Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis.

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Wang, Ping; Tan, Gang; Zhu, Mingxin; Li, Weidong; Zhai, Bo; Sun, Xueying

2018-01-01

Sorafenib remains the only standard first-line drug for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a very common side-effect in patients treated with sorafenib, and also affects the treatment schedule and quality of life. However, the association of HFSR and response of HCC to sorafenib remain unclear. Databases including PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched up to May 7 th , 2017. Review Manager 5.3 software was adopted for performing meta-analyses, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofler software for further assessing outcomes obtained from meta-analyses. 1478 articles were reviewed, and 12 cohort studies with 1017 participants were included in the analyses. The pooled hazard ratio (HR) of overall survival is 0.45 (95% confidence interval (CI) 0.36, 0.55; P The pooled HR of time to progression is 0.41 (95% CI 0.28, 0.60; P The results indicate that HFSR is a beneficial indicator for HCC patients receiving sorafenib therapy. However, molecular mechanisms accounting for sorafenib-induced HFSR in HCC patients remain.

Metronomic capecitabine in patients with hepatocellular carcinoma unresponsive to or ineligible for sorafenib treatment: report of two cases.

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Marinelli, Sara; Granito, Alessandro; Piscaglia, Fabio; Renzulli, Matteo; Stagni, Angela; Bolondi, Luigi

2013-01-01

Sorafenib, an oral multikinase inhibitor, is the only systemic agent proven to be effective in patients with hepatocellular carcinoma (HCC). There are no approved second line systemic therapies in patients who have had disease progression on or are not eligible to sorafenib. We describe two cases of unresectable HCC that were treated with low, "metronomic" doses of capecitabine. In the first patient, capecitabine was used after sorafenib failure. In the second case, treatment with capecitabine was attempted since the patient was considered not eligible for sorafenib due to spontaneous hepatic bleeding of a large HCC lesion. Treatment was effective and well tolerated in both patients with long-lasting objective responses. Lacking established second-line therapy, metronomic capecitabine may be a valid alternative in the treatment of HCC patients who are judged not eligible for sorafenib or those having progression disease on sorafenib.

PHARMACOECONOMICAL RESEARCH OF THE USE OF SORAFENIB IN MALIGNANT TUMORS

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M. Y. Frolov

2016-01-01

Full Text Available Purpose. Pharmacoeconomic rationale for the use of sorafenib in malignant tumors in comparison with drugs that are included in the list of pharmaceuticals to provide to certain categories of citizens.Method of the study. Pharmacoeconomic rationale for the use of sorafenib in this study is made by analyzing the impact on the budget. The calculated costs of treatment with sorafenib at a hypothetical group of 100 patients with metastatic renal cell carcinoma (MRCC, hepatocellular carcinoma (HCC and differentiated thyroid cancer resistant to radioactive iodine (DCT. These costs were compared with costs of treatment of a similar group of 100 patients, with treatment of MRCC applied bevacizumab (original or generic in combination with interferon α, and patients with HCC and DCT were excluded from receiving drugs from a program of providing with necessary medicines (PNM. As a result the potential economic effect of the inclusion of sorafenib in the list of PNM was calculated.Results. Treatment of MRCC is cheaper with the use of sorafenib compared to bevacizumab in combination with interferon α: savings is 592 878 rubles in the original use of bevacizumab and 274 976 rubles in the use of generic bevacizumab for one patient-year. If we use sorafenib in a group of 100 people with MRCC, HCC and DCT suitable for treatment with sorafenib, the overall expenses are more than 175 million rubles, while using the original combination of bevacizumab with interferon α – more than 204 million rubles, and in the application of the generic combination of bevacizumab with interferon α – more than 176 million rubles, while in the two last cases the treatment of patients with HCC and DCT is not carried out. The total amount of annual budget savings in the treatment of 100 patients is more than 28.5 million rubles at the account of original of bevacizumab or more than 1 million rubles in accounting of generic bevacizumab.Conclusion. The inclusion of

Sorafenib in advanced hepatocellular carcinoma

DEFF Research Database (Denmark)

Køstner, Anne Helene; Sørensen, M; Olesen, René Krøjgaard

2013-01-01

Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore ...

Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer

International Nuclear Information System (INIS)

Brose, Marcia S; Schlumberger, Martin; Nutting, Christopher M; Sherman, Steven I; Shong, Young Kee; Smit, Johannes WA; Reike, Gerhard; Chung, John; Kalmus, Joachim; Kappeler, Christian

2011-01-01

The incidence of thyroid cancer and the number of patients who die from this disease are increasing globally. Differentiated thyroid cancer (DTC) is the histologic subtype present in most patients and is primarily responsible for the increased overall incidence of thyroid cancer. Sorafenib is a multikinase inhibitor that targets several molecular signals believed to be involved in the pathogenesis of thyroid cancer, including those implicated in DTC. In phase II studies of patients with DTC, sorafenib treatment has yielded a median progression-free survival (PFS) of 58 to 84 weeks and disease control rates of 59% to 100%. The DECISION trial was designed to assess the ability of sorafenib to improve PFS in patients with locally advanced or metastatic, radioactive iodine (RAI)-refractory DTC. DECISION is a multicenter, double-blind, randomized, placebo-controlled phase III study in patients with locally advanced/metastatic RAI-refractory DTC. Study treatment will continue until radiographically documented disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent. Efficacy will be evaluated every 56 days (2 cycles), whereas safety will be evaluated every 28 days (1 cycle) for the first 8 months and every 56 days thereafter. Following disease progression, patients may continue or start sorafenib, depending on whether they were randomized to receive sorafenib or placebo, at investigator discretion. Patients originally randomized to receive sorafenib will be followed up every 3 months for overall survival (OS); patients originally randomized to receive placebo will be followed up every month for 8 months after cross-over to sorafenib. The duration of the trial is expected to be 30 months from the time the first patient is randomized until the planned number of PFS events is attained. The primary endpoint is PFS; secondary endpoints include OS, time to disease progression, disease control rate, response rate, duration of response, safety, and

Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient.

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Ling Ye

Full Text Available BACKGROUND: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC, is metabolized by cytochrome P450 (CYP 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients. METHODS: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs and adjacent normal hepatic microsomes (NHLMs of HCC patients (n = 18. Commercial hepatic microsomes (CHLMs were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting. RESULTS: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs. CONCLUSIONS: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

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

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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.

Sorafenib neoadjuvant therapy in the treatment of high risk renal cell carcinoma.

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Yushi Zhang

Full Text Available To evaluate the clinical efficacy of sorafenib as preoperative neoadjuvant therapy in patients with high risk renal cell carcinoma (RCC.Clinical data of 18 patients with high risk RCC who received surgery done successfully after preoperative neoadjuvant therapy with sorafenib in Peking Union Medical College Hospital (PUMCH from April 2007 to October 2013 have been reviewed and analyzed in this study.Among the 18 patients there were 13 male and 5 female, with a median age of 54.6 years. The objective response rate (ORR of the operation on the selected patients is very high (94.4%, including 4 cases (22.2% of partial response (PR and 13 cases (72.2% of stable disease (SD. After preoperative sorafenib treatment, the average tumor size of the 18 patients decreased from 7.8 cm (ranging from 3.6 to 19.2 cm to 6.2 cm (ranging from 2.4 to 16.8 cm, and the median value of average tumor CT value decreased from 61HU to 52 HU. Among the 5 patients who had IVC tumor thrombi, the grades of tumor thrombi in 2 patients who were grade II before sorafenib treatment became grade I and grade 0 respectively, 2 patients of grade III both became grade II.Preoperative neoadjuvant therapy with sorafenib for high risk RCC patients can significantly decrease primary tumor volume as well as tumor thrombus, which could help the nephron-sparing surgery (NSS or radical nephrectomy to be done successfully.

Initial Experience of Sorafenib Neoadjuvant Therapy Combined with Retroperitoneoscopy in Treating T2 Large Renal Carcinoma

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Chun-hua Lin

2015-01-01

Full Text Available Objectives. To investigate the safety and feasibility of sorafenib neoadjuvant therapy combined with retroperitoneoscopic radical nephrectomy (RRN in treating T2 large renal cell carcinoma (RCC. Methods. Retrospectively analyzed 5 cases (2 males and 3 females, aged 52–73 years of T2 stage large RCC who receive preoperative sorafenib targeted treatment (400 mg bid for 1–3 months and RRN between March, 2013, and July, 2014. Patient information, therapeutic regimen, drug adverse effect, tumor changes before and after surgery, and perioperative parameters were recorded. Results. During the sorafenib therapy adverse effects included 2 cases of hypertension (Grade I toxicity, 1 case of hand-foot syndrome (Grade I, and 1 case of diarrhea (Grade II, which were all tolerable for patients. CT scan and histopathological tests confirmed significant reduction in the longest dimension (LD and medium density (MD of the tumor after therapy as well as tumor hemorrhage, necrosis, and cystic degeneration. All 5 patients received RRN surgery successfully around 2 weeks after drug discontinuation with only 1 case of perioperative complication. Conclusions. Sorafenib neoadjuvant therapy could significantly reduce the size and aggressiveness of T2 large renal tumors, thus reducing the operative challenge and enabling patients who were previously disqualified for operation to receive surgical treatment.

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”.

Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

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Pitoia Fabian; Abelleira, Erika; Jerkovich, Fernando; Urciuoli, Carolina; Cross, Graciela, E-mail: fpitoia@intramed.net [Division de Endocrinologia, Hospital de Clinicas, Universidad de Buenos Aires Buenos Aires (Argentina)

2015-08-15

Advanced radioactive refractory and progressive or symptomatic differentiated thyroid carcinoma (DTC) is a rare condition. Sorafenib was recently approved for the treatment of these patients. We present the case of a 67 year old woman diagnosed with DTC who underwent a total thyroidectomy with central, lateral-compartment neck dissection and shaving of the trachea and esophagus due to tumor infiltration. A local recurrence was detected 14 months later requiring, additionally, two tracheal rings resection. The patient received a cumulative {sup 131}I dose of 650 mCi and developed dysphagia and dyspnea 63 months after initial surgery. A {sup 18}FGD-PET/CT showed progression of the local mass associated to hypermetabolic pulmonary nodules. Sorafenib 800 mg/day was then prescribed. A dose reduction to 400 mg/day was necessary due to grade 3 thrombocytopenia that appeared four months after drug prescription. Platelet count went to normal after this dose reduction. Five months after initiation of sorafenib, a partial response of the local mass with significant intra-tumoral necrosis was observed. We conclude that sorafenib is a valid option for locally advanced DTC and that the platelet count should be evaluated regularly because it seems that thrombocytopenia might be more frequently observed in DTC than in other types of tumors. (author)

Sorafenib prescribed by gastroenterologists and hepatologists for hepatocellular carcinoma

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Kaplan, David E.; Mehta, Rajni; D’Addeo, Kathryn; Valderrama, Adriana; Taddei, Tamar H.

2018-01-01

Abstract Sorafenib is the only Food and Drug Administration (FDA)-approved first-line therapy shown to have survival benefit for patients with advanced hepatocellular carcinoma (HCC). Patients with advanced HCC are often but not exclusively transferred from non-oncologists to oncologists to initiate systemic therapy. The objective of this study was to assess whether sorafenib prescribing by non-oncologists has any impact on utilization, adverse effects, cost or outcome. This was a retrospective cohort study utilizing data from patients prescribed sorafenib for HCC within Veterans Health Administration hospitals with 100% chart abstraction to confirm HCC diagnosis, identify prescribing provider specialty (oncology versus gastroenterology/hepatology), and obtain data required for cancer staging by the Barcelona Clinic Liver Cancer (BCLC) system. The primary outcome was overall survival from the time of sorafenib prescription. A total of 4903 patients who prescribed sorafenib for HCC were identified, for whom 340 patients (6.9%) were prescribed drug by a non-oncologist (Onc). BCLC Stage, age, Child–Turcotte–Pugh score, and comorbidity indices were similar between patients prescribed sorafenib by oncologists and non-oncologists. Oncologists more often discontinued sorafenib due to progression, whereas non-oncologists were more likely to continue sorafenib until death resulting in greater pill utilization and cost. Overall survival in both unadjusted and multivariable models showed no significant impact of prescriber type on survival (222 vs 217 days, P = .96), confirmed with propensity-matched subcohorts. Similar survival outcomes were observed for patients with HCC prescribed sorafenib by non-oncologists and oncologists, suggesting that non-oncologists with expertise in the management of HCC can safely and effectively administer sorafenib. PMID:29369224

A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients.

