Everolimus in Renal Cell Carcinoma

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Malek Meskawi

2015-12-01

Full Text Available Everolimus (RAD001 is an orally administered agent that inhibits the mammalian target of rapamycin serine-threonine kinase. A phase III pivotal trial on everolimus, published in 2008, provided the first evidence for the efficacy of sequential therapy for patients with metastatic clear cell renal cell carcinoma (RCC. In this study, everolimus was used after failure of one or several previous lines of therapy, and it demonstrated a 3-month survival benefit relative to placebo. Currently, based on the level 1 evidence, everolimus represents the molecule of choice for third-line therapy after failure of previous two tyrosine kinase inhibitors (TKIs. However, second-line use after failure of one TKI is challenged by two new molecules (nivolumab and cabozantinib, which proved to have better efficacy with similar toxicity profile. In non-clear cell metastatic RCC, the current evidence recommends everolimus as a second-line therapy after failure of previous first-line sunitinib.

Gastrointestinal Stromal Tumors with Unusual Localization: Report of Three Cases with a Brief Literature Review.

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Yucel, Ahmet Fikret; Sunar, Haldun; Hut, Adnan; Kocakusak, Ahmet; Pergel, Ahmet; Barut, Gul; Dikici, Suleyman

2010-07-26

The most common tumors derived from the mesenchyme of the gastrointestinal system are stromal tumors. These tumors are typically seen in the stomach and small intestine and less frequently in the colon, rectum and esophagus and are very rarely located outside the gastrointestinal system. Cure is provided with complete surgical resection with resection borders free of tumor. Tumor size, mitotic index, localization, CD117 and CD34 negativity in immunohistochemical studies, mucosal ulceration and presence of necrosis help to predict recurrence of the illness and patient survival. In high-risk gastrointestinal stromal tumors (GISTs) there is an increased rate of recurrence and shortened survival despite complete surgical resection. Thus patients with a high-risk GIST should be given adjuvant therapy with imatinib mesylate. Sunitinib maleate is another FDA-approved agent only for cases who cannot tolerate imatinib or who are resistant to it. Herein we present three cases with GISTs in different locations of the gastrointestinal system with a review of the relevant literature.

Gastrointestinal Stromal Tumors with Unusual Localization: Report of Three Cases with a Brief Literature Review

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Ahmet Fikret Yucel

2010-07-01

Full Text Available The most common tumors derived from the mesenchyme of the gastrointestinal system are stromal tumors. These tumors are typically seen in the stomach and small intestine and less frequently in the colon, rectum and esophagus and are very rarely located outside the gastrointestinal system. Cure is provided with complete surgical resection with resection borders free of tumor. Tumor size, mitotic index, localization, CD117 and CD34 negativity in immunohistochemical studies, mucosal ulceration and presence of necrosis help to predict recurrence of the illness and patient survival. In high-risk gastrointestinal stromal tumors (GISTs there is an increased rate of recurrence and shortened survival despite complete surgical resection. Thus patients with a high-risk GIST should be given adjuvant therapy with imatinib mesylate. Sunitinib maleate is another FDA-approved agent only for cases who cannot tolerate imatinib or who are resistant to it. Herein we present three cases with GISTs in different locations of the gastrointestinal system with a review of the relevant literature.

Three cases of bone metastases in patients with gastrointestinal stromal tumors

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Maurizio Zompatori

2011-04-01

Full Text Available Gastrointestinal stromal tumors (GISTs are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. Tumor resection is the treatment of choice for localized disease. Tyrosine kinase inhibitors (imatinib, sunitinib are the standard therapy for metastatic or unresectable GISTs. GISTs usually metastasize to the liver and peritoneum. Bone metastases are uncommon. We describe three cases of bone metastases in patients with advanced GISTs: two women (82 and 54 years of age, and one man (62 years of age. Bones metastases involved the spine, pelvis and ribs in one patient, multiple vertebral bodies and pelvis in one, and the spine and iliac wings in the third case. The lesions presented a lytic pattern in all cases. Two patients presented with multiple bone metastases at the time of initial diagnosis and one patient after seven years during the follow-up period. This report describes the diagnosis and treatment of the lesions and may help clinicians to manage bones metastases in GIST patients.

Levels of circulating CD45dimCD34+VEGFR2+ progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

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Farace, F; Gross-Goupil, M; Tournay, E; Taylor, M; Vimond, N; Jacques, N; Billiot, F; Mauguen, A; Hill, C; Escudier, B

2011-01-01

Background: Predicting the efficacy of antiangiogenic therapy would be of clinical value in patients (pts) with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45dimCD34+VEGFR2+ progenitor cell or plasma angiogenic factor levels are associated with clinical outcome in mRCC pts undergoing treatment with tyrosine kinase inhibitors (TKI). Methods: Fifty-five mRCC pts were prospectively monitored at baseline (day 1) and day 14 during treatment (46 pts received sunitinib and 9 pts received sorafenib). Circulating endothelial cells (CD45−CD31+CD146+7-amino-actinomycin (7AAD)− cells) were measured in 1 ml whole blood using four-color flow cytometry (FCM). Circulating CD45dimCD34+VEGFR2+7AAD− progenitor cells were measured in progenitor-enriched fractions by four-color FCM. Plasma VEGF, sVEGFR2, SDF-1α and sVCAM-1 levels were determined by ELISA. Correlations between baseline CEC, CD45dimCD34+VEGFR2+7AAD− progenitor cells, plasma factors, as well as day 1–day 14 changes in CEC, CD45dimCD34+VEGFR2+7AAD− progenitor, plasma factor levels, and response to TKI, progression-free survival (PFS) and overall survival (OS) were examined. Results: No significant correlation between markers and response to TKI was observed. No association between baseline CEC, plasma VEGF, sVEGFR-2, SDF-1α, sVCAM-1 levels with PFS and OS was observed. However, baseline CD45dimCD34+VEGFR2+7AAD− progenitor cell levels were associated with PFS (P=0.01) and OS (P=0.006). Changes in this population and in SDF-1α levels between day 1 and day 14 were associated with PFS (P=0.03, P=0.002). Changes in VEGF and SDF-1α levels were associated with OS (P=0.02, P=0.007). Conclusion: Monitoring CD45dimCD34+VEGFR2+ progenitor cells, plasma VEGF and SDF-1α levels could be of clinical interest in TKI-treated mRCC pts to predict outcome. PMID:21386843

Associative Symmetry versus Independent Associations in the Memory for Object-Location Associations

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Sommer, Tobias; Rose, Michael; Buchel, Christian

2007-01-01

The formation of associations between objects and locations is a vital aspect of episodic memory. More specifically, remembering the location where one experienced an object and, vice versa, the object one encountered at a specific location are both important elements for the memory of an event. Whether episodic associations are holistic…

Combination of capecitabine and oxaliplatin is an effective treatment option for advanced neuroendocrine tumors

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Renata Ferrarotto

2013-09-01

Full Text Available The role of chemotherapy in well differentiated neuroendocrine tumors (NET has been questioned. It was recently demonstrated that everolimus and sunitinib have activity in low and intermediate grade pancreatic NET. The aim of this study was to evaluate the activity of capecitabine and oxaliplatin (CapOx combination in treating NET in an unselected population. In this regard, we retrospectively evaluated 24 patients diagnosed with metastatic NET treated with CapOx at two Brazilian institutes that are reference centers in cancer care. Tumor response was measured by RECIST criteria. Median age at diagnosis was 56 years, 71% had ECOG 0 or 1, the majority of tumors were primary from pancreas (67% followed by lung (17%, and 29% were functional. According to WHO classification criteria, 25% were grade 1, 37.5% grade 2 and 37.5% grade 3. Most patients received CapOx as second-line therapy, with a median of 6 cycles. Twenty-nine percent of patients had partial response by RECIST criteria. No association was observed between response rate and tumor grade, primary site or line of CapOx. The median time to progression was 9.8 months and median time to treatment failure was 12.1 months. Seventy-five percent of patients are alive at the time of this analysis; therefore, median overall survival was not reached. The CapOx combination was shown to be active in an unselected population with metastatic NET and may be a good platform for the incorporation of the newer molecular targeted agents being investigated for the treatment of this entity.

Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

Science.gov (United States)

Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Molinolo, Alfredo A.; Hodge, James W.

2014-01-01

This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771

Identification of novel therapeutic targets in microdissected clear cell ovarian cancers.

Directory of Open Access Journals (Sweden)

Michael P Stany

Full Text Available Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

Pazopanib-Induced Severe Acute Pancreatitis

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Kazumichi Kawakubo

2015-08-01

Full Text Available Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and c-Kit approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Nonselective kinase inhibitors, such as sunitinib and sorafenib, are known to be associated with acute pancreatitis. There are few case reports of severe acute pancreatitis induced by pazopanib treatment. We present a case of severe acute pancreatitis caused by pazopanib treatment for cutaneous angiosarcoma. The patient was an 82-year-old female diagnosed with cutaneous angiosarcoma. She had been refractory to docetaxel treatment and began pazopanib therapy. Three months after pazopanib treatment, CT imaging of the abdomen showed the swelling of the pancreas and surrounding soft tissue inflammation without abdominal pain. After she continued pazopanib treatment for 2 months, she presented with nausea and appetite loss. Abdominal CT showed the worsening of the surrounding soft tissue inflammation of the pancreas. Serum amylase and lipase levels were 296 and 177 IU/l, respectively. She was diagnosed with acute pancreatitis induced by pazopanib treatment and was managed conservatively with discontinuation of pazopanib, but the symptoms did not improve. Subsequently, an abdominal CT scan demonstrated the appearance of a pancreatic pseudocyst. She underwent endoscopic ultrasound-guided pseudocyst drainage using a flared-end fully covered self-expandable metallic stent. Then, the symptoms resolved without recurrence. Due to the remarkable progress of molecular targeted therapy, the oncologist should know that acute pancreatitis was recognized as a potential adverse event of pazopanib treatment and could proceed to severe acute pancreatitis.

A comparative analysis of immunorestoration and recovery with conventional and immunotherapeutic protocols in canine generalized demodicosis: a newer insight of immunotherapeutic efficacy of T11TS.