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Davies, Janine M; Dhruva, Nirav S; Walko, Christine M; Socinski, Mark A; Bernard, Stephen; Hayes, D Neil; Kim, William Y; Ivanova, Anastasia; Keller, Kimberly; Hilbun, Layla R; Chiu, Michael; Dees, E Claire; Stinchcombe, Thomas E

2011-02-01

Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases. A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin. Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42-73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1-4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200 mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level -1 (sorafenib 200 mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200 mg BID). On Arm C at dose level 0 (sorafenib 200 mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400 mg BID) 2 of 5 patients experienced a DLT. The MTD of sorafenib was 200 mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500 mg/m² every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

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Li, Qiaoqiao; Hu, Yonghong; Xi, Mian; He, Liru; Zhao, Lei; Liu, Mengzhong

2012-01-01

receiving radiation alone (25.0 ± 3.0%; P < 0.001). In addition, irradiation (6 Gy) caused a significant increase in the percentage of both SMMC-7721 and BEL-7402 cells in G2/M at 12 to 16 h post irradiation, which was markedly delayed by pre-irradiation sorafenib. Sorafenib combined with irradiation exerted a schedule-dependent effect in HCC cells in vitro, which has significant implications for the combined use of sorafenib and radiotherapy for HCC patients

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.

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Bruix, Jordi; Qin, Shukui; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Breder, Valeriy; Gerolami, René; Masi, Gianluca; Ross, Paul J; Song, Tianqiang; Bronowicki, Jean-Pierre; Ollivier-Hourmand, Isabelle; Kudo, Masatoshi; Cheng, Ann-Lii; Llovet, Josep M; Finn, Richard S; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Han, Guohong

2017-01-07

There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group

Correlation between LDH levels and response to sorafenib in HCC patients: an analysis of the ITA.LI.CA database.

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Sacco, Rodolfo; Mismas, Valeria; Granito, Alessandro; Musettini, Gianna; Masi, Gianluca; Caparello, Chiara; Vivaldi, Caterina; Felder, Martina; Bresci, Giampaolo; Fornaro, Lorenzo

2015-02-24

Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes.

Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma.

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Pierce K H Chow

Full Text Available The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279 was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC not amenable to curative therapies.Sorafenib (400 mg twice-daily was initiated 14 days post-radioembolization with yttrium-90 (90Y resin microspheres given as a single procedure. The primary endpoints were safety and tolerability and best overall response rate (ORR using RECIST v1.0.Secondary endpoints included: disease control rate (complete [CR] plus partial responses [PR] and stable disease [SD] and overall survival (OS.Twenty-nine patients with Barcelona Clinic Liver Cancer (BCLC stage B (38% or C (62% HCC received a median of 3.0 GBq (interquartile range, 1.0 90Y-microspheres followed by sorafenib (median dose/day, 600.0 mg; median duration, 4.1 months. Twenty eight patients experienced ≥1 toxicity; 15 (52% grade ≥3. Best ORR was 25%, including 2 (7% CR and 5 (18% PR, and 15 (54% SD. Disease control was 100% and 65% in BCLC stage B and C, respectively. Two patients (7% had sufficient response to enable radical therapy. Median survivals for BCLC stage B and C were 20.3 and 8.6 months, respectively.This study shows the potential efficacy and manageable toxicity of sequential radioembolization-sorafenib.ClinicalTrials.gov NCT00712790.

Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure.

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Granito, Alessandro; Marinelli, Sara; Terzi, Eleonora; Piscaglia, Fabio; Renzulli, Matteo; Venerandi, Laura; Benevento, Francesca; Bolondi, Luigi

2015-06-01

No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. Twenty-six patients (80% Child-Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6-31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand-foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2-4.7). Median overall survival was 8 months (95% confidence interval 3.7-12.3). Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.

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Yuki Haga

Full Text Available Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC. Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.The expression of molecules involved in the mitogen-activated protein kinase (MAPK signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun was measured.The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

Successful treatment of paraganglioma with sorafenib: a case report and brief review of the literature

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Lin Y

2013-11-01

Full Text Available Yun Lin,1,* Qun Li,1,* Wei Huang,1 Xinyan Jia,1 Hong Jiang,1 Yong Gao,1 Qi Li1,21Department of Oncology, Shanghai East Hospital, 2Department of Oncology, Shanghai First People's Hospital, Shanghai, People's Republic of China*These authors contributed equally to this work, and are joint first authorsIntroduction: To date, no effective systemic therapies have been made available for paraganglioma. However, multiple mutations in susceptibility genes have been identified that are potential targets for sorafenib, an oral multitargeted tyrosine-kinase inhibitor.Case presentation: We report the case of a 69-year-old Chinese man with mediastinal paraganglioma that had metastasized to the bone. The paraganglioma responded to sorafenib, a novel multi-tyrosine kinase inhibitor that targets angiogenesis, the Raf-kinase pathway, the platelet-derived growth factor Ret, and c-Kit. The patient was diagnosed as having paraganglioma after biopsy of the mediastinal mass. We first treated the patient with radiotherapy. Then he tolerated an etoposide-and-cisplatin chemotherapy regimen. Subsequently, he received 6 months of maintenance treatment with sorafenib (400 mg twice daily. A dramatic reduction in tumor volume was observed. At present, the patient has achieved a partial response, and his clinical status remains unchanged.Conclusion: We suggest that sorafenib should be further investigated in the management of patients with paraganglioma.Keywords: sorafenib, paraganglioma, molecular-targeted drug

Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial

International Nuclear Information System (INIS)

Hoffmann, Katrin; Ganten, Tom; Gotthardtp, Daniel; Radeleff, Boris; Settmacher, Utz; Kollmar, Otto; Nadalin, Silvio; Karapanagiotou-Schenkel, Irini; Kalle, Christof von; Jäger, Dirk; Büchler, Markus W; Schemmer, Peter

2015-01-01

Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group

Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

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Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

2015-01-01

Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment

Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation.

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Trevisani, Franco; Brandi, Giovanni; Garuti, Francesca; Barbera, Maria Aurelia; Tortora, Raffaella; Casadei Gardini, Andrea; Granito, Alessandro; Tovoli, Francesco; De Lorenzo, Stefania; Inghilesi, Andrea Lorenzo; Foschi, Francesco Giuseppe; Bernardi, Mauro; Marra, Fabio; Sacco, Rodolfo; Di Costanzo, Giovan Giuseppe

2018-02-01

Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

Prognosis of patients with hepatocellular carcinoma treated with sorafenib: a comparison of five models in a large Canadian database.

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Samawi, Haider H; Sim, Hao-Wen; Chan, Kelvin K; Alghamdi, Mohammad A; Lee-Ying, Richard M; Knox, Jennifer J; Gill, Parneet; Romagnino, Adriana; Batuyong, Eugene; Ko, Yoo-Joung; Davies, Janine M; Lim, Howard J; Cheung, Winson Y; Tam, Vincent C

2018-05-15

Several systems (tumor-node-metastasis [TNM], Barcelona Clinic Liver Cancer [BCLC], Okuda, Cancer of the Liver Italian Program [CLIP], and albumin-bilirubin grade [ALBI]) were developed to estimate the prognosis of patients with hepatocellular carcinoma (HCC) mostly prior to the prevalent use of sorafenib. We aimed to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib and to identify independent prognostic factors for survival in this population. Patients who received sorafenib for the treatment of HCC between 1 January 2008 and 30 June 2015 in the provinces of British Columbia and Alberta, and two large cancer centers in Toronto, Ontario, were included. Survival was assessed using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of survival. The models were compared with respect to homogeneity, discriminatory ability, monotonicity of gradients, time-dependent area under the curve, and Akaike information criterion. A total of 681 patients were included. 80% were males, 86% had Child-Pugh class A, and 37% of patients were East Asians. The most common etiology for liver disease was hepatitis B (34%) and C (31%). In all model comparisons, CLIP performed better while BCLC and TNM7 performed less favorably but the differences were small. The utility of each system in allocating patients into different prognostic groups varied, for example, TNM poorly differentiated patients in advanced stages (8.7 months (m) (95% CI 6.5-11.5) versus 8.4 m (95% CI 7.0-9.6) for stages III and IV, respectively) while ALBI had excellent discrimination of early grades (15.6 m [95% CI 13.0-18.4] versus 8.3 m [95% CI 7.0-9.2] for grades 1 and 2, respectively). On multivariate analysis, hepatitis C, alcoholism, and prior hepatic resection were independently prognostic of better survival (P < 0.01). In conclusion, none of the prognostic systems was optimal in predicting survival

Measurement of sorafenib plasma concentration by high-performance liquid chromatography in patients with advanced hepatocellular carcinoma: is it useful the application in clinical practice? A pilot study.

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Fucile, Carmen; Marenco, Simona; Bazzica, Marco; Zuccoli, Maria Laura; Lantieri, Francesca; Robbiano, Luigi; Marini, Valeria; Di Gion, Paola; Pieri, Giulia; Stura, Paola; Martelli, Antonietta; Savarino, Vincenzo; Mattioli, Francesca; Picciotto, Antonino

2015-01-01

Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at α = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful.

Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma

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Saif, Muhammad W.; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N.

2011-01-01

Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. La...

Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

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Li Qiaoqiao

2012-10-01

Full Text Available Abstract Background Hepatocellular carcinoma (HCC has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. Methods Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl-5(3-carboxymethoxyphenyl-2(4-sulfophenyl-2 H-terazolium (MTT assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM added 30 min prior to radiation (pre-irradiation sorafenib of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. Results The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9% than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P  Conclusions Sorafenib combined with irradiation exerted a schedule-dependent effect in

Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer

NARCIS (Netherlands)

Worden, F.; Fassnacht, M.; Shi, Y.; Hadjieva, T.; Bonichon, F.; Gao, M.; Fugazzola, L.; Ando, Y.; Hasegawa, Y.; do, J. Park; Shong, Y.K.; Smit, J.W.A.; Chung, J.; Kappeler, C.; Meinhardt, G.; Schlumberger, M.; Brose, M.S.

2015-01-01

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive

Early α-fetoprotein response predicts survival in patients with advanced hepatocellular carcinoma treated with sorafenib

Directory of Open Access Journals (Sweden)

Lee SH

2015-04-01

Full Text Available Sangheun Lee,1,* Beom Kyung Kim,2–5,* Seung Up Kim,2–5 Jun Yong Park,2–5 Do Young Kim,2–5 Sang Hoon Ahn,2–6 Kwang-Hyub Han2–6 1Department of Internal Medicine, International St Mary’s Hospital, Catholic Kwandong University, Incheon Metropolitan City, Republic of Korea; 2Department of Internal Medicine, 3Institute of Gastroenterology, 4Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Liver Cirrhosis Clinical Research Center, Seoul, Republic of Korea; 6Brain Korea 21 Project for Medical Science, Seoul, Republic of Korea.   *These authors contributed equally to this work Background: It is not clear whether tumor marker responses can predict survival during sorafenib treatment in hepatocellular carcinoma (HCC. We investigated whether the α-fetoprotein (AFP response is associated with survival in patients with advanced HCC treated with sorafenib. Methods: We retrospectively reviewed the records of 126 patients with advanced HCC treated with sorafenib between 2007 and 2012. An AFP response was defined as >20% decrease from baseline. At 6–8 weeks after commencing sorafenib, AFP and radiological responses were assessed by modified Response Evaluation Criteria in Solid Tumors. Results: The median overall survival (OS and progression-free survival (PFS were 6.2 and 3.5 months, respectively. Of the study population, a partial response (PR was identified in 5 patients (4.0%, stable disease (SD in 65 patients (51.6%, and progressive disease (PD in 57 patients (44.4%, respectively. AFP non-response was an independent prognostic factor for poor OS (median 10.9 months for AFP response vs 5.2 months for AFP non-response, together with Child-Pugh B, tumor diameter ≥10 cm, and portal vein invasion (all P<0.05, and PFS (median 5.3 months for AFP response vs 2.9 months for AFP non-response, together with tumor diameter ≥10 cm and portal vein invasion (all P<0.05. SD or PR was more frequently found

Phase 2 Study of Combined Sorafenib and Radiation Therapy in Patients With Advanced Hepatocellular Carcinoma

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Chen, Shang-Wen, E-mail: sjfchiou@gmail.com [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); School of Medicine, China Medical University, Taichung, Taiwan (China); Lin, Li-Ching [Department of Radiation Oncology, Chi-Mei Hospital, Tainan, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Kuo, Yu-Cheng [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan (China); Liang, Ji-An [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); School of Medicine, China Medical University, Taichung, Taiwan (China); Kuo, Chia-Chun [Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); Chiou, Jeng-Fong [Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China)

2014-04-01

Purpose: This phase 2 study evaluated the efficacy of radiation therapy (RT) with concurrent and sequential sorafenib therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods and Materials: Forty patients with unresectable HCC unfit for transarterial chemoembolization were treated with RT with concurrent and sequential sorafenib. Sorafenib was administered from the commencement of RT at a dose of 400 mg twice daily and continued to clinical or radiologic progression, unacceptable adverse events, or death. All patients had underlying Child-Pugh A cirrhosis. The maximal tumor diameter ranged from 3.0 cm to 15.5 cm. Coexisting portal vein thrombosis was found in 24 patients and was irradiated simultaneously. The cumulative RT dose ranged from 40 Gy to 60 Gy (median, 50 Gy). Image studies were done 1 month after RT and then every 3 months thereafter. Results: Thirty-three (83%) completed the allocated RT. During RT, the incidence of hand-foot skin reactions ≥ grade 2 and diarrhea were 37.5% and 25%, respectively, and 35% of patients had hepatic toxicities grade ≥2. Twenty-two (55.0%) patients achieved complete or partial remission at the initial assessment, and 18 (45%) had stable or progressive disease. The 2-year overall survival and infield progression-free survival (IFPS) were 32% and 39%, respectively. A Cancer of the Liver Italian Program (CLIP) score ≥2 was associated with an inferior outcome in overall survival. Six patients (15%) developed treatment-related hepatic toxicity grade ≥3 during the sequential phase, and 3 of them were fatal. Conclusions: When RT and sorafenib therapy were combined in patients with unresectable HCC, the initial complete or partial response rate was 55% with a 2-year IFPS of 39%. A CLIP score ≥2 was associated with an inferior outcome in overall survival. Hepatic toxicities are a major determinant of the safety; the combination should be used with caution and needs further investigation.

Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

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Ricke, Jens; Bulla, Karsten; Kolligs, Frank; Peck-Radosavljevic, Markus; Reimer, Peter; Sangro, Bruno; Schott, Eckart; Schütte, Kerstin; Verslype, Chris; Walecki, Jerzy; Malfertheiner, Peter

2015-02-01

The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status arm. Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis

International Nuclear Information System (INIS)

Edeline, Julien; Crouzet, Laurence; Pracht, Marc; Boucher, Eveline; Campillo-Gimenez, Boris; Rolland, Yan; Rohou, Tanguy; Guillygomarc'h, Anne; Boudjema, Karim; Lenoir, Laurence; Adhoute, Xavier; Clement, Bruno; Blanc, Jean-Frederic; Garin, Etienne

2016-01-01

Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or 90 Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials. (orig.)

Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis

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Edeline, Julien [Centre Eugene Marquis, Medical Oncology Department, Rennes (France); Inserm UMR991, Rennes (France); Crouzet, Laurence; Pracht, Marc; Boucher, Eveline [Centre Eugene Marquis, Medical Oncology Department, Rennes (France); Campillo-Gimenez, Boris [Centre Eugene Marquis, Clinical Research Department, Rennes (France); Rolland, Yan; Rohou, Tanguy [Centre Eugene Marquis, Imaging Department, Rennes (France); Guillygomarc' h, Anne [CHU Pontchaillou, Hepatology Department, Rennes (France); Boudjema, Karim [CHU Pontchaillou, Hepatobiliary Surgery, Rennes (France); Lenoir, Laurence [Centre Eugene Marquis, Nuclear Medicine Department, Rennes (France); Adhoute, Xavier [Hopital Saint-Joseph, Hepato-Gastroenterology Department, Marseille (France); Clement, Bruno [Inserm UMR991, Rennes (France); Blanc, Jean-Frederic [Hopital Saint-Andre, Hepato-Gastroenterology Department, Bordeaux (France); Garin, Etienne [Inserm UMR991, Rennes (France); Centre Eugene Marquis, Nuclear Medicine Department, Rennes (France)

2016-04-15

Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or {sup 90}Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials. (orig.)

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

Science.gov (United States)

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

Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

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Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Coelho, A.M.M. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Xerfan, M.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Cogliati, B. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Barbeiro, D.F. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Mazo, D.F.C. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Kubrusly, M.S.; D' Albuquerque, L.A.C. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Souza, H.P. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Carrilho, F.J.; Oliveira, C.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

2015-02-24

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg{sup -1}·day{sup -1} by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

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Yan WANG; Lin WANG; Yutao LIU; Shufei YU; Xiangru ZHANG; Yuankai SHI; Yan SUN

2011-01-01

Background and objective Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Methods Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or ...

Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma.

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Kissel, Maria; Berndt, Sandra; Fiebig, Lukas; Kling, Simon; Ji, Qunsheng; Gu, Qingyang; Lang, Tina; Hafner, Frank-Thorsten; Teufel, Michael; Zopf, Dieter

2017-12-05

The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.

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

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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.

Efficacy and safety of sorafenib versus apatinib in the treatment of intermediate and advanced hepatocellular carcinoma: a comparative retrospective study

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Wang Y

2018-06-01

Full Text Available Yizhuo Wang,1,2 Qing Gou,1 Rongde Xu,1 Xiaoming Chen,1 Zejian Zhou1 1Department of Interventional Oncology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong, People’s Republic of China; 2Medical College Shantou University, Shantou, Guangdong, People’s Republic of China Objective: To compare the efficacy and safety profiles of sorafenib and apatinib in patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC. Methods: This was a single-center, retrospective study where we collected the clinical data of 72 patients, diagnosed with intermediate or advanced HCC from January 2014 to December 2016. Depending on the treatment received, 38 patients were categorized into group S (sorafenib group and 34 into group A (apatinib group. The patients in group A received the initial recommended dose of 750 mg once daily (QD, which was reduced to 250 mg QD in the case of any class 3 or 4 adverse event (AE. Sorafenib was administered orally 400 mg twice daily (BID, and dose was modified to 400 mg or 200 mg QD in the case of grade 3 or 4 AEs. The median overall survival (OS, progression-free survival (PFS, and AEs reported in the two groups were analyzed and compared. Results: Among the 38 patients treated with sorafenib, one patient had complete response (CR, 5 patients had partial response (PR, and 10 patients had stable disease (SD, and among the 34 patients treated with apatinib, 6 patients had PR and 7 patients had SD with no cases of CR. PFS in group S was significantly longer compared with that in group A (7.39 vs 4.79 months, respectively, P=0.031. Similar observations were made for median OS (10.4 months in group S vs 7.18 months in group A, P=0.011. However, there was no significant difference in the objective response rates (ORRs among the study population (15.7 vs 17.6%, P=0.829. Common AEs in group S included hand and foot syndrome (HFS and diarrhea, whereas common AEs in group A

Optimal therapy for patients with hepatocellular carcinoma and resistance or intolerance to sorafenib: challenges and solutions

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Ray EM

2017-11-01

Full Text Available Emily M Ray, Hanna K Sanoff Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA Abstract: The only US Food and Drug Administration (FDA-approved first-line systemic therapy for hepatocellular carcinoma (HCC is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin and GEMOX (gemcitabine-oxaliplatin. Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib. Keywords: liver cancer, chemotherapy, immunotherapy

Cost-effectiveness analysis of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib.

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Zhang, Pengfei; Yang, Yu; Wen, Feng; Wheeler, John; Fu, Ping; Li, Qiu

2016-12-01

Antiviral therapy has been demonstrated to significantly improve the survival in patients with advanced hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The aim of the study was to investigate the cost-effectiveness of antiviral therapy in patients with advanced HBV-related HCC treated with sorafenib. To conduct the analysis, a Markov model comprising three health states (progression-free survival, progressive disease, and death) was created. The efficacy data were derived from medical records. Cost data were collected based on the Chinese national drug prices. Utility data came from the previously published studies. One-way sensitivity analyses as well as probabilistic sensitivity analyses were performed to explore model uncertainties. In the base-case analysis, addition of antiviral therapy to sorafenib generated an effectiveness of 0.68 quality-adjusted life years (QALYs) at a cost of $25 026.04, while sorafenib monotherapy gained an effectiveness of 0.42 QALYs at a cost of $20 249.64. The incremental cost-effectiveness ratio (ICER) was $18 370.77/QALY for antiviral therapy group versus non-antiviral therapy group. On the other hand, the ICER between the two groups in patients with high or low HBV-DNA load, with or without cirrhosis, normal or elevated alanine aminotransferase/aspartate aminotransferase were $16 613.97/QALY, $19 774.16/QALY, $14 587.66/QALY, $19 873.84/QALY, $17 947.07/QALY, and $18 785.58/QALY, respectively. Based on the cost-effectiveness threshold ($20 301.00/QALY in China), addition of antiviral therapy to sorafenib is considered to be a cost-effective option compared with sorafenib monotherapy in patients with advanced HBV-related HCC in China from the patient's perspective. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.

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Pascaline Boudou-Rouquette

Full Text Available BACKGROUND: Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors. METHODS: Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis. RESULTS: Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008. Multivariate analysis showed that increased cumulated sorafenib (AUC(cum was independently associated with any grade ≥ 3 toxicity (p = 0.037; UGT1A9 polymorphism (rs17868320 with grade ≥ 2 diarrhea (p = 0.015 and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018. Using ROC curve, the threshold AUC(cum value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018. CONCLUSION: In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320 identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.

Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

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Yan WANG

2011-03-01

Full Text Available Background and objective Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC. This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Methods Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. Results Overall demographics were balanced between experimental group (sorafenib+chemotherapy and controlled group (chemotherapy only. Overall response (OS rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905. Median progressivefree survival (PFS and median overall survial were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68. Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. Conclusion No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

[Randomize trial of cisplatin plus gemcitabine with either sorafenib or placebo as first-line therapy for non-small cell lung cancer].

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Wang, Yan; Wang, Lin; Liu, Yutao; Yu, Shufei; Zhang, Xiangru; Shi, Yuankai; Sun, Yan

2011-03-01

Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. Overall demographics were balanced between experimental group (sorafenib+chemotherapy) and controlled group (chemotherapy only). Overall response (OS) rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905). Median progressive-free survival (PFS) and median overall survival were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68). Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

Sorafenib-triggered radiation recall dermatitis with a disseminated exanthematous reaction

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Oh, Dong Ryul; Park, Hee Chul; Lim, Ho Yeong; Yoo, Byung Chul [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2013-09-15

Sorafenib is a multi-targeted kinase inhibitor, which is the current standard treatment for advanced hepatocellular carcinoma (HCC). Only one case of radiation recall dermatitis (RRD) associated with sorafenib has been reported so far. Our patient with recurrent HCC was treated with palliative radiotherapy (RT) for the chest wall mass. Sorafenib at 400 mg twice daily was begun on the day following RT. On the 14th day post-RT, an erythematous patch was observed on right chest wall which matched area previously irradiated. It was consistent with RRD. Ten days later, a disseminated exanthematous rash and severe pruritus occurred. Sorafenib was stopped and an oral antihistamine was prescribed to relieve symptoms. At the 1-week follow-up after the cessation of sorafenib, all symptoms were resolved. Physicians should be alert to this recall phenomenon as it can occur both in the skin and elsewhere and the occurrence of RRD may be unpredictable.

Radiation recall dermatitis triggered by sorafenib after radiation therapy for hepatocellular carcinoma

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Kim, Gwi Eon; Song, Hee Sung; Kim, Young Suk [Jeju National University Hospital, Jeju National University School of Medicine, Jeju (Korea, Republic of); Ahn, Ki Jung [Dept. of Radiation Oncology, Inje University Busan Paik Hospital, Inje University of Medicine, Busan (Korea, Republic of)

2017-09-15

Sorafenib is widely used for unresectable and metastatic hepatocellular carcinomas. Radiation recall dermatitis (RRD) is an acute inflammatory reaction confined to previously irradiated skin that occurs after the administration of certain drugs. RRD after sorafenib treatment is rare; five cases have been reported thus far. We describe a 44-year-old man irradiated for chest wall bone metastasis from hepatocellular carcinoma. Eight days after radiotherapy completion, systemic therapy for metastatic hepatocellular carcinoma was initiated with sorafenib treatment. Eleven days after starting sorafenib, the patient complained of erythematous rash with pruritus in the chest wall, in a location consistent with the previous radiation field. Sorafenib was continued at the same dose, despite the RRD. The skin reaction subsided over the next 2 weeks without any medical intervention.