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Sarkar, P; Mukherjee, J; Ghosh, A; Bhattacharjee, M; Mahato, S; Chakraborty, A; Mondal, M; Banerjee, C; Chaudhuri, Swapna

2004-01-01

Demodex canis is a natural inhabiting mite of canine skin. Immunological disorder or genetic disorder induces the Demodex population to proliferate vigorously resulting in generalized demodicosis with consequent chronic immunosuppression. Signs of generalized demodicosis include alopecia, crysting, erythema, secondary pyoderma etc. Amitraz, an acaricide, is used conventionally for the treatment of generalized demodicosis. In many instances, the disease relapses due to the residual immunosuppression. The need of an immunorestorative therapy has been urged in generalized demodicosis. Two immunorestorative drugs, namely, Immuplus, a herbal drug, and T11TS, a sheep erythrocyte surface glycoprotein, has been used in two separate groups of dogs having generalized demodicosis and receiving Amitraz treatment. It was observed that though Amitraz treated group responded to the therapy showing increased E-rosettes and nonspecific cytotoxic efficacy of T-lymphocytes and decrease in phagocytic potential of macrophages, the groups treated with the immunotherapeutics like Immuplus and T11TS, responded better. However, the group treated with T11TS showed best recovery. These results emphasize the need for an immunorestorative therapy in generalized demodicosis and provide data in favor of T11TS as a better immunomodulator in comparison to Immuplus.

Intended Brand Associations

DEFF Research Database (Denmark)

Koll, Oliver; von Wallpach, Sylvia

2014-01-01

of actual consumer brand associations and management-intended brand associations (brand association match). The article presents results from two large-scale studies (3353 and 1201 respondents) involving one consumer goods and one service brand with multiple operationalizations of consumer response...... (attitudinal and behavioral). The results show that consumers with high brand association match show more positive brand response. However, after accounting for the valence of associations match does not add explanatory power. This outcome challenges a key foundation of brand management. The discussion......Brand managers exhibit considerable effort to define intended brand associations to anchor in consumers' minds. They follow a credo deeply rooted in branding literature: intended brand associations drive consumer response and brand equity. This article investigates the benefits of a strong overlap...

Aberrant cortical associative plasticity associated with severe adult Tourette syndrome.

Science.gov (United States)

Martín-Rodríguez, Juan Francisco; Ruiz-Rodríguez, María Adilia; Palomar, Francisco J; Cáceres-Redondo, María Teresa; Vargas, Laura; Porcacchia, Paolo; Gómez-Crespo, Mercedes; Huertas-Fernández, Ismael; Carrillo, Fátima; Madruga-Garrido, Marcos; Mir, Pablo

2015-03-01

Recent studies have shown altered cortical plasticity in adult patients with Tourette syndrome. However, the clinical significance of this finding remains elusive. Motor cortical plasticity was evaluated in 15 adult patients with severe Tourette syndrome and 16 healthy controls using the paired associative stimulation protocol by transcranial magnetic stimulation. Associations between paired associative stimulation-induced plasticity and relevant clinical variables, including cortical excitability, psychiatric comorbidities, drug treatment and tic severity, were assessed. Motor cortical plasticity was abnormally increased in patients with Tourette syndrome compared with healthy subjects. This abnormal plasticity was independently associated with tic severity. Patients with severe Tourette syndrome display abnormally increased cortical associative plasticity. This aberrant cortical plasticity was associated with tic severity, suggesting an underlying mechanism for tic pathophysiology. © 2015 International Parkinson and Movement Disorder Society.

Evaluation of the efficiency of combination palliative treatment in patients with metastatic clear-cell renal cell carcinoma

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P. S. Borisov

2015-01-01

patients with mRCC: 1 20 patients who underwent iCR and 2 27 patients who received systemic therapy (immunotherapy (n = 12, sorafenib (n = 8, and sunitinib (n = 7. The control points were estimation of overall survival (OS, optimal indications for iCR in patients with mRCC, and time to progression (TTP during first- and second-line systemic treatment.Resuts. The median OS duration in Group 1 was longer: 46 months versus 31 months (p = 0.09. TTP was comparable: 9 and 6 months, respectively. Comparison of first-line systemic treatment showed that the median TTP was twice longer (13 and 17 months in the targeted (sorafenib and sunitinib therapy group than that in the cytokine therapy group (6 months (p = 0.0174. TTP during second-line therapy was 10 months. Median OS after immunotherapy, sorafenib and sunitinib therapy demonstrated no differences and was 34.2, 36.5, and 39.2 months (р = 0.8. Conclusion. This investigation suggests that the comprehensive approach in effective in treating mRCC. iRC may be used as an individual treatment in a certain patient group. However, survival rates in the examined group of patients can be increased only when targeted drugs are necessarily used in both first- and second-line treatment regimens. In spite of the metastatic pattern of RCC, the treatment algorithm for these patients should estimate the possibilities of using palliative cytoreductive treatment since its use may provide a median TTP of as many as 9 months. Just the same, over 30-month survival rates may be obtained when the latter is used in combination with systemic treatment.

Associations From Pictures.

Science.gov (United States)

Pettersson, Rune

A picture can be interpreted in different ways by various persons. There is often a difference between a picture's denotation (literal meaning), connotation (associative meaning), and private associations. Two studies were conducted in order to observe the private associations that pictures awaken in people. One study deals with associations made…

Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Science.gov (United States)

Wells, J Connor; Stukalin, Igor; Norton, Craig; Srinivas, Sandy; Lee, Jae Lyun; Donskov, Frede; Bjarnason, Georg A; Yamamoto, Haru; Beuselinck, Benoit; Rini, Brian I; Knox, Jennifer J; Agarwal, Neeraj; Ernst, D Scott; Pal, Sumanta K; Wood, Lori A; Bamias, Aristotelis; Alva, Ajjai S; Kanesvaran, Ravindran; Choueiri, Toni K; Heng, Daniel Y C

2017-02-01

The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. To evaluate the use and efficacy of targeted therapy in a third-line setting. Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated

Risk factors associated with development of ventilator associated pneumonia.

Science.gov (United States)

Noor, Ahmed; Hussain, Syed Fayyaz

2005-02-01

To assess the risk factors associated with development of ventilator associated pneumonia (VAP). A case control study. Intensive Care Unit (ICU) at the Aga Khan University Hospital, Karachi, between January 1999 and June 2000. All patients with assisted mechanical ventilation were assessed for the development of VAP. Risk factors associated with development of VAP were determined. Adult patients who developed pneumonia, 48 hours after ventilation, were called cases while those who did not develop pneumonia were called controls. Seventy (28%) out of 250 mechanically ventilated patients developed VAP (rate of VAP was 26 cases per 1000 ventilator days). Shock during first 48 hours of ventilation (odds ratio (OR), 5.95; 95% confidence interval (CI), 2.83-12.52), transport out of ICU during mechanical ventilation (OR, 6.0; 95% CI, 2.92-12.37), re-intubation (OR, 4.23; 95% CI, 2.53-9.85), prior episode of aspiration of gastric content (OR, 3.07; 95% CI, 1.35-7.01), and use of antibiotics prior to intubation (OR,2.55; 95% CI, 1.20-5.41) were found to be independently associated with a higher risk of developing VAP. Gram negative organisms and Staphylococcus aureus were responsible for over 90% of cases. Patients with VAP had higher crude mortality rate (57.1%) compared with controls (32.2%). Ventilator associated pneumonia is associated with a high mortality. This study has identified risk factors associated with VAP.

Priming in a free association task as a function of association directionality.

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Zeelenberg, R; Shiffrin, R M; Raaijmakers, J G

1999-11-01

Two experiments investigated priming in free association, a conceptual implicit memory task. The stimuli consisted of bidirectionally associated word pairs (e.g., BEACH-SAND) and unidirectionally associated word pairs that have no association from the target response back to the stimulus cue (e.g., BONE-DOG). In the study phase, target words (e.g., SAND, DOG) were presented in an incidental learning task. In the test phase, participants generated an associate to the stimulus cues (e.g., BEACH, BONE). In both experiments, priming was obtained for targets (e.g., SAND) that had an association back to the cue, but not for targets (e.g., DOG) for which such a backward association was absent. These results are problematic for theoretical accounts that attribute priming in free association to the strengthening of target responses. It is argued that priming in free association depends on the strengthening of cue-target associations.

Association of prediabetes-associated single nucleotide polymorphisms with microalbuminuria.

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Choi, Jong Wook; Moon, Shinje; Jang, Eun Jung; Lee, Chang Hwa; Park, Joon-Sung

2017-01-01

Increased glycemic exposure, even below the diagnostic criteria for diabetes mellitus, is crucial in the pathogenesis of diabetic microvascular complications represented by microalbuminuria. Nonetheless, there is limited evidence regarding which single nucleotide polymorphisms (SNPs) are associated with prediabetes and whether genetic predisposition to prediabetes is related to microalbuminuria, especially in the general population. Our objective was to answer these questions. We conducted a genomewide association study (GWAS) separately on two population-based cohorts, Ansung and Ansan, in the Korean Genome and Epidemiology Study (KoGES). The initial GWAS was carried out on the Ansung cohort, followed by a replication study on the Ansan cohort. A total of 5682 native Korean participants without a significant medical illness were classified into either control group (n = 3153) or prediabetic group (n = 2529). In the GWAS, we identified two susceptibility loci associated with prediabetes, one at 17p15.3-p15.1 in the GCK gene and another at 7p15.1 in YKT6. When variations in GCK and YKT6 were used as a model of prediabetes, this genetically determined prediabetes increased microalbuminuria. Multiple logistic regression analyses revealed that fasting glucose concentration in plasma and SNP rs2908289 in GCK were associated with microalbuminuria, and adjustment for age, gender, smoking history, systolic blood pressure, waist circumference, and serum triglyceride levels did not attenuate this association. Our results suggest that prediabetes and the associated SNPs may predispose to microalbuminuria before the diagnosis of diabetes mellitus. Further studies are needed to explore the details of the physiological and molecular mechanisms underlying this genetic association.

Juvenile cellulitis in dogs: 15 cases (1979-1988).