Research advances in sorafenib-induced apoptotic signaling pathways in liver cancer cells

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ZHANG Chaoya

2016-04-01

Full Text Available Currently, sorafenib is the multi-target inhibitor for the treatment of advanced primary liver cancer, and can effectively prolong the progression-free survival and overall survival in patients with advanced primary liver cancer. The application of sorafenib in the targeted therapy for liver cancer has become a hot topic. Major targets or signaling pathways include Raf/Mek/Erk, Jak/Stat, PI3K/Akt/mTOR, VEGFR and PDGFR, STAT, microRNA, Wnt/β-catenin, autolysosome, and tumor-related proteins, and sorafenib can regulate the proliferation, differentiation, metastasis, and apoptosis of liver cancer cells through these targets. This article reviews the current research on the action of sorafenib on these targets or signaling pathways to provide useful references for further clinical research on sorafenib.

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.

Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer.

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Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo; Shi, Yuankai

2015-06-01

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

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Chiorean, E. Gabriela, E-mail: gchiorea@uw.edu [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Department of Medicine, University of Washington, Seattle, Washington (United States); Schneider, Bryan P. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Akisik, Fatih M. [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Perkins, Susan M. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); Anderson, Stephen [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Johnson, Cynthia S. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); DeWitt, John [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Deluca, Jill [Department of Radiation Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Bu, Guixue [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Shahda, Safi; Loehrer, Patrick J. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Sandrasegaran, Kumar [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Cardenes, Higinia R. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana (United States)

2014-06-01

Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m{sup 2} intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m{sup 2} intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K{sup trans} in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.

Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

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Chiorean, E. Gabriela; Schneider, Bryan P.; Akisik, Fatih M.; Perkins, Susan M.; Anderson, Stephen; Johnson, Cynthia S.; DeWitt, John; Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John; Deluca, Jill; Bu, Guixue; Shahda, Safi; Loehrer, Patrick J.; Sandrasegaran, Kumar; Cardenes, Higinia R.

2014-01-01

Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m 2 intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m 2 intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K trans in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival

Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer

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Cardin, Dana B; Goff, Laura; Li, Chung-I; Shyr, Yu; Winkler, Charles; DeVore, Russell; Schlabach, Larry; Holloway, Melanie; McClanahan, Pam; Meyer, Krista; Grigorieva, Julia; Berlin, Jordan; Chan, Emily

2014-01-01

This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry-based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8-week progression free survival (PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups (by VeriStrat classification) was assessed using log-rank P values; hazard ratios (HR) were obtained from Cox proportional hazards model. Thirty-six patients received study drug and were included in the survival analysis. Eight-week PFS rate of 46% (95% confidence interval (CI): 0.32–0.67) did not meet the primary endpoint of a rate ≥70%. Thirty-two patients were included in the correlative analysis, and VeriStrat “Good” patients had superior PFS (HR = 0.18, 95% CI: 0.06–0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13–0.77, P = 0.008) compared to VeriStrat “Poor” patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies

Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase 3 RESORCE trial.

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Finn, Richard S; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Gerolami, René; Caparello, Chiara; Cabrera, Roniel; Chang, Charissa; Sun, Weijing; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Bruix, Jordi

2018-04-25

The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50, 0.78; P<.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. In RESORCE, 573 patients were randomized 2:1 to regorafenib 160mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day versus <800 mg/day) were 52%, 11%, and 15% versus 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6, 28.1) for regorafenib and 19.2 months (16.3, 22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45, 0.96; Q1); 0.26 (0.17, 0.40; Q2); 0.40 (0.27, 0.60; Q3); and 0.54 (0.36, 0.81; Q4). These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. This analysis examined characteristics and outcomes of patients with HCC who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib

Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells.

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Hai-Shan Peng

Full Text Available OBJECTIVES: Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS: Hepatoma cell lines (BEL-7402 and SK-Hep1 were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS: Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS: We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression

Radiation recall dermatitis induced by sorafenib. A case study and review of the literature

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Stieb, Sonja [University Hospital Zurich, Department of Radiation Oncology, Zurich (Switzerland); Paul Scherrer Institute, Villigen PSI, Center for Proton Therapy, Villigen (Switzerland); Riesterer, Oliver; Bruessow, Cornelia; Guckenberger, Matthias [University Hospital Zurich, Department of Radiation Oncology, Zurich (Switzerland); Pestalozzi, Bernhard [University Hospital Zurich, Department of Oncology, Zurich (Switzerland); Weiler, Stefan [University Hospital and University of Zurich, Department of Clinical Pharmacology and Toxicology, Zurich (Switzerland)

2016-05-15

Radiation recall dermatitis (RRD) is an acute inflammatory reaction confined to previously irradiated skin, mainly subsequent to the administration of certain chemotherapeutics. Here we present a rare case of RRD induced by the oral multikinase inhibitor sorafenib. A 77-year-old male with hepatocellular carcinoma was irradiated at ten different sites for bone metastases with 20-36 Gray in 5-12 fractions from January to March 2015. Sorafenib 400 mg was administered twice daily from mid-March. One week later the patient presented with fever and erythematous lesions on the right upper arm, mandible, and trunk. All skin symptoms were confined to previously irradiated areas. After RRD was diagnosed by exclusion of other causes and skin biopsy, sorafenib was paused. With the administration of topical corticosteroids and oral antihistamines, the skin reaction subsided within several days. Sorafenib was readministered after 3 weeks, which did not lead to recurrence of RRD but did cause fluctuating fever. Only four other such cases have been reported in the literature and WHO pharmacovigilance database on individual case safety reports. The current report is the first to show a potential relationship between the severity of sorafenib-induced RRD and radiation dose, histopathological features, and simultaneous acute radiation dermatitis and mucositis. RRD induced by sorafenib is a rare phenomenon, but should be considered in patients showing erythematous skin lesions 1-2 weeks after initiation of the drug, predominantly in areas where skin has been irradiated with an equivalent dose ≥ 30 Gy. Discontinuation of sorafenib with possible readministration should be evaluated with respect to the clinical situation and severity of reaction. (orig.) [German] Recall-Strahlendermatitis (RRD) ist eine akute Entzuendungsreaktion der Haut in zuvor bestrahlten Arealen, welche meist nach Einnahme bestimmter Chemotherapeutika auftritt. Nachfolgend praesentieren wir einen seltenen Fall von

Cost-effectiveness of sorafenib versus SBRT for unresectable advanced hepatocellular carcinoma

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Leung, Henry W. C.; Liu, Chung-Feng; Chan, Agnes L. F.

2016-01-01

Stereotactic body radiotherapy (SBRT) has been shown to improve overall survival in patients with advanced hepatocellular carcinoma. This study aimed to assess the cost-effectiveness of SBRT compared to sorafenib which is the only drug for advanced hepatocellular carcinoma. A Markov decision-analytic model was performed to compare the cost-effectiveness of SBRT and sorafenib for unresectable advanced hepatocellular carcinoma. Patients transitioned between three health states: stable disease, progression disease and death. We calculated the data on cost from the perspective of our National Health Insurance Bureau. Sensitivity analyses were conducted to determine the impact of several variables. The incremental cost effectiveness ratio (ICER) for sorafenib compared to SBRT was NT$3,788,238 per quality-adjusted life year gained (cost/QALY), which was higher than the willingness to pay threshold of Taiwan according to WHO’s guideline. One-way sensitivity analysis revealed that the utility of progression disease for the sorafenib treatment, utility of progression free survival for SBRT, utility of progression free survival for sorafenib, utility of PFS to progression disease for SBRT and transition probability of progression disease to dead for SBRT were the most sensitive parameters in all cost scenarios. The Monte-Carlo simulation demonstrated that the probability of cost-effectiveness at a willingness to pay threshold of NT$ 2,213,145 per QALY was 100 % and 0 % chance for SBRT and sorafenib. This study indicated that SBRT for advanced hepatocellular carcinoma is cost-effective at a willingness to pay threshold as defined by WHO guideline in Taiwan

Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.

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Vilgrain, Valérie; Pereira, Helena; Assenat, Eric; Guiu, Boris; Ilonca, Alina Diana; Pageaux, Georges-Philippe; Sibert, Annie; Bouattour, Mohamed; Lebtahi, Rachida; Allaham, Wassim; Barraud, Hélène; Laurent, Valérie; Mathias, Elodie; Bronowicki, Jean-Pierre; Tasu, Jean-Pierre; Perdrisot, Rémy; Silvain, Christine; Gerolami, René; Mundler, Olivier; Seitz, Jean-Francois; Vidal, Vincent; Aubé, Christophe; Oberti, Frédéric; Couturier, Olivier; Brenot-Rossi, Isabelle; Raoul, Jean-Luc; Sarran, Anthony; Costentin, Charlotte; Itti, Emmanuel; Luciani, Alain; Adam, René; Lewin, Maïté; Samuel, Didier; Ronot, Maxime; Dinut, Aurelia; Castera, Laurent; Chatellier, Gilles

2017-12-01

Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 ( 90 Y) resin microspheres in patients with hepatocellular carcinoma. SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90 Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to

Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience.

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Ueshima, Kazuomi; Nishida, Naoshi; Kudo, Masatoshi

2017-01-01

Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC. © 2017 S. Karger AG, Basel.

Questiomycin A stimulates sorafenib-induced cell death via suppression of glucose-regulated protein 78.

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Machihara, Kayo; Tanaka, Hidenori; Hayashi, Yoshihiro; Murakami, Ichiro; Namba, Takushi

2017-10-07

Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat owing to the lack of effective chemotherapeutic methods. Sorafenib, the first-line and only available treatment for HCC, extends patient overall survival by several months, with a response rate below 10%. Thus, the identification of an agent that enhances the anticancer effect of sorafenib is critical for the development of therapeutic options for HCC. Endoplasmic reticulum (ER) stress response is one of the methods of sorafenib-induced cell death. Here we report that questiomycin A suppresses expression of GRP78, a cell-protective ER chaperone protein. Analysis of the molecular mechanisms of questiomycin A revealed that this compound stimulated GRP78 protein degradation in an ER stress response-independent manner. Cotreatment with sorafenib and questiomycin A suppressed GRP78 protein expression, which is essential for the stimulation of sorafenib-induced cell death. Moreover, our in vivo study demonstrated that the coadministration of sorafenib and questiomycin A suppressed tumor formation in HCC-induced xenograft models. These results suggest that cotreatment with sorafenib and questiomycin A is a novel therapeutic strategy for HCC by enhancing sorafenib-dependent ER stress-induced cell death, and downregulation of GRP78 is a new target for the stimulation of the therapeutic effects of sorafenib in HCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Sorafenib in Advanced Hepatocellular Carcinoma: A Nationwide Retrospective Study of Efficacy and Tolerability

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Anne Helene Køstner

2013-01-01

Full Text Available Background. Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore we explore the role of alpha-fetoprotein (αFP as a potential biomarker for treatment efficacy and correlation to survival. Methods. Seventy-six patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib between 2007 and 2009 were included. Followup was until 2011. Results. Patients in PS 0-1 had a median overall survival (mOS of 6.2 months, compared to 1.8 months in patients with poorer PS (P=0.005. Child-Pugh A patients had a mOS of 6.6 months versus 3.6 months among patients in Child-Pugh B or C (P=0.0001. Serum αFP ≥ 200 at baseline was prognostic for a shorter survival. All patients with radiologically verified tumor response and baseline αFP ≥ 200 experienced a significant decline in αFP within the first four weeks of treatment. Conclusion. The survival of patients with advanced HCC treated with sorafenib is dependent on performance status and liver function. Treatment of patients with compromised liver function and poor performance status cannot be recommended. The correlation between αFP and objective tumor response warrants further investigation.

Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation

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Honma, Yuichi; Harada, Masaru

2013-01-01

Hepatocellular carcinoma (HCC) is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Recent studies of the molecular mechanisms responsible for tumor initiation and progression have identified several potential molecular targets in HCC. Sorafenib is a multi-kinase inhibitor shown to have survival benefits in advanced HCC. It acts by inhibiting the serine/threonine kinases and the receptor type tyrosine kinases. In preclinical experiments sorafenib had anti-proliferative activity in hepatoma cells and it reduced tumor angiogenesis and increased apoptosis. Here, we demonstrate for the first time that the cytotoxic mechanisms of sorafenib include its inhibitory effects on protein ubiquitination, unfolded protein response (UPR) and keratin phosphorylation in response to endoplasmic reticulum (ER) stress. Moreover, we show that combined treatment with sorafenib and proteasome inhibitors (PIs) synergistically induced a marked increase in cell death in hepatoma- and hepatocyte-derived cells. These observations may open the way to potentially interesting treatment combinations that may augment the effect of sorafenib, possibly including drugs that promote ER stress. Because sorafenib blocked the cellular defense mechanisms against hepatotoxic injury not only in hepatoma cells but also in hepatocyte-derived cells, we must be careful to avoid severe liver injury. -- Graphical abstract: Display Omitted -- Highlights: •We examined the cytotoxic mechanisms of sorafenib in hepatoma cells. •Sorafenib induces cell death via apoptotic and necrotic fashion. •Sorafenib inhibits protein ubiquitination and unfolded protein response. •Autophagy induced by sorafenib may affect its cytotoxicity. •Sorafenib inhibits keratin phosphorylation and cytoplasmic inclusion formation

Benefit-Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib.

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Pelosof, Lorraine; Lemery, Steven; Casak, Sandra; Jiang, Xiaoping; Rodriguez, Lisa; Pierre, Vadryn; Bi, Youwei; Liu, Jiang; Zirkelbach, Jeanne Fourie; Patel, Anuja; Goldberg, Kirsten B; McKee, Amy E; Keegan, Patricia; Pazdur, Richard

2018-04-01

On April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo-controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28-day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50-0.79, p  regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression-free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52-60] (HR = 0.46; 95% CI, 0.37-0.56, p  regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar-plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit-to-risk evaluation led to approval for treatment of patients with advanced HCC. Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Pro-angiogenic TIE-2-expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma.

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Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Doi, Hiroyoshi; Sugiyama, Masaya; Osawa, Yosuke; Kimura, Kiminori; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aoki, Yoshihiko; Fukai, Moto; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

2017-09-01

Sorafenib, a multi-kinase inhibitor, inhibits tumor angiogenesis and is the first-line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE-2-expressing monocytes (TEMs) to predict the response in sorafenib-treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51-48.16, p = 0.015] and Child-Pugh class (HR = 5.59, 95% CI = 1.06-29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib-treated patients with advanced HCC. © 2017 UICC.

Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis.

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Gramenzi, Annagiulia; Golfieri, Rita; Mosconi, Cristina; Cappelli, Alberta; Granito, Alessandro; Cucchetti, Alessandro; Marinelli, Sara; Pettinato, Cinzia; Erroi, Virginia; Fiumana, Silvia; Bolondi, Luigi; Bernardi, Mauro; Trevisani, Franco

2015-03-01

Sorafenib and transarterial (90) Y-radioembolization (TARE) are possible treatments for Barcelona Clinic Liver Cancer (BCLC) intermediate-advanced stage hepatocellular carcinoma (HCC). No study directly comparing sorafenib and TARE is currently available. This single-centre retrospective study compares the outcomes achieved with sorafenib and TARE in HCC patients potentially amenable to either therapy. Seventy-four sorafenib (71 ± 10 years, male 87%, BCLC B/C 53%/47%) and 63 TARE HCC patients (66 ± 9 years, male 79%, BCLC B/C 41%/59%) were included based on the following criteria: Child-Pugh class A/B, performance status ≤1, HCC unfit for other effective therapies, no metastases and no previous systemic chemotherapy. Median overall survivals of the two groups were comparable, being 14.4 months (95% CI: 4.3-24.5) in sorafenib and 13.2 months (95% CI: 6.1-20.2) in TARE patients, with 1-, 2- and 3-year survival rates of 52.1%, 29.3% and 14.7% vs 51.8%, 27.8% and 21.6% respectively. Two TARE patients underwent liver transplantation after successful down-staging. To minimize the impact of confounding factors on survival analysis, propensity model matched 32 patients of each group for median age, tumour gross pathology and the independent prognostic factors (portal vein thrombosis, performance status, Model for End Liver Disease). Even after matching, the median survival did not differ between sorafenib (13.1 months; 95% CI: 1.2-25.9) and TARE patients (11.2 months; 95% CI: 6.7-15.7), with comparable 1-, 2- and 3-year survival rates. In cirrhotic patients with intermediate-advanced or not-otherwise-treatable HCC, sorafenib and TARE provide similar survivals. Down-staging allowing liver transplantation only occurred after TARE. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats

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Chin-Tsung Ting

2017-06-01

Full Text Available Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC. In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT and with two cytochrome P450 3A4 (CYP3A4 inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.

Sub-classification of Advanced-Stage Hepatocellular Carcinoma: A Cohort Study Including 612 Patients Treated with Sorafenib.

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Yoo, Jeong-Ju; Chung, Goh Eun; Lee, Jeong-Hoon; Nam, Joon Yeul; Chang, Young; Lee, Jeong Min; Lee, Dong Ho; Kim, Hwi Young; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

2018-04-01

Advanced hepatocellular carcinoma (HCC) is associated with various clinical conditions including major vessel invasion, metastasis, and poor performance status. The aim of this study was to establish a prognostic scoring system and to propose a sub-classification of the Barcelona-Clinic Liver Cancer (BCLC) stage C. This retrospective study included consecutive patientswho received sorafenib for BCLC stage C HCC at a single tertiary hospital in Korea. A Cox proportional hazard model was used to develop a scoring system, and internal validationwas performed by a 5-fold cross-validation. The performance of the model in predicting risk was assessed by the area under the curve and the Hosmer-Lemeshow test. A total of 612 BCLC stage C HCC patients were sub- classified into strata depending on their performance status. Five independent prognostic factors (Child-Pugh score, α-fetoprotein, tumor type, extrahepatic metastasis, and portal vein invasion) were identified and used in the prognostic scoring system. This scoring system showed good discrimination (area under the receiver operating characteristic curve, 0.734 to 0.818) and calibration functions (both p advanced HCC. A prognostic scoring system with five independent factors is useful in predicting the survival of patients with BCLC stage C HCC.

Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer

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Brose, Marcia S; Nutting, Christopher M; Jarzab, Barbara

2014-01-01

cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria...... cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals...

Nucleoside-Lipid-Based Nanocarriers for Sorafenib Delivery

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Benizri, Sebastien; Ferey, Ludivine; Alies, Bruno; Mebarek, Naila; Vacher, Gaelle; Appavoo, Ananda; Staedel, Cathy; Gaudin, Karen; Barthélémy, Philippe

2018-01-01

Although the application of sorafenib, a small inhibitor of tyrosine protein kinases, to cancer treatments remains a worldwide option in chemotherapy, novel strategies are needed to address the low water solubility (drug. In this context, the use of nanocarriers is currently investigated in order to overcome these drawbacks. In this contribution, we report a new type of sorafenib-based nanoparticles stabilized by hybrid nucleoside-lipids. The solid lipid nanoparticles (SLNs) showed negative or positive zeta potential values depending on the nucleoside-lipid charge. Transmission electron microscopy of sorafenib-loaded SLNs revealed parallelepiped nanoparticles of about 200 nm. Biological studies achieved on four different cell lines, including liver and breast cancers, revealed enhanced anticancer activities of Sorafenib-based SLNs compared to the free drug. Importantly, contrast phase microscopy images recorded after incubation of cancer cells in the presence of SLNs at high concentration in sorafenib (> 80 μM) revealed a total cancer cell death in all cases. These results highlight the potential of nucleoside-lipid-based SLNs as drug delivery systems.

Therapeutic evaluation of sorafenib for hepatocellular carcinoma using contrast-enhanced ultrasonography: Preliminary result.

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Shiozawa, Kazue; Watanabe, Manabu; Ikehara, Takashi; Kogame, Michio; Kikuchi, Yoshinori; Igarashi, Yoshinori; Sumino, Yasukiyo

2016-07-01

The present study aimed to determine the usefulness of contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating the therapeutic response to sorafenib for hepatocellular carcinoma (HCC). In total, 26 patients with advanced HCC who received sorafenib and were followed up by CEUS were enrolled in the present study. CEUS was performed prior to and within 2-4 weeks of treatment, and the images of the target lesion in the post-vascular phase with a re-injection method were analyzed. The presence (+) or absence (-) of intratumoral necrosis and the intratumoral vascular architecture on micro-flow imaging (MFI) were compared prior to and subsequent to treatment. Target lesions that exhibited non-enhancement after re-injection were considered to indicate intratumoral necrosis. The intratumoral vascular architecture was classified into three groups, as follows: Vd, the intratumoral vessels visually narrowed or decreased; Vnc, the vessels remained unchanged; and Vi, the vessels were thickened or increased. Survival curves were estimated using the Kaplan-Meier method and compared using the log rank test between the intratumoral necrosis (+) and (-) groups, and among the Vd, Vnc and Vi groups. PVnc group and 5 patients in the Vi group. The MSTs in the Vd, Vnc and Vi groups were 15.6 months (95% CI, 5.0-23.3), 11.0 months (95% CI, 3.5-17.6) and 3.6 months (95% CI: 1.2-6.0), respectively. The P-value for the differences between the Vd and Vnc groups, Vd and Vi groups, and Vnc and Vi groups were 0.78, 0.016 and 0.047, respectively, which indicated that the survival time decreased significantly in the Vi group. Evaluation of intratumoral vascular architecture using MFI demonstrates promise for assessing the therapeutic response to sorafenib in patients with HCC.

Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America.

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Stadler, Walter M; Figlin, Robert A; McDermott, David F; Dutcher, Janice P; Knox, Jennifer J; Miller, Wilson H; Hainsworth, John D; Henderson, Charles A; George, Jeffrey R; Hajdenberg, Julio; Kindwall-Keller, Tamila L; Ernstoff, Marc S; Drabkin, Harry A; Curti, Brendan D; Chu, Luis; Ryan, Christopher W; Hotte, Sebastien J; Xia, Chenghua; Cupit, Lisa; Bukowski, Ronald M

2010-03-01

The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months. The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups. Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).

Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study.

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Kim, Hwi Young; Lee, Dong Hyeon; Lee, Jeong-Hoon; Cho, Young Youn; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

2018-03-20

Prediction of the outcome of sorafenib therapy using biomarkers is an unmet clinical need in patients with advanced hepatocellular carcinoma (HCC). The aim was to develop and validate a biomarker-based model for predicting sorafenib response and overall survival (OS). This prospective cohort study included 124 consecutive HCC patients (44 with disease control, 80 with progression) with Child-Pugh class A liver function, who received sorafenib. Potential serum biomarkers (namely, hepatocyte growth factor [HGF], fibroblast growth factor [FGF], vascular endothelial growth factor receptor-1, CD117, and angiopoietin-2) were tested. After identifying independent predictors of tumor response, a risk scoring system for predicting OS was developed and 3-fold internal validation was conducted. A risk scoring system was developed with six covariates: etiology, platelet count, Barcelona Clinic Liver Cancer stage, protein induced by vitamin K absence-II, HGF, and FGF. When patients were stratified into low-risk (score ≤ 5), intermediate-risk (score 6), and high-risk (score ≥ 7) groups, the model provided good discriminant functions on tumor response (concordance [c]-index, 0.884) and 12-month survival (area under the curve [AUC], 0.825). The median OS was 19.0, 11.2, and 6.1 months in the low-, intermediate-, and high-risk group, respectively (P functions on tumor response (c-index, 0.825) and 12-month survival (AUC, 0.803), and good calibration functions (all P > 0.05 between expected and observed values). This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells.