Science.gov (United States)

White, S D; Rosychuk, R A; Stewart, L J; Cape, L; Hughes, B J

1989-12-01

The records of 15 dogs diagnosed as having juvenile cellulitis (juvenile pyoderma, puppy strangles) were evaluated for clinical, laboratory, and therapeutic results. Mandibular lymphadenopathy was observed in 14 dogs, and was not associated with skin lesions in 5 dogs. Edema, pustules, papules, or crusts were noticed periorally, periocularly, on the chin or muzzle, or in the ears of those dogs with skin lesions. Eight dogs were lethargic; fever and anorexia were inconsistent findings. Four dogs had signs of pain on manipulation of their joints. Complete blood counts revealed leukocytosis with neutrophilia in 4 dogs, and normocytic, normochromic anemia in 6 dogs. Three dogs had suppurative lymphadenitis with many neutrophils. Cytology of the aspirate of pustules or abscesses in 6 dogs revealed many neutrophils without bacteria. Coagulase-positive Staphylococcus spp were isolated from draining lesions in 2 dogs. Intact abscesses and lymph nodes were negative for bacterial growth in 4 dogs. Three of these dogs were being administered antibiotics at the time of bacterial culturing. Cytology of the aspirates of joints in 3 of the 4 dogs with joint pain revealed suppurative arthritis with no bacteria, and the aspirates were negative for bacterial growth on culturing, although all 3 dogs were being administered antibiotics at the time of culturing. Of 12 dogs initially treated with antibiotics, only 4 (33%) responded favorably; the other 8 dogs were then given antibiotics and corticosteroids. Three dogs were initially given antibiotics and corticosteroids. All dogs treated concurrently with antibiotics and corticosteroids responded favorably. One of these dogs had a relapse after treatment was discontinued. The concurrent arthritis in 4 of the dogs resolved with treatment of the juvenile cellulitis and did not redevelop once the medication was discontinued. Concurrent treatment with antibiotics (cephalosporins) and prednisone (2.2 mg/kg of body weight/day) was the most

Association of prediabetes-associated single nucleotide polymorphisms with microalbuminuria

Science.gov (United States)

Choi, Jong Wook; Moon, Shinje; Jang, Eun Jung; Lee, Chang Hwa; Park, Joon-Sung

2017-01-01

Increased glycemic exposure, even below the diagnostic criteria for diabetes mellitus, is crucial in the pathogenesis of diabetic microvascular complications represented by microalbuminuria. Nonetheless, there is limited evidence regarding which single nucleotide polymorphisms (SNPs) are associated with prediabetes and whether genetic predisposition to prediabetes is related to microalbuminuria, especially in the general population. Our objective was to answer these questions. We conducted a genomewide association study (GWAS) separately on two population-based cohorts, Ansung and Ansan, in the Korean Genome and Epidemiology Study (KoGES). The initial GWAS was carried out on the Ansung cohort, followed by a replication study on the Ansan cohort. A total of 5682 native Korean participants without a significant medical illness were classified into either control group (n = 3153) or prediabetic group (n = 2529). In the GWAS, we identified two susceptibility loci associated with prediabetes, one at 17p15.3-p15.1 in the GCK gene and another at 7p15.1 in YKT6. When variations in GCK and YKT6 were used as a model of prediabetes, this genetically determined prediabetes increased microalbuminuria. Multiple logistic regression analyses revealed that fasting glucose concentration in plasma and SNP rs2908289 in GCK were associated with microalbuminuria, and adjustment for age, gender, smoking history, systolic blood pressure, waist circumference, and serum triglyceride levels did not attenuate this association. Our results suggest that prediabetes and the associated SNPs may predispose to microalbuminuria before the diagnosis of diabetes mellitus. Further studies are needed to explore the details of the physiological and molecular mechanisms underlying this genetic association. PMID:28158221

Catheter-associated UTI

Science.gov (United States)

... UTI; Health care-associated UTI; Catheter-associated bacteriuria; Hospital acquired-UTI Images Bladder catheterization, female Bladder catheterization, male References Calfee DP. Prevention and control of health care-associated infections. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

Protein complexes associated with the Kaposi's sarcoma-associated herpesvirus-encoded LANA

International Nuclear Information System (INIS)

Kaul, Rajeev; Verma, Subhash C.; Robertson, Erle S.

2007-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) is the major biological cofactor contributing to development of Kaposi's sarcoma. KSHV establishes a latent infection in human B cells expressing the latency-associated nuclear antigen (LANA), a critical factor in the regulation of viral latency. LANA is known to modulate viral and cellular gene expression. We report here on some initial proteomic studies to identify cellular proteins associated with the amino and carboxy-terminal domains of LANA. The results of these studies show an association of known cellular proteins which support LANA functions and have identified additional LANA-associated proteins. These results provide new evidence for complexes involving LANA with a number of previously unreported functional classes of proteins including DNA polymerase, RNA helicase and cell cycle control proteins. The results also indicate that the amino terminus of LANA can interact with its carboxy-terminal domain. This interaction is potentially important for facilitating associations with other cell cycle regulatory proteins which include CENP-F identified in association with both the amino and carboxy-termini. These novel associations add to the diversity of LANA functions in relation to the maintenance of latency and subsequent transformation of KSHV infected cells

Staff Association

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Staff Association

2014-01-01

Remove of the staff association office   The Staff Association offices are going to be renovated during the coming four months, February to May 2014. The physical move from our current premises 64/R-002 to our temporary office in  510/R-010 will take place on Friday January 31st, so the Secretariat will be closed on that day. Hence, from Monday February 3rd until the end of May 2014 the Staff Association Secretariat will be located in 510/R-010 (entrance just across the CERN Printshop).    

Helicobacter heilmannii-associated Gastritis: Clinicopathologic Findings and Comparison with Helicobacter pylori-associated Gastritis

Science.gov (United States)

Kwak, Ji Eun; Chang, Sun Hee; Kim, Hanseong; Chi, Je G.; Kim, Kyung-Ah; Yang, Jeon Ho; Lee, June Sung; Moon, Young-Soo; Kim, Kyoung-Mee

2007-01-01

The aims of this study were to evaluate the clinicopathologic features of Helicobacter heilmannii-associated gastritis and to compare H. heilmannii-associated gastritis with H. pylori-associated gastritis. We reviewed 5,985 consecutive gastric biopsy specimens. All cases of chronic gastritis with Helicobacter infection were evaluated with the Updated Sydney System, and the grades of all gastritis variables were compared between H. heilmannii-associated gastritis and H. pylori-associated gastritis groups. There were 10 cases of H. heilmannii-associated gastritis (0.17%) and 3,285 cases of H. pylori-associated gastritis (54.9%). The organisms were superficially located within the mucous layer without adhesion to epithelial cells. Interestingly, in one case many intracytoplasmic H. heilmannii organisms were observed in parietal cells with cell damage. A case of low-grade mucosa-associated lymphoid tissue (MALT) lymphoma concomitant with H. heilmannii infection was detected. Compared to H. pylori-associated gastritis, H. heilmannii-associated gastritis showed less severe neutrophilic activity (pgastritis devoid of erosion or ulcer (p=0.0309). In conclusion, we present the detailed clinicopathologic findings of H. heilmannii-associated gastritis compared to H. pylori-associated gastritis. H. heilmannii-associated gastritis is uncommon and milder than H. pylori-associated gastritis, however it may be noteworthy with respect to the development of MALT lymphoma. PMID:17297253

Cdk1-Cyclin B1-mediated Phosphorylation of Tumor-associated Microtubule-associated Protein/Cytoskeleton-associated Protein 2 in Mitosis*

OpenAIRE

Uk Hong, Kyung; Kim, Hyun-Jun; Kim, Hyo-Sil; Seong, Yeon-Sun; Hong, Kyeong-Man; Bae, Chang-Dae; Park, Joobae

2009-01-01

During mitosis, establishment of structurally and functionally sound bipolar spindles is necessary for maintaining the fidelity of chromosome segregation. Tumor-associated microtubule-associated protein (TMAP), also known as cytoskeleton-associated protein 2 (CKAP2), is a mitotic spindle-associated protein whose level is frequently up-regulated in various malignancies. Previous reports have suggested that TMAP is a potential regulator of mitotic spindle assembly and dynamics and that it is re...

Advances and Challenges on Management of Gastrointestinal Stromal Tumors

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Lin Mei

2018-05-01

Full Text Available Gastrointestinal stromal tumors (GISTs originate from interstitial cells of Cajal and account for over 5,000 newly diagnosed cases in the United States. The discovery of activated KIT and PDGFRA mutations and introduction of imatinib revolutionized the treatment strategy and opened up the new era of target therapy for solid tumors. Although surgery remains the primary modality of treatment for curative purpose, almost half of the patients experienced disease recurrence. Tailoring (neo-adjuvant treatment with imatinib is ongoing to meet the need for an effective therapy. Currently, two drugs (sunitinib and regorafenib have obtained Food and Drug Administration approval for GISTs after imatinib failure. However, most of the patients eventually progress due to primary or secondary resistance. Deeper understanding of the molecular mechanisms will guide us to develop personalized strategies in the future. Discussion in this review includes current standard management and the most recent advances and multiple ongoing clinical trials with different approaches. This review will provide further steps to be taken to conquer refractory disease.

mTOR inhibitors in the treatment of advanced renal cell carcinoma

International Nuclear Information System (INIS)

Barilla, R.; Sycova-Mila, Z.

2009-01-01

Renal Cell Carcinoma (RCC) accounts for approximately 4 % of all malignancies. Much is known about the pathogenesis of RCC because of studies examining its close relationship with dysfunction of the Von Hippel-Lindau gene (VHL) and hypoxia inducible factor (HIF). Mammalian target of rapamycin (mTOR) regulates nutritional needs, cell growth, and angiogenesisi in cells by down regulating or up regulating a variety of proteins including HIF. Until 2005, only a single agent high dose interleukin 2 was approved by Food and Drug Administration (FDA) for treatment of advanced renal cell carcinoma. More recently thanks to better knowledge in the field of molecular biology new treatment options appeared. Sunitinib and bevacizumab are currently considered to be treatment of first choice for patients in good and intermediate prognostic group and sorafenib is preferred second line treatment in the same patient population pretreated with cytokines after disease progression. Temsirolimus and everolimus, rapamycin analouges, have recently been tested in III trials in first and second line treatment in patients with advanced metastatic clear cell renal cell carcinoma. (author)

Current Immunotherapeutic Strategies to Enhance Oncolytic Virotherapy

Directory of Open Access Journals (Sweden)

Daniel E. Meyers

2017-06-01

Full Text Available Oncolytic viruses (OV represent a promising strategy to augment the spectrum of cancer therapeutics. For efficacy, they rely on two general mechanisms: tumor-specific infection/cell-killing, followed by subsequent activation of the host’s adaptive immune response. Numerous OV genera have been utilized in clinical trials, ultimately culminating in the 2015 Food and Drug Administration approval of a genetically engineered herpes virus, Talminogene laherparepvec (T-VEC. It is generally accepted that OV as monotherapy have only modest clinical efficacy. However, due to their ability to elicit specific antitumor immune responses, they are prime candidates to be paired with other immune-modulating strategies in order to optimize therapeutic efficacy. Synergistic strategies to enhance the efficacy of OV include augmenting the host antitumor response through the insertion of therapeutic transgenes such as GM-CSF, utilization of the prime-boost strategy, and combining OV with immune-modulatory drugs such as cyclophosphamide, sunitinib, and immune checkpoint inhibitors. This review provides an overview of these immune-based strategies to improve the clinical efficacy of oncolytic virotherapy.