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Zhang, Yafei; Zhang, Bicheng; Zhang, Anran; Zhao, Yong; Zhao, Jie; Liu, Jian; Gao, Jianfei; Fang, Dianchun; Rao, Zhiguo

2012-09-01

Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients

Multiple Roles of Autophagy in the Sorafenib Resistance of Hepatocellular Carcinoma

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Ting Sun

2017-11-01

Full Text Available Hepatocellular carcinoma (HCC is the second leading cause of cancer-related death worldwide, and prognosis remains unsatisfactory since the disease is often diagnosed at the advanced stages. Currently, the multikinase inhibitor sorafenib is the only drug approved for the treatment of advanced HCC. However, primary or acquired resistance to sorafenib develops, generating a roadblock in HCC therapy. Autophagy is an intracellular lysosomal pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. Current understanding of the role of autophagy in the progression of cancer and the response to cancer therapy remains controversial. Sorafenib is able to induce autophagy in HCC, but the effect of autophagy is indistinct. Some studies established that sorafenib-induced autophagy serves as a pro-survival response. However, other studies found that sorafenib-induced autophagy improves the lethality of sorafenib against HCC cells. The mechanisms underlying autophagy and sorafenib resistance remain elusive. The purpose of this review is to summarize the progress of research focused on autophagy and sorafenib resistance and to update current knowledge of how cellular autophagy impacts sorafenib sensitivity in HCC treatment.

Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells

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Wu M

2018-05-01

Full Text Available Man Wu,1,2 Guanren Zhao,2 Xiaomei Zhuang,1 Tianhong Zhang,1 Ce Zhang,2 Wenpeng Zhang,1 Zhenqing Zhang1 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China; 2Department of Pharmacy, The 309th Hospital of PLA, Beijing, China Background: Triclosan is a widely applied antimicrobial agent which affects the endocrine system and homeostasis; it may also promote the cirrhosis and hepatocellular carcinoma (HCC growth in a mice model. The exact roles of triclosan in regulating human hepatocellular carcinoma development and treatment remain unknown. Methods: MHCC97-H, a highly aggressive HCC cell line, was treated with indicated concentration of triclosan or sorafenib. The expression of drug-resistance genes was examined by qPCR. The clearance or metabolism of sorafenib was determined by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS. MTT assay was used to examine the MHCC97-H cell proliferation. Nude mice were used to exam the anti-tumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H cells. Results: In the present study, triclosan could induce the expression of drug-resistance genes in MHCC97-H cells (a highly aggressive HCC cell line, accelerate the clearance of sorafenib, and attenuate the anti-proliferation effect of this molecular targeted agent in MHCC97-H cells. Triclosan decreased the antitumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H in nude mice. Conclusion: By discovering the fact that triclosan treatment enhances sorafenib resistance in HCC cells, this work suggests exposure of triclosan is detrimental to HCC patients during chemotherapy. Keywords: HCC, triclosan, sorafenib resistance, drug clearance 

A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

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Den, Robert B.; Kamrava, Mitchell; Sheng, Zhi; Werner-Wasik, Maria; Dougherty, Erin; Marinucchi, Michelle; Lawrence, Yaacov R.; Hegarty, Sarah; Hyslop, Terry; Andrews, David W.; Glass, Jon; Friedman, David P.; Green, Michael R.; Camphausen, Kevin; Dicker, Adam P.

2013-01-01

Purpose: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. Methods and Materials: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m 2 ) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Results: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. Conclusions: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma.

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Li, Sainan; Dai, Weiqi; Mo, Wenhui; Li, Jingjing; Feng, Jiao; Wu, Liwei; Liu, Tong; Yu, Qiang; Xu, Shizan; Wang, Wenwen; Lu, Xiya; Zhang, Qinghui; Chen, Kan; Xia, Yujing; Lu, Jie; Zhou, Yingqun; Fan, Xiaoming; Xu, Ling; Guo, Chuanyong

2017-12-15

Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC. © 2017 UICC.

Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus

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Zhang YF

2016-07-01

Full Text Available Yong-Fa Zhang,1–3,* Wei Wei,1–3,* Jia-Hong Wang,1–3,* Li Xu,1–3 Pei-En Jian,1–3 Cheng-Zuo Xiao,4 Xiao-Ping Zhong,1–3 Ming Shi,1–3 Rong-Ping Guo1–3 1Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 2State Key Laboratory of Oncology in South China, 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, 4Department of General Surgery, Shenzhen Shajing Affiliated Hospital of Guangzhou Medical University, Shenzhen, People’s Republic of China *These authors contributed equally to this work Objective: To compare the treatment outcomes of sorafenib plus transarterial chemoembolization (TACE vs TACE alone in patients with hepatocellular carcinoma (HCC and hepatic vein tumor thrombus (HVTT.Methods: Twenty patients who were initially diagnosed with HCC and HVTT and received TACE combined with sorafenib during February 2009 to October 2013 were included in the study. To minimize selection bias, these patients were compared with 60 case-matched controls selected from a pool of 81 patients (in a 1:3 ratio who received TACE alone during the same period. The primary end point was overall survival (OS. The secondary end points were time to progression, disease control rate, and adverse events.Results: After a median follow-up period of 12.5 months (range, 1.03–44.23 months, the OS of the combined group was found to be significantly higher compared with the monotherapy group (14.9 vs 6.1 months, P=0.010. The time to progression was found to be significantly longer in the combined group (4.9 vs 2.4 months, P=0.016. Univariate and multivariate analyses revealed that the treatment allocation was an independent predictor of OS.Conclusion: Sorafenib plus TACE was well tolerated and was more effective in treating patients with advanced HCC and HVTT. Future trials with prospective larger samples are required to validate these results. Keywords: hepatocellular carcinoma, hepatic vein tumor thrombus, prognosis

A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

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Fernando, Joan; Malfettone, Andrea; Cepeda, Edgar B; Vilarrasa-Blasi, Roser; Bertran, Esther; Raimondi, Giulia; Fabra, Àngels; Alvarez-Barrientos, Alberto; Fernández-Salguero, Pedro; Fernández-Rodríguez, Conrado M; Giannelli, Gianluigi; Sancho, Patricia; Fabregat, Isabel

2015-02-15

The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients. © 2014 UICC.

Sorafenib-Associated Heart Failure Complicated by Cardiogenic Shock after Treatment of Advanced Stage Hepatocellular Carcinoma: A Clinical Case Discussion

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Candace Wu

2017-01-01

Full Text Available Background. Sorafenib, an oral tyrosine kinase inhibitor (TKI, targets multiple tyrosine kinase receptors (TKRs involved in angiogenesis and tumor growth. Studies suggest that inhibition of TKR impacts cardiomyocyte survival. Inhibition of VEGF signaling interrupts angiogenesis and is associated with the development of hypertension and compensatory hypertrophy. Compensated hypertrophy ultimately leads to heart failure. Case Description. A 76-year-old man with a past medical history of systolic heart failure due to ischemic cardiomyopathy and stage IIIC hepatocellular carcinoma (HCC presented with symptoms of decompensated heart failure. Four months prior to admission, he was started on sorafenib. Results. Our patient was treated with intravenous furosemide and guideline directed therapy. Clinical status was complicated by the development of low cardiac output and shock requiring inotropic support. Careful titration of heart failure medication led to hemodynamic improvement and discontinuation of dobutamine. Conclusion. Greater awareness of sorafenib cardiotoxicity is essential. As TKI usage grows for treatment of cancers, heart failure-related complications will increase. In our patient, routine heart failure management and cessation of sorafenib led to clinical improvement. Future studies on the treatment of sorafenib cardiotoxicity should be explored further in this unique patient population.

Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus

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Pan, T.; Li, X.-S.; Xie, Q.-K.; Wang, J.-P.; Li, W.; Wu, P.-H.; Zhao, M.

2014-01-01

Aim: To evaluate the safety and efficacy of combined therapy with transarterial chemoembolization (TACE) and sorafenib for hepatocellular carcinoma (HCC) with portal venous tumour thrombus (PVTT). Materials and methods: This study was approved by the institutional review board. From May 2009 to May 2012, 170 consecutive patients were newly diagnosed with advanced-stage HCC and treated with TACE plus sorafenib. Among them, 41 patients with PVTT were retrospectively enrolled in the study. The adverse events (AEs), overall survival (OS), time to progression (TTP), and prognostic factors were analysed. Statistical analysis was performed with the Kaplan–Meier method using the log-rank test and Cox regression models. Results: The most common AEs were hand–foot skin reaction related to sorafenib and fever related to TACE. Procedure-related mortality and grade 4 AEs were not observed. Grade 3 AEs were observed in five patients. During the median follow-up period of 13.5 months (range 1.4–45 months), the 6-month and 1-year survival rates were 87.7% and 53.6%, respectively. The median OS was 13 months (range 1.4–44.8 months), and the median TTP was 7 months (range 1–18.6 months). The Child–Pugh class (p = 0.022), extrahepatic metastasis (p = 0.009), and gross morphological type (nodular type versus diffuse type; p = 0.008) were prognostic factors related to OS in the multivariate analysis. Conclusion: TACE plus sorafenib in an interrupted therapeutic scheme was well tolerated and might improve OS for HCC patients with PVTT, especially in those with Child–Pugh class A, no extrahepatic metastasis, or nodular-type HCC. - Highlights: • We introduce the safety of TACE plus sorafenib for patients with advanced HCC and PVTT. • We suggest that the combined therapy might prolong the TTP and OS than sorafenib alone. • Clinic benefit determinations with the Child-Pugh class, extrahepatic metastasis or gross type

Magnetic resonance imaging following treatment of advanced hepatocellular carcinoma with sorafenib

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Joon-Il Choi

2014-06-01

Full Text Available Hepatocellular carcinomas are highly vascular tumors, showing progressive hypervascularity by the process of neoangiogenesis. Tumor angiogenesis is critical for tumor growth as well as metastatic spread therefore, imaging and quantification of tumor neo-angiogenesis is essential for monitoring response to targeted therapies and predicting disease progression. Sorafenib is a molecular targeting agent used for treating hypervascular tumors. This drug is now the standard of care in treatment of patients with advanced hepatocellular carcinoma. Due to its anti-angiogenic and anti-proliferative actions, imaging findings following treatment with Sorafenib are quite distinct when compared to conventional chemotherapeutic agents. Liver MRI is a widely adopted imaging modality for assessing treatment response in hepatocellular carcinoma and imaging features may reflect pathophysiological changes within the tumor. In this mini-review, we will discuss MRI findings after Sorafenib treatment in hepatocellular carcinoma and review the feasibility of MRI as an early biomarker in differentiating responders from non-responders after treatment with molecular targeting agents.

Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib

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Xia, Hongping; Lee, Kee Wah; Chen, Jianxiang; Kong, Shik Nie; Sekar, Karthik; Deivasigamani, Amudha; Seshachalam, Veerabrahma Pratap; Goh, Brian Kim Poh; Ooi, London Lucien; Hui, Kam M

2017-01-01

Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro. Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4highGADD45Blow was significantly poorer compared to patients with ACSL4lowGADD45Bhigh, thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4highGADD45Blow. In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4highGADD45Blow expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits. PMID:28900541

Inhibition of retinopathy of prematurity in rat by intravitreal injection of sorafenib

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Li-Li Tian

2014-04-01

Full Text Available AIM:To investigate the effect of intravitreal injection administered sorafenib, a multikinase inhibitor, in a rat model of oxygen-induced retinopathy (OIR.METHODS:Seven-day-old Sprague-Dawley rats (n=144 were randomly assigned to six groups. Group A received normal partial oxygen pressure and groups B, C, D, E and F were exposed to hyperoxia (75±2% from postnatal 7d (P7 to P12 to induce retinopathy of prematurity. The rats in groups C, D, E and F were received intravitreal injections of either vehicle (DMSO or sorafenib at P12 (5, 20 and 80 μg, respectively. Then they returned to normoxia after P12. The retinas were whole-mounted and imaged with a confocal microscopy. The vascular branching points were counted to quantify neovascularization at P17. Cross-sections of the retina were stained with hematoxylin and eosin (HE. The nuclei of new vessels breaking the internal limiting membrane were counted to quantify the proliferative neovascular response.RESULTS:The retinal vessel in groups B and C turned into tortuosity and a great deal of neovascularization were observed. Sorafenib-treated rats had significantly less neovascularization as compared with vehicle-treated and control rats in a dose dependent manner (P<0.05. The number of vascular branching points in A, B, C, D, E and F were 16.50±3.90, 37.44±6.47, 37.08±5.10, 30.80±6.85, 26.08±5.08 and 19.83±3.51, respectively. The number of the nuclei of retinal new vessel in A, B, C, D, E and F were 0.22±0.42, 35.66±4.70, 35.30±4.54, 27.30±4.28, 21.41±3.53, and 7.41±2.87, respectively. There were significant difference between each group (P＜0.05 except groups B and C.CONCLUSION: In the rat OIR model, sorafenib could inhibit retinal neovascularization in a dose dependent manner.

Plectin deficiency in liver cancer cells promotes cell migration and sensitivity to sorafenib treatment.

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Cheng, Chiung-Chi; Chao, Wei-Ting; Liao, Chen-Chun; Tseng, Yu-Hui; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Hsu, Yung-Hsiang; Liu, Yi-Hsiang

2018-01-02

Plectin involved in activation of kinases in cell signaling pathway and plays important role in cell morphology and migration. Plectin knockdown promotes cell migration by activating focal adhesion kinase and Rac1-GTPase activity in liver cells. Sorafenib is a multi-targeting tyrosine kinase inhibitor that improves patient survival on hepatocellular carcinoma. The aim of this study is to investigate the correlation between the expression of plectin and cell migration as well as the sensitivity of hepatoma cell lines exposing to sorafenib. Hepatoma cell lines PLC/PRF/5 and HepG2 were used to examine the level of plectin expression and cell migration in comparison with Chang liver cell line. In addition, sensitivity of the 3 cell lines to sorafenib treatment was also measured. Expression of plectin was lower in PLC/PRF/5 and HepG2 hepatoma cells than that of Chang liver cells whereas HepG2 and PLC/PRF/5 cells exhibit higher rate of cell migration in trans-well migration assay. Immunohistofluorecent staining on E-cadherin revealed the highest rate of collective cell migration in HepG2 cells and the lowest was found in Chang liver cells. Likewise, HepG2 cell line was most sensitive to sorafenib treatment and Chang liver cells exhibited the least sensitivity. The drug sensitivity to sorafenib treatment showed inverse correlation with the expression of plectin. We suggest that plectin deficiency and increased E-cadherin in hepatoma cells were associated with higher rates of cell motility, collective cell migration as well as higher drug sensitivity to sorafenib treatment.

State of the art of the therapeutic perspective of sorafenib against hematological malignancies.

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Zauli, G; Voltan, R; Tisato, V; Secchiero, P

2012-01-01

The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti-neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the

Antagonism of Sorafenib and Regorafenib actions by platelet factors in hepatocellular carcinoma cell lines

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D’Alessandro, Rosalba; Refolo, Maria G; Lippolis, Catia; Giannuzzi, Grazia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian I

2014-01-01

Platelets are frequently altered in hepatocellular carcinoma (HCC) patients. Platelet lysates (hPL) can enhance HCC cell growth and decrease apoptosis. The aims were to evaluate whether hPL can modulate the actions of Sorafenib or Regorafenib, two clinical HCC multikinase antagonists. Several human HCC cell lines were grown in the presence and absence of Sorafenib or Regorafenib, with or without hPL. Growth was measured by MTT assay, apoptosis was assessed by Annexin V and by western blot, and autophagy and MAPK growth signaling were also measured by western blot, and migration and invasion were measured by standard in vitro assays. Both Sorafenib and Regorafenib-mediated inhibition of cell growth, migration and invasion were all antagonized by hPL. Drug-mediated apoptosis and decrease in phospho-ERK levels were both blocked by hPL, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-xL levels. Preliminary data, obtained with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), included in hPL, revealed that these factors were able to antagonized Sorafenib in a proliferation assay, in particular when used in combination. Platelet factors can antagonize Sorafenib or Regorafenib-mediated growth inhibition and apoptosis in HCC cells. The modulation of platelet activity or numbers has the potential to enhance multikinase drug actions

The multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating IRES-dependent translation of viral proteins.

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Gao, Meng; Duan, Hao; Liu, Jing; Zhang, Hao; Wang, Xin; Zhu, Meng; Guo, Jitao; Zhao, Zhenlong; Meng, Lirong; Peng, Yihong

2014-06-01

The activation of ERK and p38 signal cascade in host cells has been demonstrated to be essential for picornavirus enterovirus 71 (EV71) replication and up-regulation of virus-induced cyclooxygenase-2 (COX-2)/prostaglandins E2 (PGE2) expression. The aim of this study was to examine the effects of sorafenib, a clinically approved anti-cancer multi-targeted kinase inhibitor, on the propagation and pathogenesis of EV71, with a view to its possible mechanism and potential use in the design of therapy regimes for Hand foot and mouth disease (HFMD) patients with life threatening neurological complications. In this study, non-toxic concentrations of sorafenib were shown to inhibit the yield of infectious progeny EV71 (clinical BC08 strain) by about 90% in three different cell types. A similar inhibitory effect of sorafenib was observed on the synthesis of both viral genomic RNA and the VP1 protein. Interestingly, sorafenib exerted obvious inhibition of the EV71 internal ribosomal entry site (IRES)-mediated translation, the first step in picornavirus replication, by linking it to a firefly luciferase reporter gene. Sorafenib was also able to prevent both EV71-induced CPE and the activation of ERK and p38, which contributes to up-regulation COX-2/PGE2 expression induced by the virus. Overall, this study shows that sorafenib strongly inhibits EV71 replication at least in part by regulating viral IRES-dependent translation of viral proteins, indicating a novel potential strategy for the treatment of HFMD patients with severe neurological complications. To our knowledge, this is the first report that investigates the mechanism by which sorafenib inhibits EV71 replication. Copyright © 2014 Elsevier B.V. All rights reserved.

Radiosensitization effects of sorafenib on colon cancer cells

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Kim, Eun Ho; Kim, Mi-Sook; Jung, Won-Gyun; Jeong, Youn Kyoung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2014-11-15

Radiotherapy is a standard therapy in the adjuvant treatment of resected colon and rectum cancers, and its combination with chemotherapy has been shown to reduce local failure and distant metastasis still further, thereby improving the outcome of treatment. One potential chemotherapeutic agent for this, sorafenib (Nexavar, BAY43-9006), is an oral multikinase inhibitor that blocks tumor cell proliferation and angiogenesis, and induces tumor cell apoptosis by inhibiting serine/threonine kinases (c-RAF and mutant and wild-type BRAF) as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 and 3 (VEGFR2 and VEGFR3), platelet- derived growth factor receptor , FLT3, and c-KIT. Sorafenib is currently used in clinics to treat patients with advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer. These findings provide a molecular evidence base for the use of chemoradiation to treat colon cancer, and in vivo modeling should be used to further assess its suitability for clinical applications.

GSK-3beta inhibition enhances sorafenib-induced apoptosis in melanoma cell lines.

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Panka, David J; Cho, Daniel C; Atkins, Michael B; Mier, James W

2008-01-11

Glycogen synthase kinase-3beta (GSK-3beta) can participate in the induction of apoptosis or, alternatively, provide a survival signal that minimizes cellular injury. We previously demonstrated that the multikinase inhibitor sorafenib induces apoptosis in melanoma cell lines. In this report, we show that sorafenib activates GSK-3beta in multiple subcellular compartments and that this activation undermines the lethality of the drug. Pharmacologic inhibition and/or down-modulation of the kinase enhances sorafenib-induced apoptosis as determined by propidium iodide staining and by assessing the mitochondrial release of apoptosis-inducing factor and Smac/DIABLO. Conversely, the forced expression of a constitutively active form of the enzyme (GSK-3beta(S9A)) protects the cells from the apoptotic effects of the drug. This protective effect is associated with a marked increase in basal levels of Bcl-2, Bcl-x(L), and survivin and a diminution in the degree to which these anti-apoptotic proteins are down-modulated by sorafenib exposure. Sorafenib down-modulates the pro-apoptotic Bcl-2 family member Noxa in cells with high constitutive GSK-3beta activity. Pharmacologic inhibition of GSK-3beta prevents the disappearance of Noxa induced by sorafenib and enhances the down-modulation of Mcl-1. Down-modulation of Noxa largely eliminates the enhancing effect of GSK-3 inhibition on sorafenib-induced apoptosis. These data provide a strong rationale for the use of GSK-3beta inhibitors as adjuncts to sorafenib treatment and suggest that preservation of Noxa may contribute to their efficacy.

Sorafenib-induced defective autophagy promotes cell death by necroptosis.

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Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Björklund, Ann-Charlotte; Zhivotovsky, Boris; Grandér, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

2015-11-10

Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5-/- cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis.

Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

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Groenendijk, Floris H; Mellema, Wouter W; van der Burg, Eline; Schut, Eva; Hauptmann, Michael; Horlings, Hugo M; Willems, Stefan M; van den Heuvel, Michel M; Jonkers, Jos; Smit, Egbert F; Bernards, René

2015-01-01

The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical

Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

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Krege, Susanne; Rexer, Heidrun; vom Dorp, Frank; de Geeter, Patrick; Klotz, Theodor; Retz, Margitte; Heidenreich, Axel; Kühn, Michael; Kamradt, Joern; Feyerabend, Susan; Wülfing, Christian; Zastrow, Stefan; Albers, Peter; Hakenberg, Oliver; Roigas, Jan; Fenner, Martin; Heinzer, Hans; Schrader, Mark

2014-03-01

To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS. © 2013 The Authors

A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function

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Hyun Yang

2017-06-01

Full Text Available Background/Aims Metronomic chemotherapy (MET is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC patients with portal vein tumor thrombosis (PVTT. Methods A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. Results The median number of MET cycles was two (1-15. The OS values for the MET group and sorafenib group were 158 days (132-184 and 117 days (92-142, respectively (P=0.029. The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014 and Child-Pugh class B (HR=1.856, P=0.008. Conclusions MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

A rare adverse reaction of sorafenib | Wang | Libyan Journal of ...

African Journals Online (AJOL)

2007-10-30

Sorafenib is a multikinase inhibitor thought to target vascular endothelial growth factor and its receptor. The European Medicines Agency (EAMA) and Food and Drug Administration (FDA) approved the use of sorafenib in late-stage hepatic cellular cancer (HCC) on October 30, 2007, and November 19, 2007, respectively.

Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib.

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Beldner, Matthew; Jacobson, Michael; Burges, Gene E; Dewaay, Deborah; Maize, John C; Chaudhary, Uzair B

2007-10-01

The development of multitargeted tyrosine kinase inhibitors has provided significant advances in the treatment of renal cell carcinoma. This case describes initial therapy for managing renal cell cancer with the administration of sorafenib, a multitargeted tyrosine kinase inhibitor. We report the development of localized palmar-plantar epidermal hyperplasia, a rare but significant cutaneous adverse event from sorafenib therapy. Mild-to-moderate dermatologic toxicity from sorafenib has been well described in the literature. We also review the current knowledge and the proposed hypothesis for the development of cutaneous events related to tyrosine kinase inhibitors. This particular case represents a unique form of dermatologic toxicity to sorafenib that has not previously been described in the literature.

Quantitative therapy response assessment by volumetric iodine-uptake measurement: Initial experience in patients with advanced hepatocellular carcinoma treated with sorafenib

International Nuclear Information System (INIS)

Dai, Xu; Schlemmer, Heinz-Peter; Schmidt, Bernhard; Höh, Karolin; Xu, Ke; Ganten, Tom M.; Ganten, Maria-Katharina

2013-01-01

Objectives: To investigate the volumetric iodine-uptake (VIU) changes by dual-energy CT (DECT) in assessing the response to sorafenib treated hepatocellular carcinoma (HCC) patients, compared with AASLD (American Association for the Study of Liver Diseases) and Choi criteria. Materials and methods: Fifteen patients with HCC receiving sorafenib, monitored with contrast-enhanced DECT scans at baseline and a minimum of one follow-up (8–12 weeks) were retrospectively evaluated. 30 target lesions in total were analyzed for tumor response according to VIU and adapted Choi criteria and compared with the standard AASLD. Results: According to AASLD criteria, 67% target lesions showed disease control: partial response (PR) in 3% and stable disease (SD) in 63%. 33% lesions progressed (PD). Disease control rate presented by VIU (60%) was similar to AASLD (67%) and Choi (63%) (P > 0.05). For disease control group, change in mean VIU was from 149.5 ± 338.3 mg to 108.5 ± 284.1 mg (decreased 19.1 ± 42.9%); and for progressive disease group, change in mean VIU was from 163.7 ± 346.7 mg to 263.9 ± 537.2 mg (increased 230.5 ± 253.1%). Compared to AASLD (PR, 3%), VIU and Choi presented more PR (33% and 30%, respectively) in disease control group (P < 0.05). VIU has moderate consistency with both AASLD (kappa = 0.714; P < 0.005) and Choi (kappa = 0.648; P < 0.005), while VIU showed a better consistency and correlation with AASLD (kappa = 0.714; P < 0.005; r = 0.666, P < 0.005) than Choi with AASLD (kappa = 0.634, P < 0.005; r = 0.102, P = 0.296). Conclusion: VIU measurements by DECT can evaluate the disease control consistent with the current standard AASLD. Measurements are semi-automatic and therefore easy and robust to apply. As VIU reflects vital tumor burden in HCC, it is likely to be an optimal tumor response biomarker in HCC

Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition.