Metastatic gastric cancer – focus on targeted therapies

Directory of Open Access Journals (Sweden)

Meza-Junco J

2012-06-01

Full Text Available Judith Meza-Junco, Michael B SawyerDepartment of Oncology, Cross Cancer Institute, Edmonton, Alberta, CanadaAbstract: Gastric cancer (GC is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.Keywords: gastric cancer, targeted therapy, antiangiogenesis drugs, anti-EGFR drugs

Development and plasticity of meningeal lymphatic vessels.

Science.gov (United States)

Antila, Salli; Karaman, Sinem; Nurmi, Harri; Airavaara, Mikko; Voutilainen, Merja H; Mathivet, Thomas; Chilov, Dmitri; Li, Zhilin; Koppinen, Tapani; Park, Jun-Hee; Fang, Shentong; Aspelund, Aleksanteri; Saarma, Mart; Eichmann, Anne; Thomas, Jean-Léon; Alitalo, Kari

2017-12-04

The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS. © 2017 Antila et al.

Tumor therapy with a urokinase plasminogen activator-activated anthrax lethal toxin alone and in combination with paclitaxel.

Science.gov (United States)

Wein, Alexander N; Liu, Shihui; Zhang, Yi; McKenzie, Andrew T; Leppla, Stephen H

2013-02-01

PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on prior reports suggesting synergy between ERK1/2 inhibition and chemotherapeutics. Colo205 was sensitive to PA-U2/LF while B16-BL6 was not. For the combination treatment of B16-BL6, paclitaxel showed a dose response in vitro, but cells remained resistant to PA-U2/LF even in the presence of paclitaxel. In vivo, each therapy slowed tumor progression, and an additive effect between the two was observed. Since LF targets tumor vasculature while paclitaxel is an antimitotic, it is possible the agents were acting against different cells in the stroma, precluding a synergistic effect. The engineered anthrax toxin PA-U2/LF warrants further development and testing, possibly in combination with an antiangiogenesis therapy such as sunitinib or sorafinib.

New advancements and developments in treatment of renal cell carcinoma: focus on pazopanib

Directory of Open Access Journals (Sweden)

C Lance Cowey

2010-09-01

Full Text Available C Lance Cowey1, Guru Sonpavde2, Thomas E Hutson11Baylor-Sammons Cancer Center/Texas Oncology, PA, GU Oncology Program, Dallas, 2Baylor College of Medicine/Texas Oncology, PA, Houston, Texas, USAAbstract: With the recent approval of pazopanib, an oral multitargeted tyrosine kinase inhibitor which potently targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor, and c-kit, six agents are now available for use in the management of metastatic renal cell carcinoma (RCC. Pazopanib has shown improved progression-free survival compared with placebo in treatment-naïve or cytokine-treated patients with metastatic RCC in large Phase II and Phase III clinical trials. Pazopanib has demonstrated a tolerable side effect profile and is currently being compared with sunitinib in a Phase III noninferiority trial. In this review, the outcomes of the clinical testing of pazopanib are discussed, as well as a perspective on the placement of pazopanib among other approved agents.Keywords: renal cell carcinoma, targeted agents, vascular endothelial growth factor ­inhibitors, pazopanib

Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: A Review of Its Incidence, Pathophysiology, Clinical Relevance, and Treatment

Directory of Open Access Journals (Sweden)

Hala Ahmadieh

2013-01-01

Full Text Available Tyrosine kinase inhibitors (TKI belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST, a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level.

Management Options for Advanced Low or Intermediate Grade Gastroenteropancreatic Neuroendocrine Tumors: Review of Recent Literature

Directory of Open Access Journals (Sweden)

Vladimir Neychev

2017-01-01

Full Text Available Our understanding of the biology, genetics, and natural history of neuroendocrine tumors (NETs of the gastrointestinal tract and pancreas has improved considerably in the last several decades and the spectrum of available therapeutic options is rapidly expanding. The management of patients with metastatic low or intermediate grade NETs has been revolutionized by the development of new treatment strategies such as molecular targeting therapies with everolimus and sunitinib, somatostatin analogs, tryptophan hydroxylase inhibitors, and peptide receptor radionuclide therapy that can be used alone or as a multimodal approach with or without surgery. To further define and clarify the utility, appropriateness, and the sequence of the growing list of available therapies for this patient population will require more high level evidence; however, data from well-designed randomized phase III clinical trials is rapidly accumulating that will further stimulate development of new management strategies. It is therefore important to thoroughly review emerging evidence and report major findings in frequent updates, which will expand our knowledge and contribute to a better understanding, characterization, and management of advanced NETs.

Staff Association Cocktail

CERN Multimedia

Staff Association

2017-01-01

The Staff Association has been organising for many years a cocktail with delegates of the Member States participating in Finance Committees of March and September. This cocktail is held at the end of the day, after the Finance Committee meeting. This direct and regular communication helps establish an ongoing contact between the Staff Association and CERN Member States and, more recently, the Associate Member States. Ambassadors of the CERN Staff Association, who are Members of the Personnel, have the opportunity to meet their national delegation in an informal and friendly atmosphere. These exchanges, facilitated by the use of the national language, allow the personnel via the Staff Association to express its ideas and positions on current affairs and fundamental issues, and also to hear about those of the delegations in return.

Associative Memory Acceptors.

Science.gov (United States)

Card, Roger

The properties of an associative memory are examined in this paper from the viewpoint of automata theory. A device called an associative memory acceptor is studied under real-time operation. The family "L" of languages accepted by real-time associative memory acceptors is shown to properly contain the family of languages accepted by one-tape,…

Grouping by association: using associative networks for document categorization

NARCIS (Netherlands)

Bloom, Niels

2015-01-01

In this thesis we describe a method of using associative networks for automatic doc- ument grouping. Associative networks are networks of ideas or concepts in which each concept is linked to concepts that are semantically similar to it. By activating concepts in the network based on the text of a

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.

Science.gov (United States)

Zhang, Liang; Wang, Xiaoen; Bullock, Andrea J; Callea, Marcella; Shah, Harleen; Song, Jiaxi; Moreno, Kelli; Visentin, Barbara; Deutschman, Douglas; Alsop, David C; Atkins, Michael B; Mier, James W; Signoretti, Sabina; Bhasin, Manoj; Sabbadini, Roger A; Bhatt, Rupal S

2015-04-15

VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC. In this study, we performed transcriptome analysis of VEGFR TKI-resistant tumors in a murine model and discovered that the SPHK-S1P pathway is upregulated at the time of resistance. We tested sphingosine-1-phosphate (S1P) pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC. Resistant tumors expressed several hypoxia-regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC, suggesting that human RCC behavior could, in part, be due to overproduction of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI. Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment-naïve RCC and also in the setting of resistance to VEGFR TKI therapy. ©2015 American Association for Cancer Research.

Imatinib induced severe skin reactions and neutropenia in a patient with gastrointestinal stromal tumor

International Nuclear Information System (INIS)

Hwang, Jun-Eul; Yoon, Ju-Young; Bae, Woo-Kyun; Shim, Hyun-Jeong; Cho, Sang-Hee; Chung, Ik-Joo

2010-01-01

Imatinib mesylate has been used for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST). The current recommended dose of imatinib is 400 mg/day that is increased to 800 mg/day in cases with disease progression. However, imatinib can be associated with diverse adverse events, which has limited its use. We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment in a patient with GIST. A 71-year-old man was admitted with a one month history of epigastric pain and a palpable mass in the right upper quadrant. An abdominal CT scan revealed a 20 × 19 cm intraabdominal mass with tumor invasion into the peritoneum. Needle biopsy was performed and the results showed spindle shaped tumor cells that were positive for c-KIT. The patient was diagnosed with unresectable GIST. Imatinib 400 mg/day was started. The patient tolerated the first eight weeks of treatment. However, about three months later, the patient developed a grade 4 febrile neutropenia and a grade 3 exfoliative skin rash. The patient recovered from this serious adverse events after discontinuation of imatinib with supportive care. However, the skin lesions recurred whenever the patient received imatinib over 100 mg/day. Therefore, imatinib 100 mg/day was maintained. Despite the low dose imatinib, follow up CT showed a marked partial response without grade 3 or 4 toxicities. The recommended dose of imatinib for the treatment of GIST is 400 mg/day but patients at risk for adverse drug reaction may benefit from lower doses. Individualized treatment is needed for such patients, and we may also try sunitinib as a alternative drug

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

DEFF Research Database (Denmark)

Rohde, Palle Duun; Demontis, Ditte; Castro Dias Cuyabano, Beatriz

2016-01-01

was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case–control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism......Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited...... genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT...

Class Association Rule Pada Metode Associative Classification

Directory of Open Access Journals (Sweden)

Eka Karyawati

2011-11-01

Full Text Available Frequent patterns (itemsets discovery is an important problem in associative classification rule mining.  Differents approaches have been proposed such as the Apriori-like, Frequent Pattern (FP-growth, and Transaction Data Location (Tid-list Intersection algorithm. This paper focuses on surveying and comparing the state of the art associative classification techniques with regards to the rule generation phase of associative classification algorithms.  This phase includes frequent itemsets discovery and rules mining/extracting methods to generate the set of class association rules (CARs.  There are some techniques proposed to improve the rule generation method.  A technique by utilizing the concepts of discriminative power of itemsets can reduce the size of frequent itemset.  It can prune the useless frequent itemsets. The closed frequent itemset concept can be utilized to compress the rules to be compact rules.  This technique may reduce the size of generated rules.  Other technique is in determining the support threshold value of the itemset. Specifying not single but multiple support threshold values with regard to the class label frequencies can give more appropriate support threshold value.  This technique may generate more accurate rules. Alternative technique to generate rule is utilizing the vertical layout to represent dataset.  This method is very effective because it only needs one scan over dataset, compare with other techniques that need multiple scan over dataset.   However, one problem with these approaches is that the initial set of tid-lists may be too large to fit into main memory. It requires more sophisticated techniques to compress the tid-lists.

Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.

Science.gov (United States)

de Boer, Ynto S; van Gerven, Nicole M F; Zwiers, Antonie; Verwer, Bart J; van Hoek, Bart; van Erpecum, Karel J; Beuers, Ulrich; van Buuren, Henk R; Drenth, Joost P H; den Ouden, Jannie W; Verdonk, Robert C; Koek, Ger H; Brouwer, Johannes T; Guichelaar, Maureen M J; Vrolijk, Jan M; Kraal, Georg; Mulder, Chris J J; van Nieuwkerk, Carin M J; Fischer, Janett; Berg, Thomas; Stickel, Felix; Sarrazin, Christoph; Schramm, Christoph; Lohse, Ansgar W; Weiler-Normann, Christina; Lerch, Markus M; Nauck, Matthias; Völzke, Henry; Homuth, Georg; Bloemena, Elisabeth; Verspaget, Hein W; Kumar, Vinod; Zhernakova, Alexandra; Wijmenga, Cisca; Franke, Lude; Bouma, Gerd

2014-08-01

Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Characterization of mitosis-specific phosphorylation of tumor-associated microtubule-associated protein

OpenAIRE

Hong, Kyung Uk; Kim, Hyun-Jun; Bae, Chang-Dae; Park, Joobae

2009-01-01

Tumor-associated microtubule-associated protein (TMAP), also known as cytoskeleton associated protein 2 (CKAP2), has been recently shown to be involved in the assembly and maintenance of mitotic spindle and also plays an essential role in maintaining the fidelity of chromosome segregation during mitosis. We have previously reported that TMAP is phosphorylated at multiple residues specifically during mitosis, and characterized the mechanism and functional importance of phosphorylation at one o...

ClaimAssociationService

Data.gov (United States)

Department of Veterans Affairs — Retrieves and updates a veteranÆs claim status and claim-rating association (claim association for current rating) from the Corporate database for a claim selected...

Role of presurgical targeted molecular therapy in renal cell carcinoma with an inferior vena cava tumor thrombus

Directory of Open Access Journals (Sweden)

Peng C

2018-04-01

Full Text Available Cheng Peng,1,* Liangyou Gu,1,* Lei Wang,2 Qingbo Huang,1 Baojun Wang,1 Gang Guo,1 Yang Fan,1 Yu Gao,1 Xin Ma,1 Xu Zhang1 1Department of Urology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical Academy, Beijing, People’s Republic of China; 2Department of Urology, Chinese PLA 534 Hospital, Luoyang, People’s Republic of China *These authors contributed equally to this work Purpose: The clinical benefit of targeted molecular therapy (TMT in renal cell carcinoma (RCC with an inferior vena cava (IVC tumor thrombus remains controversial. The aim of this study was to investigate the effects of presurgical TMT on the heights and levels of IVC thrombi, and to assess its impact on surgical strategy. Patients and methods: We retrospectively reviewed data from 18 patients with RCC involving IVC tumor thrombi who were treated at our hospital with presurgical TMT followed by an IVC thrombectomy. The changes in heights and levels of the IVC thrombi were compared using computed tomography or magnetic resonance imaging. Clinicopathological factors were also evaluated to assess their association with TMT efficacy. Results: The tumor thrombus levels before TMT were stage I in 1 patient (5.6%, II in 12 patients (66.7%, III in 4 patients (22.2%, and IV in 1 patient (5.6%. After a median of two treatment cycles (range: 1–3, the thrombus height decreased measurably in 11 patients (61.1% with an average shrinkage of 17.7%. The thrombus height remained stable in five patients (27.8% and was enlarged in two (11.1%. Downstaging of the thrombus level occurred in four patients (22.2%; the surgical strategy was modified in three patients (16.7% to avoid cardiopulmonary bypass and complicated liver mobilization under robot-assisted laparoscopy. Furthermore, a higher neutrophil count tended to be associated with a worse clinical TMT-associated outcome (P=0.056. Conclusion: Our data suggest a limited influence of presurgical TMT

12 CFR 619.9050 - Associations.

Science.gov (United States)

2010-01-01

... credit associations, production credit associations, and agricultural credit associations. [55 FR 24888... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Associations. 619.9050 Section 619.9050 Banks and Banking FARM CREDIT ADMINISTRATION FARM CREDIT SYSTEM DEFINITIONS § 619.9050 Associations. The...

The Association of Academic Health Sciences Libraries' collaboration with the Association of American Medical Colleges, Medical Library Association, and other organizations.

Science.gov (United States)

Jenkins, Carol G; Bader, Shelley A

2003-04-01

The Association of Academic Health Sciences Libraries has made collaboration with other organizations a fundamental success strategy throughout its twenty-five year history. From the beginning its relationships with Association of American Medical Colleges and with the Medical Library Association have shaped its mission and influenced its success at promoting academic health sciences libraries' roles in their institutions. This article describes and evaluates those relationships. It also describes evolving relationships with other organizations including the National Library of Medicine and the Association of Research Libraries.

Entity associations for search

NARCIS (Netherlands)

Reinanda, R.

2017-01-01

In this thesis, we investigate the broad problem of computing entity associations for search. Specifically, we consider three types of entity association: entity-entity, entity-document, and entity-aspect associations. We touch upon various domains, starting with specific domains such as the

Search of associative memory.

NARCIS (Netherlands)

Raaijmakers, J.G.W.; Shiffrin, R.M.

1981-01-01

Describes search of associative memory (SAM), a general theory of retrieval from long-term memory that combines features of associative network models and random search models. It posits cue-dependent probabilistic sampling and recovery from an associative network, but the network is specified as a

Mesh Association by Projection along Smoothed-Normal-Vector Fields : Association of Closed Manifolds

NARCIS (Netherlands)

Van Brummelen, E.H.

2006-01-01

The necessity to associate two geometrically distinct meshes arises in many engineering applications. Current mesh-association algorithms are generally unsuitable for the high-order geometry representations associated with high-order finite-element discretizations. In the present work we therefore

American Thyroid Association

Science.gov (United States)

... More October 20, 2017 0 American Thyroid Association: Charles H. Emerson, MD, Will Lead New Board of Directors By ATA | 2017 ... Featured , News Releases | No Comments American Thyroid Association: Charles H. Emerson, MD, Will Lead New Board of Directors October 19,… Read ...

Unilateral CHARGE association

NARCIS (Netherlands)

Trip, J; van Stuijvenberg, M; Dikkers, FG; Pijnenburg, MWH

A case with a predominantly unilateral CHARGE association is reported. The CHARGE association refers to a combination of congenital malformations. This boy had left-sided anomalies consisting of choanal atresia. coloboma and peripheral facial palsy. The infant had a frontal encephalocele. an anomaly

Finnish Bioenergy Association - Finbio

International Nuclear Information System (INIS)

Sopo, R.

1999-01-01

The Finnish Bioenergy Association, was founded in November 1991 in the city of Jyvaeskylae. In November 1996, the membership of FINBIO consisted of 17 contributing collective members and 75 individual members. Members of the organization include e.g. the Association of Finnish Peat Industries, Wood Energy Association and Finnish Biogas Centre, all of which represent specific bioenergy fields in Finland. The Finnish Bioenergy Association is a private, non-profit organization the objectives of which are to promote and develop harvesting, transportation and processing of biofuels and other biomass (wood-based biofuels, non-food crops, peat, biowaste); to promote the use of biomass in energy production and in other applications, in accordance with environmentally sound and sustainable development. The objectives of FINBIO is to promote the production and application of all forms of bioenergy in Finland. FINBIO acts as a coordinator for AEBIOM (the European Biomass Association) and its member associations, as well as for other international bioenergy-related organizations

Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy

DEFF Research Database (Denmark)

Feenstra, Bjarke; Bager, Peter; Liu, Xueping

2017-01-01

BACKGROUND: Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered. OBJECTIVE: To identify common genetic variants associate...... the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system.......BACKGROUND: Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered. OBJECTIVE: To identify common genetic variants associated...... with tonsillectomy. METHODS: We used tonsillectomy information from Danish health registers and carried out a genome-wide association study comprising 1464 patients and 12 019 controls of Northwestern European ancestry, with replication in an independent sample set of 1575 patients and 1367 controls. RESULTS...

The Growth-Inequality Association:

DEFF Research Database (Denmark)

Bjørnskov, Christian

2008-01-01

This note suggests that the association between income inequality and economic growth rates might arguably depend on the political ideology of incumbent governments. Estimates indicate that under leftwing governments, inequality is negatively associated with growth while the association is positive...... under rightwing governments. This may provide a qualification to recent studies of inequality....

Genome-wide association study identifies genetic loci associated with iron deficiency.

Directory of Open Access Journals (Sweden)

Christine E McLaren

2011-03-01

Full Text Available The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS was performed using DNA collected from white men aged≥25 y and women≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS Study with serum ferritin (SF≤12 µg/L (cases and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women. Regression analysis was used to examine the association between case-control status (336 cases, 343 controls and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7 for all. An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9, corrected P=0.012 was replicated within the VA samples (observed P=0.012. Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.

Associative learning and animal cognition.

Science.gov (United States)

Dickinson, Anthony

2012-10-05

Associative learning plays a variety of roles in the study of animal cognition from a core theoretical component to a null hypothesis against which the contribution of cognitive processes is assessed. Two developments in contemporary associative learning have enhanced its relevance to animal cognition. The first concerns the role of associatively activated representations, whereas the second is the development of hybrid theories in which learning is determined by prediction errors, both directly and indirectly through associability processes. However, it remains unclear whether these developments allow associative theory to capture the psychological rationality of cognition. I argue that embodying associative processes within specific processing architectures provides mechanisms that can mediate psychological rationality and illustrate such embodiment by discussing the relationship between practical reasoning and the associative-cybernetic model of goal-directed action.

12 CFR 615.5172 - Production credit association and agricultural credit association investment in farmers' notes...

Science.gov (United States)

2010-01-01

... credit association investment in farmers' notes given to cooperatives and dealers. 615.5172 Section 615....5172 Production credit association and agricultural credit association investment in farmers' notes... farmers and ranchers eligible to borrow from such associations. (b) Such notes and other obligations...

Prediction of disease and phenotype associations from genome-wide association studies.

Directory of Open Access Journals (Sweden)

Stephanie N Lewis

Full Text Available Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases.Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits.The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

Dynamics of associating networks

Science.gov (United States)

Tang, Shengchang; Habicht, Axel; Wang, Muzhou; Li, Shuaili; Seiffert, Sebastian; Olsen, Bradley

Associating polymers offer important technological solutions to renewable and self-healing materials, conducting electrolytes for energy storage and transport, and vehicles for cell and protein deliveries. The interplay between polymer topologies and association chemistries warrants new interesting physics from associating networks, yet poses significant challenges to study these systems over a wide range of time and length scales. In a series of studies, we explored self-diffusion mechanisms of associating polymers above the percolation threshold, by combining experimental measurements using forced Rayleigh scattering and analytical insights from a two-state model. Despite the differences in molecular structures, a universal super-diffusion phenomenon is observed when diffusion of molecular species is hindered by dissociation kinetics. The molecular dissociation rate can be used to renormalize shear rheology data, which yields an unprecedented time-temperature-concentration superposition. The obtained shear rheology master curves provide experimental evidence of the relaxation hierarchy in associating networks.

Dengue-associated neuromuscular complications

OpenAIRE

Ravindra Kumar Garg; Hardeep Singh Malhotra; Amita Jain; Kiran Preet Malhotra

2015-01-01

Dengue is associated with many neurological dysfunctions. Up to 4% of dengue patients may develop neuromuscular complications. Muscle involvement can manifest with myalgias, myositis, rhabdomyolysis and hypokalemic paralysis. Diffuse myalgia is the most characteristic neurological symptom of dengue fever. Dengue-associated myositis can be of varying severity ranging from self-limiting muscle involvement to severe dengue myositis. Dengue-associated hypokalemic paralysis often has a rapidly evo...

Functional imaging of implicit marijuana associations during performance on an Implicit Association Test (IAT)

NARCIS (Netherlands)

Ames, S.L.; Grenard, J.L.; Stacy, A.W.; Xiao, L.; He, Q.; Wong, S.W; Xue, G.; Wiers, R.W.; Bechara, A.

2013-01-01

This research evaluated the neural correlates of implicit associative memory processes (habit-based processes) through the imaging (fMRI) of a marijuana Implicit Association Test. Drug-related associative memory effects have been shown to consistently predict level of drug use. To observe

Genome-wide association scan for variants associated with early-onset prostate cancer.

Directory of Open Access Journals (Sweden)

Ethan M Lange

Full Text Available Prostate cancer is the most common non-skin cancer and the second leading cause of cancer related mortality for men in the United States. There is strong empirical and epidemiological evidence supporting a stronger role of genetics in early-onset prostate cancer. We performed a genome-wide association scan for early-onset prostate cancer. Novel aspects of this study include the focus on early-onset disease (defined as men with prostate cancer diagnosed before age 56 years and use of publically available control genotype data from previous genome-wide association studies. We found genome-wide significant (p<5×10(-8 evidence for variants at 8q24 and 11p15 and strong supportive evidence for a number of previously reported loci. We found little evidence for individual or systematic inflated association findings resulting from using public controls, demonstrating the utility of using public control data in large-scale genetic association studies of common variants. Taken together, these results demonstrate the importance of established common genetic variants for early-onset prostate cancer and the power of including early-onset prostate cancer cases in genetic association studies.

Transient phosphorylation of tumor associated microtubule associated protein (TMAP)/cytoskeleton associated protein 2 (CKAP2) at Thr-596 during early phases of mitosis

OpenAIRE

Hong, Kyung Uk; Choi, Yong-Bock; Lee, Jung-Hwa; Kim, Hyun-Jun; Kwon, Hye-Rim; Seong, Yeon-Sun; Kim, Heung Tae; Park, Joobae; Bae, Chang-Dae; Hong, Kyeong-Man

2008-01-01

Tumor associated microtubule associated protein (TMAP), also known as cytoskeleton associated protein 2 (CKAP2) is a mitotic spindle-associated protein whose expression is cell cycle-regulated and also frequently deregulated in cancer cells. Two monoclonal antibodies (mAbs) against TMAP/CKAP2 were produced: B-1-13 and D-12-3. Interestingly, the reactivity of mAb D-12-3 to TMAP/CKAP2 was markedly decreased specifically in mitotic cell lysate. The epitope mapping study showed that mAb D-12-3 re...

Filaggrin gene polymorphism associated with Epstein-Barr virus-associated tumors in China.

Science.gov (United States)

Yang, Yang; Liu, Wen; Zhao, Zhenzhen; Zhang, Yan; Xiao, Hua; Luo, Bing

2017-08-01

Mutations of filaggrin gene (FLG) have been identified as the cause of ichthyosis vulgaris, while recently FLG mutations were found to be associated with gastric cancer. This study aimed to investigate the association of filaggrin polymorphism with Epstein-Barr virus-associated tumors in China. A total of 200 patients with three types of tumors and 117 normal control samples were genotyped at three common FLG mutation loci (rs3126085, K4671X, R501X) by using Sequenom MassARRAY technique. The χ 2 test was used to evaluate the relationship between the mutation and the three kinds of tumors. A two-sided P value of Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC), respectively. Furthermore, allele distributions in EBVaGC and EBVnGC were verified to be different in both SNP loci.

Blastogenetic associations: General considerations.

Science.gov (United States)

Lubinsky, Mark

2015-11-01

Associations of anomalies, with VACTERL as the prototype, have been the source of much debate, including questions about the validity and definition of this category. Evidence is presented for a teratologic basis for associations involving interactions between disruptive events and specific vulnerabilities. Because the embryo is organized in time and space, differences in the timing, location, and severity of exposures will create variable sequelae for any specific vulnerability, creating associations. The blastogenetic stage of development involves distinct properties that affect the nature of associations arising during this time, including relatively undifferentiated developmental fields and causally nonspecific malformations. With this, single anomalies can be part of the spectrum of findings that comprise a specific association. A specific defect defines a subset of disturbances, biasing frequencies of other defects. Processes are basic, integrated, and general, so disruptions are often lethal, and can have multiple effects, accounting for high incidences of multiple anomalies, and overlaps between associations. Blastogenetic disturbances also do not affect the late "fine tuning" of minor anomalies, although pathogenetic sequences can occur. This model suggests that certain combinations of congenital anomalies can arise from causally nonspecific teratogenetic fields determined by timing, location, and vulnerabilities, rather than polytopic developmental fields. © 2015 Wiley Periodicals, Inc.

Current Molecular Targeted Therapies for Bone and Soft Tissue Sarcomas

Directory of Open Access Journals (Sweden)

Kenji Nakano

2018-03-01

Full Text Available Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib’s approval as a treatment for gastrointestinal stromal tumors (GISTs has been a great achievement. Following imatinib, other tyrosine kinase inhibitors (TKIs have been approved for GISTs such as sunitinib and regorafenib, and pazopanib was approved for non-GIST soft tissue sarcomas. Olaratumab, the monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR-α, was shown to extend the overall survival of soft tissue sarcoma patients and was approved in 2016 in the U.S. as a breakthrough therapy. For bone tumors, new drugs are limited to denosumab, a receptor activator of nuclear factor κB ligand (RANKL inhibitor, for treating giant cell tumors of bone. In this review, we explain and summarize the current molecular targeting therapies approved and in development for bone and soft tissue sarcomas.

Clinical use of cabozantinib in the treatment of advanced kidney cancer: efficacy, safety, and patient selection

Directory of Open Access Journals (Sweden)

Yu SS

2016-09-01

Full Text Available Steven S Yu, David I Quinn, Tanya B Dorff Division of Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Abstract: Clear cell (cc renal cell carcinoma (RCC is the most common type of cancer found in the kidney accounting for ~90% of all kidney cancers. In 2012, there were ~337,000 new cases of RCC diagnosed worldwide with an estimated 143,000 deaths, with the highest incidence and mortality in Western countries. Despite improvements in cancer control achieved with VEGF- and mTOR-targeted therapy for RCC, progression remains virtually universal and additional therapies are needed. The pivotal results of the METEOR trial led to cabozantinib’s designation as a breakthrough drug by the US Food and Drug Administration and its approval for treatment of advanced RCC in 2016. Subsequent data from the CABOSUN trial, where caboxantinib is compared with sunitinib, will provide information on the relative activity of cabozantinib as first-line therapy for ccRCC. We review the development of cabozantinib in advanced RCC and its role in the treatment landscape for advanced RCC. Keywords: cabozantinib, renal cell carcinoma, kidney cancer, clear cell carcinoma, tyrosine kinase inhibitor

Efficacy of a protocol including heparin ointment for treatment of multikinase inhibitor-induced hand-foot skin reactions.

Science.gov (United States)

Li, Jian-ri; Yang, Chi-rei; Cheng, Chen-li; Ho, Hao-chung; Chiu, Kun-yuan; Su, Chung-Kuang; Chen, Wen-Ming; Wang, Shian-Shiang; Chen, Chuan-Shu; Yang, Cheng-Kuang; Ou, Yen-chuan

2013-03-01

The purpose of this study is to evaluate the efficacy of a protocol including topical heparin therapy for hand-foot skin reactions (HFSR) during multikinase (MKI) treatment. We prospectively collected 26 patients who had HFSRs during treatment with the MKIs, sunitinib, sorafenib, or axitinib. The age distribution ranged from 46 to 87 years, with a mean of 66 years. The distribution of HFSR severity was 12 patients with grade 1, 12 with grade 2, and 2 with grade 3. A heparin-containing topical ointment treatment, combined with hand-foot shock absorbers and skin moisturizers, was used at the lesion sites. Changes in the grade of HFSR, MKI dosage, and interruptions of MKI therapy were recorded. The results showed that 66.7% of grade 1 patients were cured of disease, 83.3% of grade 2 patients had improved symptoms, and both grade 3 patients (100%) had improved symptoms and were downgraded to grade 2. Four (15.4%) patients required reduction of MKI dosage, but there were no treatment interruptions or dropouts. Our protocol is beneficial in promoting resolution of HFSRs induced by MKIs. Further validation in large control studies should be investigated.

Giant Lysosomes as a Chemotherapy Resistance Mechanism in Hepatocellular Carcinoma Cells.

Science.gov (United States)

Colombo, Federico; Trombetta, Elena; Cetrangolo, Paola; Maggioni, Marco; Razini, Paola; De Santis, Francesca; Torrente, Yvan; Prati, Daniele; Torresani, Erminio; Porretti, Laura

2014-01-01

Despite continuous improvements in therapeutic protocols, cancer-related mortality is still one of the main problems facing public health. The main cause of treatment failure is multi-drug resistance (MDR: simultaneous insensitivity to different anti-cancer agents), the underlying molecular and biological mechanisms of which include the activity of ATP binding cassette (ABC) proteins and drug compartmentalisation in cell organelles. We investigated the expression of the main ABC proteins and the role of cytoplasmic vacuoles in the MDR of six hepatocellular carcinoma (HCC) cell lines, and confirmed the accumulation of the yellow anti-cancer drug sunitinib in giant (four lines) and small cytoplasmic vacuoles of lysosomal origin (two lines). ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes. MTT assays showed that the cell lines with giant lysosomes were more resistant to sorafenib treatment than those with small lysosomes (plysosomes in drug sequestration and MDR in HCC cell lines. The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment.

Molecular Targeted Agents for Gastric Cancer: A Step Forward Towards Personalized Therapy

Directory of Open Access Journals (Sweden)

Tom Geldart

2013-01-01

Full Text Available Gastric cancer (GC represents a major cancer burden worldwide, and remains the second leading cause of cancer-related death. Due to its insidious nature, presentation is usually late and often carries a poor prognosis. Despite having improved treatment modalities over the last decade, for most patients only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and its signaling pathways, offers the hope of clinically significant promising advances for selected groups of patients. Patients with Her-2 overexpression or amplification have experienced benefit from the integration of monoclonal antibodies such as trastuzumab to the standard chemotherapy. Additionally, drugs targeting angiogenesis (bevacizumab, sorafenib, sunitinib are under investigation and other targeted agents such as mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors are in preclinical or early clinical development. Patient selection and the development of reliable biomarkers to accurately select patients most likely to benefit from these tailored therapies is now key. Future trials should focus on these advances to optimize the treatment for GC patients. This article will review recent progress and current status of targeted agents in GC.

Complementary information from magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography in the assessment of the response to an antiangiogenic treatment in a rat brain tumor model

International Nuclear Information System (INIS)

Valable, Samuel; Petit, Edwige; Roussel, Simon; Marteau, Lena; Toutain, Jerome; Divoux, Didier; Sobrio, Franck; Delamare, Jerome; Barre, Louisa; Bernaudin, Myriam

2011-01-01

Introduction: No direct proof has been brought to light in a link between hypoxic changes in glioma models and the effects of antiangiogenic treatments. Here, we assessed the sensitivity of the detection of hypoxia through the use of 18 F-fluoromisonidazole positron emission tomography ([ 18 F]-FMISO PET) in response to the evolution of the tumor and its vasculature. Methods: Orthotopic glioma tumors were induced in rats after implantation of C6 or 9L cells. Sunitinib was administered from day (D) 17 to D24. At D17 and D24, multiparametric magnetic resonance imaging was performed to characterize tumor growth and vasculature. Hypoxia was assessed by [ 18 F]-FMISO PET. Results: We showed that brain hypoxic volumes are related to glioma volume and its vasculature and that an antiangiogenic treatment, leading to an increase in cerebral blood volume and a decrease in vessel permeability, is accompanied by a decrease in the degree of hypoxia. Conclusions: We propose that [ 18 F]-FMISO PET and multiparametric magnetic resonance imaging are pertinent complementary tools in the evaluation of the effects of an antiangiogenic treatment in glioma.

Systematic review of mixed cryoglobulinemia associated with hepatitis E virus infection: association or causation?

OpenAIRE

Bazerbachi, Fateh; Leise, Michael D.; Watt, Kymberly D.; Murad, M. Hassan; Prokop, Larry J.; Haffar, Samir

2017-01-01

Abstract Background and aim: Mixed cryoglobulinemia (MC) has been associated with several viral infections, and chronic hepatitis C is recognized as a major cause. MC associated with hepatitis E virus (HEV) has been described and little is known about this rare association. The aim of this study is to perform a systematic review of MC associated with HEV, and examine the presence of a causal relationship. Methods: An experienced librarian conducted a search of databases from each database?s i...

Extension of the new proposed association equation of state (AEOS) to associating fluid mixtures

International Nuclear Information System (INIS)

Rezaei, H.; Modarress, H.; Mohsen-Nia, M.

2010-01-01

Recently, a new statistical mechanic-based equation of state has been proposed by Mohsen-Nia and Modarress [M. Mohsen-Nia, H. Modarress, Chem. Phys. 336 (2007) 22-26] for associating pure fluids. The new association equation of state (AEOS) was successfully applied to calculate the saturated properties of water, methanol, and ammonia. In this work, the new proposed AEOS is used to evaluate the (vapour + liquid) equilibrium (VLE) of 25 associating pure compounds and the adjusted parameters are reported. The new AEOS is also extended to mixtures containing associating and non-associating compounds. The calculated saturated properties of the pure compounds are compared with those calculated by other AEOSs. The results of VLE calculation for various binary mixtures such as: alcohol/hydrocarbon, alcohol/CO 2 , alcohol/aromatic-hydrocarbons, and the quaternary system (H 2 O/CH 4 /CO 2 /H 2 S) indicate the capability of the new proposed AEOS for associating pure and mixture calculations.

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes.

Science.gov (United States)

Rohde, Palle Duun; Demontis, Ditte; Cuyabano, Beatriz Castro Dias; Børglum, Anders D; Sørensen, Peter

2016-08-01

Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies. Copyright © 2016 by the Genetics Society of America.

Genome-wide association study identifies 74 loci associated with educational attainment

DEFF Research Database (Denmark)

Okbay, Aysu; P. Beauchamp, Jonathan; Alan Fontana, Mark

2016-01-01

-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural......Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals1. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends...... development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals...

Categorical and associative relations increase false memory relative to purely associative relations.

Science.gov (United States)

Coane, Jennifer H; McBride, Dawn M; Termonen, Miia-Liisa; Cutting, J Cooper

2016-01-01

The goal of the present study was to examine the contributions of associative strength and similarity in terms of shared features to the production of false memories in the Deese/Roediger-McDermott list-learning paradigm. Whereas the activation/monitoring account suggests that false memories are driven by automatic associative activation from list items to nonpresented lures, combined with errors in source monitoring, other accounts (e.g., fuzzy trace theory, global-matching models) emphasize the importance of semantic-level similarity, and thus predict that shared features between list and lure items will increase false memory. Participants studied lists of nine items related to a nonpresented lure. Half of the lists consisted of items that were associated but did not share features with the lure, and the other half included items that were equally associated but also shared features with the lure (in many cases, these were taxonomically related items). The two types of lists were carefully matched in terms of a variety of lexical and semantic factors, and the same lures were used across list types. In two experiments, false recognition of the critical lures was greater following the study of lists that shared features with the critical lure, suggesting that similarity at a categorical or taxonomic level contributes to false memory above and beyond associative strength. We refer to this phenomenon as a "feature boost" that reflects additive effects of shared meaning and association strength and is generally consistent with accounts of false memory that have emphasized thematic or feature-level similarity among studied and nonstudied representations.

Genome-wide association study identifies 74 loci associated with educational attainment

Science.gov (United States)

Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark A.; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans68, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A.L.M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.M.; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E.R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J.A.; Venturini, Cristina; Vinkhuyzen, Anna A.E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J.F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L.R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W.J.H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I.A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

2016-01-01

Summary Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease. PMID:27225129

American Nephrology Nurses' Association

Science.gov (United States)

... Join/Renew Jobs Contact Corporate Shop American Nephrology Nurses Association About ANNA Association About ANNA Strategic Plan ... CExpress Events National Events Chapter / Local Events Nephrology Nurses Week ANNA Education Modules CKD Modules Education Services ...

OPATs: Omnibus P-value association tests.

Science.gov (United States)

Chen, Chia-Wei; Yang, Hsin-Chou

2017-07-10

Combining statistical significances (P-values) from a set of single-locus association tests in genome-wide association studies is a proof-of-principle method for identifying disease-associated genomic segments, functional genes and biological pathways. We review P-value combinations for genome-wide association studies and introduce an integrated analysis tool, Omnibus P-value Association Tests (OPATs), which provides popular analysis methods of P-value combinations. The software OPATs programmed in R and R graphical user interface features a user-friendly interface. In addition to analysis modules for data quality control and single-locus association tests, OPATs provides three types of set-based association test: window-, gene- and biopathway-based association tests. P-value combinations with or without threshold and rank truncation are provided. The significance of a set-based association test is evaluated by using resampling procedures. Performance of the set-based association tests in OPATs has been evaluated by simulation studies and real data analyses. These set-based association tests help boost the statistical power, alleviate the multiple-testing problem, reduce the impact of genetic heterogeneity, increase the replication efficiency of association tests and facilitate the interpretation of association signals by streamlining the testing procedures and integrating the genetic effects of multiple variants in genomic regions of biological relevance. In summary, P-value combinations facilitate the identification of marker sets associated with disease susceptibility and uncover missing heritability in association studies, thereby establishing a foundation for the genetic dissection of complex diseases and traits. OPATs provides an easy-to-use and statistically powerful analysis tool for P-value combinations. OPATs, examples, and user guide can be downloaded from http://www.stat.sinica.edu.tw/hsinchou/genetics/association/OPATs.htm. © The Author 2017

12 CFR 561.43 - Savings association.

Science.gov (United States)

2010-01-01

..., chartered under section 5 of the Act, or a building and loan, savings and loan, or homestead association, or... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Savings association. 561.43 Section 561.43... AFFECTING ALL SAVINGS ASSOCIATIONS § 561.43 Savings association. The term savings association means a...

Contrasting diversity and host association of ectomycorrhizal basidiomycetes versus root-associated ascomycetes in a dipterocarp rainforest.

Directory of Open Access Journals (Sweden)

Hirotoshi Sato

Full Text Available Root-associated fungi, including ectomycorrhizal and root-endophytic fungi, are among the most diverse and important belowground plant symbionts in dipterocarp rainforests. Our study aimed to reveal the biodiversity, host association, and community structure of ectomycorrhizal Basidiomycota and root-associated Ascomycota (including root-endophytic Ascomycota in a lowland dipterocarp rainforest in Southeast Asia. The host plant chloroplast ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (rbcL region and fungal internal transcribed spacer 2 (ITS2 region were sequenced using tag-encoded, massively parallel 454 pyrosequencing to identify host plant and root-associated fungal taxa in root samples. In total, 1245 ascomycetous and 127 putative ectomycorrhizal basidiomycetous taxa were detected from 442 root samples. The putative ectomycorrhizal Basidiomycota were likely to be associated with closely related dipterocarp taxa to greater or lesser extents, whereas host association patterns of the root-associated Ascomycota were much less distinct. The community structure of the putative ectomycorrhizal Basidiomycota was possibly more influenced by host genetic distances than was that of the root-associated Ascomycota. This study also indicated that in dipterocarp rainforests, root-associated Ascomycota were characterized by high biodiversity and indistinct host association patterns, whereas ectomycorrhizal Basidiomycota showed less biodiversity and a strong host phylogenetic preference for dipterocarp trees. Our findings lead to the working hypothesis that root-associated Ascomycota, which might be mainly represented by root-endophytic fungi, have biodiversity hotspots in the tropics, whereas biodiversity of ectomycorrhizal Basidiomycota increases with host genetic diversity.

Are Prevalent Self-reported Cardiovascular Disorders Associated with Delayed Recovery From Whiplash-associated Disorders

DEFF Research Database (Denmark)

Palmlöf, Lina; Côté, Pierre; Holm, Lena W

2015-01-01

OBJECTIVES:: The aim of this cohort study was to investigate the association between self-reported cardiovascular disorders (CVD) and recovery from whiplash associated disorder (WAD) after a traffic collision. METHODS:: This study was based on the Saskatchewan Government Insurance cohort, including...... individuals over 18 years of age, who made a traffic- injury claim or received health care after a traffic injury, between 1997 and 1999. Participants completed a baseline questionnaire and were followed up by telephone interviews at 6 weeks, 3 months, 6 months, 9 months, and 12 months post injury. Our sample....... RESULTS:: We found a crude association between comorbid CVD with moderate or severe effect on health in women. However, the adjusted association was weak and potentially affected by residual confounding. We found no association in men. DISCUSSION:: Our results suggest that CVD does not impact...

Cannabis-associated arterial disease.

Science.gov (United States)

Desbois, Anne Claire; Cacoub, Patrice

2013-10-01

The aim of this study was to describe the different arterial complications reported in cannabis smokers. This study was a literature review. Cannabis use was found to be associated with stroke, myocardial infarction, and lower limb arteritis. Arterial disease involved especially young men. There was a very strong temporal link between arterial complications and cannabis use for stroke and myocardial infarction episodes. Patient outcome was closely correlated with cannabis withdrawal and relapses associated with cannabis rechallenge. Cannabis use was associated with particular characteristics of arterial disease. The increased risk of myocardial infarction onset occurred within 1 hour of smoking marijuana compared with periods of non-use. Strokes occurred mainly in the posterior cerebral circulation. Compared with cohorts of thromboangiitis obliterans patients, those with cannabis-associated limb arteritis were younger, more often male, and had more frequent unilateral involvement of the lower limbs at clinical presentation. Cannabis use is associated with arterial disease such as stroke, myocardial infarction, and limbs arteritis. It appears essential to investigate cannabis use in young patients presenting with such arterial manifestations, as outcome is closely correlated with cannabis withdrawal. Copyright © 2013 Elsevier Inc. All rights reserved.

SMARANDACHE NON-ASSOCIATIVE RINGS

OpenAIRE

Vasantha, Kandasamy

2002-01-01

An associative ring is just realized or built using reals or complex; finite or infinite by defining two binary operations on it. But on the contrary when we want to define or study or even introduce a non-associative ring we need two separate algebraic structures say a commutative ring with 1 (or a field) together with a loop or a groupoid or a vector space or a linear algebra. The two non-associative well-known algebras viz. Lie algebras and Jordan algebras are mainly built using a vecto...

Prevalence and associated f

Directory of Open Access Journals (Sweden)

Wafaa Yousif Abdel Wahed

2017-03-01

Conclusion: A substantial proportion of medical students are suffering from depression, stress, and anxiety. Female sex, increasing age, overweight and obesity are significant associated factors. Further studies need to be carried to identify other associated factors related to academic medical education.

[TATTOO-ASSOCIATED UVEITIS].

Science.gov (United States)

Klímová, A; Heissigerová, J; Říhová, E; Holan, P; Brichová, M; Svozílková, P

2017-01-01

The clinical case of tattoo-associated uveitis was first described by Lubeck and Epstein in 1952. Uveitis is accompanied by induration and hyperemia of tattoo skin, which can precede, follow or manifest simultaneously with uveitis. The diagnosis is determined on clinical grounds after exclusion of other causes. Uveitis is usually bilateral, chronic and vision impairment is variable. Tattoo-associated uveitis should be remembered in differential diagnosis due to the growing interest in tattoo.Key words: uveitis, tattoo, masquerade syndrome.

Mesh association by projection along smoothed-normal-vector fields:association of closed manifolds

NARCIS (Netherlands)

Brummelen, van E.H.

2008-01-01

The necessity to associate two geometrically distinct meshes arises in many engineering applications. Current mesh-association algorithms have generally been developed for piecewise-linear geometry approximations, and their extension to the high-order geometry representations corresponding to

Linkage disequilibrium and association mapping.

Science.gov (United States)

Weir, B S

2008-01-01

Linkage disequilibrium refers to the association between alleles at different loci. The standard definition applies to two alleles in the same gamete, and it can be regarded as the covariance of indicator variables for the states of those two alleles. The corresponding correlation coefficient rho is the parameter that arises naturally in discussions of tests of association between markers and genetic diseases. A general treatment of association tests makes use of the additive and nonadditive components of variance for the disease gene. In almost all expressions that describe the behavior of association tests, additive variance components are modified by the squared correlation coefficient rho2 and the nonadditive variance components by rho4, suggesting that nonadditive components have less influence than additive components on association tests.

Keratoacanthoma centrifugum marginatum: unresponsive to oral retinoid and successfully treated with wide local excision.

Directory of Open Access Journals (Sweden)

Kapildev Das

2010-01-01

Full Text Available We describe a case of a 65-year-old male presenting with a large plaque with a rolled-out interrupted margin, atrophic center, and island of normal skin over the left arm. It grew peripherally with central healing, and there was a history of recurrence after inadequate excision. Investigations ruled out other clin­ical mimickers; namely, squamous cell carcinoma, lupus vulgaris, botryomycosis, and blastomycosis-like pyoderma. Histopathological sections showed irregularly shaped craters filled with keratin and epithelial pearl but no evidence of granuloma or cellular atypia. Clinico­pathological correlation proved the lesion to be keratoacanthoma centrifugum marginatum (KCM, a rare variant of keratoacanthoma, which spreads centrifugally, attains a huge size, and never involutes spontaneously. Treatment of KCM has been a problem always and, in our case, systemic retinoid (acitretin for three months proved ineffective. The patient also had a history of recurrence following surgical intervention previously, necessitating wide excision to achieve complete clearance of tumor cells. Hence, after failure of retinoid therapy, the decision of excision with a 1-centimeter margin was taken and the large defect was closed by a split thickness skin graft. The graft uptake was satisfactory, and the patient is being followed-up presently and shows no signs of recurrence after six months, highlighting wide local excision as a useful treatment option.

Cdk1-cyclin B1-mediated phosphorylation of tumor-associated microtubule-associated protein/cytoskeleton-associated protein 2 in mitosis.

Science.gov (United States)

Hong, Kyung Uk; Kim, Hyun-Jun; Kim, Hyo-Sil; Seong, Yeon-Sun; Hong, Kyeong-Man; Bae, Chang-Dae; Park, Joobae

2009-06-12

During mitosis, establishment of structurally and functionally sound bipolar spindles is necessary for maintaining the fidelity of chromosome segregation. Tumor-associated microtubule-associated protein (TMAP), also known as cytoskeleton-associated protein 2 (CKAP2), is a mitotic spindle-associated protein whose level is frequently up-regulated in various malignancies. Previous reports have suggested that TMAP is a potential regulator of mitotic spindle assembly and dynamics and that it is required for chromosome segregation to occur properly. So far, there have been no reports on how its mitosis-related functions are regulated. Here, we report that TMAP is hyper-phosphorylated at the C terminus specifically during mitosis. At least four different residues (Thr-578, Thr-596, Thr-622, and Ser-627) were responsible for the mitosis-specific phosphorylation of TMAP. Among these, Thr-622 was specifically phosphorylated by Cdk1-cyclin B1 both in vitro and in vivo. Interestingly, compared with the wild type, a phosphorylation-deficient mutant form of TMAP, in which Thr-622 had been replaced with an alanine (T622A), induced a significant increase in the frequency of metaphase cells with abnormal bipolar spindles, which often displayed disorganized, asymmetrical, or narrow and elongated morphologies. Formation of these abnormal bipolar spindles subsequently resulted in misalignment of metaphase chromosomes and ultimately caused a delay in the entry into anaphase. Moreover, such defects resulting from the T622A mutation were associated with a decrease in the rate of protein turnover at spindle microtubules. These findings suggest that Cdk1-cyclin B1-mediated phosphorylation of TMAP is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis.

Cdk1-Cyclin B1-mediated Phosphorylation of Tumor-associated Microtubule-associated Protein/Cytoskeleton-associated Protein 2 in Mitosis*

Science.gov (United States)

Uk Hong, Kyung; Kim, Hyun-Jun; Kim, Hyo-Sil; Seong, Yeon-Sun; Hong, Kyeong-Man; Bae, Chang-Dae; Park, Joobae

2009-01-01

During mitosis, establishment of structurally and functionally sound bipolar spindles is necessary for maintaining the fidelity of chromosome segregation. Tumor-associated microtubule-associated protein (TMAP), also known as cytoskeleton-associated protein 2 (CKAP2), is a mitotic spindle-associated protein whose level is frequently up-regulated in various malignancies. Previous reports have suggested that TMAP is a potential regulator of mitotic spindle assembly and dynamics and that it is required for chromosome segregation to occur properly. So far, there have been no reports on how its mitosis-related functions are regulated. Here, we report that TMAP is hyper-phosphorylated at the C terminus specifically during mitosis. At least four different residues (Thr-578, Thr-596, Thr-622, and Ser-627) were responsible for the mitosis-specific phosphorylation of TMAP. Among these, Thr-622 was specifically phosphorylated by Cdk1-cyclin B1 both in vitro and in vivo. Interestingly, compared with the wild type, a phosphorylation-deficient mutant form of TMAP, in which Thr-622 had been replaced with an alanine (T622A), induced a significant increase in the frequency of metaphase cells with abnormal bipolar spindles, which often displayed disorganized, asymmetrical, or narrow and elongated morphologies. Formation of these abnormal bipolar spindles subsequently resulted in misalignment of metaphase chromosomes and ultimately caused a delay in the entry into anaphase. Moreover, such defects resulting from the T622A mutation were associated with a decrease in the rate of protein turnover at spindle microtubules. These findings suggest that Cdk1-cyclin B1-mediated phosphorylation of TMAP is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis. PMID:19369249