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Lining Jia

Full Text Available This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect.Eight-week-old rats were subjected to unilateral ureteral obstruction (UUO and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis.HE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p<0.05. Masson staining showed that the area of fibrosis was significantly decreased in the sorafenib-treated-UUO groups compared with vehicle-treated-UUO group (p<0.01. The size of the kidney did not significantly increase; the cortex of the kidney was thicker and had a richer blood supply in the middle-dose sorafenib group compared with the vehicle-treated-UUO group (p<0.05. Compared with the vehicle-treated-UUO and TGF-β-stimulated NRK-52E groups, the expression of a-SMA and E-cadherin decreased and increased, respectively, in the UUO kidneys and NRK-52E cells of the sorafenib-treated groups (p<0.05. The apoptotic rate of NRK-52E cells treated with sorafenib decreased for 24 hours in a dose-dependent manner (p<0.05. Compared with the vehicle-treated UUO and TGF-β-stimulated NRK-52E groups, the ratio of p-Smad3 to Smad3 decreased in the sorafenib-treated groups (p<0.05.Our results suggest that

Sorafenib for Metastatic Thyroid Cancer

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A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

1082-39, an analogue of sorafenib, inhibited human cancer cell growth more potently than sorafenib.

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Chu, Jia-Hui; Zhao, Cui-Rong; Song, Zhi-Yu; Wang, Rui-Qi; Qin, Yi-Zhuo; Li, Wen-Bao; Qu, Xian-Jun

2014-04-01

1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells. Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay. 1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways. 1082-39 is a promising candidate compound which could develop as a potent anticancer agent. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC)

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Kawazoe, Hisashi; Bilim, Vladimir N. [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Ugolkov, Andrey V., E-mail: ugolkov@northwestern.edu [Tumor Biology Core, Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Silverman Hall B733, Northwestern University, Evanston, IL (United States); Yuuki, Kaori; Naito, Sei; Nagaoka, Akira; Kato, Tomoyuki [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Tomita, Yoshihiko, E-mail: ytomita@med.id.yamagata-u.ac.jp [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan)

2012-07-06

Highlights: Black-Right-Pointing-Pointer Sorafenib treatment upregulated GSK-3{beta} levels in RCC cells. Black-Right-Pointing-Pointer Pharmacologic inhibition of GSK-3 suppressed xenograft RCC tumor growth. Black-Right-Pointing-Pointer Inhibition of GSK-3 enhanced antitumor effect of sorafenib in vitro and in vivo. -- Abstract: Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.

Distinct behaviour of sorafenib in experimental cachexia-inducing tumours: the role of STAT3.

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Míriam Toledo

Full Text Available The presence of a tumour is very often associated with wasting in the host, affecting both skeletal muscle and adipose tissue. In the present study we used sorafenib, a multi-kinase inhibitor with anti-tumour activity, in order to investigate the effects of chemotherapy on wasting. Three different experimental mouse tumour models were included: C26 colon carcinoma, B16 melanoma and Lewis lung carcinoma (LLC. The results obtained clearly show that sorafenib was effective in reducing tumour growth in LLC and B16 models, while it had no effect on C26. Interestingly, sorafenib treatment reduced the signs of muscle wasting and improved the physical activity in the LLC model and also in the C26, despite the absence of antineoplastic action in the latter. Our results discard a role for IL-6 in the action of sorafenib since the drug did not affect the levels of this cytokine. Conversely, sorafenib seems to act by influencing both STAT3 and ERK activity at muscle level, leading to reduced accumulation of Pax7 and atrogin-1. Sorafenib may interfere with muscle wasting by decreasing the activation of these signal transduction pathways.

Lipid nanocarriers containing sorafenib inhibit colonies formation in human hepatocarcinoma cells.

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Bondì, Maria Luisa; Botto, Chiara; Amore, Erika; Emma, Maria Rita; Augello, Giuseppa; Craparo, Emanuela Fabiola; Cervello, Melchiorre

2015-09-30

Here, the potential of two nanostructured lipid carriers (NLC) for controlled release of sorafenib was evaluated. The obtained systems showed characteristics suitable as drug delivery systems for the treatment of hepatocellular carcinoma (HCC) through parenteral administration. The use of a mixture between a solid lipid (tripalmitin) with a liquid lipid (Captex 355 EP/NF or Miglyol 812) to prepare NLC systems could give a higher drug loading capacity and a longer term stability during storage than that obtained by using only solid lipids. The obtained nanoparticles showed a nanometer size and high negative zeta potential values. Scansion electron microscopy (SEM) of the sorafenib loaded NLC revealed a spherical shape with a diameter <300 nm. In vitro biological studies demonstrated that sorafenib loaded into NLC had enhanced anti-tumor activity compared to that of free drug. This finding raises hope in terms of future drug delivery strategy of sorafenib loaded NLC, that can be useful for therapeutic application in HCC. Copyright © 2015 Elsevier B.V. All rights reserved.

Clinical experience and critical evaluation of the role of sorafenib in renal cell carcinoma

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Zustovich F

2011-05-01

Full Text Available Fable Zustovich1, Giuseppe Lombardi1, Davide Pastorelli1, Patrizia Farina1, Massimo Dal Bianco2, Luca De Zorzi2, Maurizia Dalla Palma1, Ornella Nicoletto1, Vittorina Zagonel11Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy; 2UO Urologia, Ospedale Sant'Antonio, ULSS 16, Padova, ItalyAbstract: Renal cell carcinoma (RCC is a common malignancy worldwide with approximately 95,000 new cases per year and ranks as the sixth cause of cancer deaths. Until recently, the slightly active and very toxic cytokines were available for patients with advanced RCC. Advances have been made in understanding the molecular biology of renal cancer. The introduction of targeted agents has led to promising possibilities for treating these highly vascularized tumors. Angiogenesis inhibition is likely to represent the main potential therapeutic target. Sorafenib is an oral multikinase inhibitor with activity against tyrosine kinase receptors that are responsible for blood vessel development and has shown to be active in treating advanced RCC. In this review, we summarize the pharmacology, mode of action, pharmacokinetics, and safety of sorafenib use in therapy for advanced RCC.Keywords: sorafenib, pharmacokinetics, angiogenesis 

Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: A phase II study

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GADALETA-CALDAROLA, GENNARO; INFUSINO, STEFANIA; GALISE, IDA; RANIERI, GIROLAMO; VINCIARELLI, GIANLUCA; FAZIO, VITO; DIVELLA, ROSA; DANIELE, ANTONELLA; FILIPPELLI, GIANFRANCO; GADALETA, COSMO DAMIANO

2014-01-01

The standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib, a multikinase inhibitor of tumor cell proliferation and angiogenesis. Hyperthermia inhibits angiogenesis and promotes apoptosis. Potential synergic antiangiogenic and proapoptotic effects represent the rationale for combining sorafenib with electro-hyperthermia (EHY) in HCC. A total of 21 patients (median age, 64 years; range, 55–73 years) with advanced HCC were enrolled in the current study between February 2009 and September 2010. EHY was achieved by arranging capacitive electrodes with a deep hypothermia radiofrequency field of 13.56 Mhz at 80 W for 60 min, three times per week for six weeks, followed by two weeks without treatment, in combination with sorafenib at a dose of 800 mg every other day. According to the modified Response Evaluation Criteria in Solid Tumors criteria, 50% achieved stable disease, 5% achieved partial response and 45% achieved progressive disease. No complete response was observed. The progression-free survival (PFS) rate at six months was 38%, while the median PFS and overall survival times were 5.2 [95% confidence interval (CI), 4.2–6.2) and 10.4 (95% CI, 10–11) months, respectively. The overall incidence of treatment-related adverse events was 80%, predominantly of grade 1 or 2. Grade 3 toxicity included fatigue, diarrhea, hand-foot skin reaction and hypertension. In the present study, the sorafenib plus EHY combination was feasible and well tolerated, and no major complications were observed. The initial findings indicated that this combination offers a promising option for advanced HCC. PMID:25202410

OSU-2S/sorafenib synergistic antitumor combination against hepatocellular carcinoma: The role of PKCδ/p53

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Hany A Omar

2016-11-01

Full Text Available Background: Sorafenib (Nexavar® is an FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC. However, the low efficacy and adverse effects at high doses limit the clinical application of sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks. OSU-2S, a PKCδ activator, was selected as a potential candidate anticancer agent to be combined with sorafenib to promote the anti-cancer activity through synergistic interaction. Methods: The antitumor effects of sorafenib, OSU-2S and their combination were assessed by MTT assay, caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCδ knockdown was used to elucidate the role of PKCδ activation as a mechanism for the synergy. The knockdown/over-expression of p53 was used to explain the differential sensitivity of HCC cell lines to sorafenib and/or OSU-2S. Results: OSU-2S synergistically enhanced the anti-proliferative effects of sorafenib in the four used HCC cell lines with combination indices < 1. This effect was accompanied by parallel increases in caspase 3/7 activity, PARP cleavage, PKCδ activation and HCC cell migration/invasion. In addition, PKCδ knockdown abolished the synergy between sorafenib and OSU-2S. Furthermore, p53 restoration in Hep3B cells through the over-expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents. Conclusions: OSU-2S augments the anti-proliferative effect of sorafenib in HCC cell lines, in part, through the activation of PKCδ. The p53 status in HCC cells predicts their sensitivity towards both sorafenib and OSU-2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol.

Efficacy and Safety of Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 3 AXIS Trial

OpenAIRE

Ueda, Takeshi; Uemura, Hirotsugu; Tomita, Yoshihiko; Tsukamoto, Taiji; Kanayama, Hiroomi; Shinohara, Nobuo; Tarazi, Jamal; Chen, Connie; Kim, Sinil; Ozono, Seiichiro; Naito, Seiji; Akaza, Hideyuki

2013-01-01

Objective Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. Methods A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. Results Twenty-five (of 361) and 29 (o...

Alpha-fetoprotein is a biomarker of unfolded protein response and altered proteostasis in hepatocellular carcinoma cells exposed to sorafenib.

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Houessinon, Aline; Gicquel, Albane; Bochereau, Flora; Louandre, Christophe; Nyga, Rémy; Godin, Corinne; Degonville, James; Fournier, Emma; Saidak, Zuzana; Drullion, Claire; Barbare, Jean-Claude; Chauffert, Bruno; François, Catherine; Pluquet, Olivier; Galmiche, Antoine

2016-01-28

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Sorafenib inhibits tumor growth and vascularization of rhabdomyosarcoma cells by blocking IGF-1R-mediated signaling

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Wessen Maruwge

2008-11-01

Full Text Available Wessen Maruwge1, Pádraig D’Arcy1, Annika Folin1,2, Slavica Brnjic1, Johan Wejde1, Anthony Davis1, Fredrik Erlandsson3, Jonas Bergh1,2, Bertha Brodin11Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; 2Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden; 3Bayer Pharmaceutical Corporation, SwedenAbstract: The growth of many soft tissue sarcomas is dependent on aberrant growth factor signaling, which promotes their proliferation and motility. With this in mind, we evaluated the effect of sorafenib, a receptor tyrosine kinase inhibitor, on cell growth and apoptosis in sarcoma cell lines of various histological subtypes. We found that sorafenib effectively inhibited cell proliferation in rhabdomyosarcoma, synovial sarcoma and Ewing’s sarcoma with IC50 values <5 µM. Sorafenib effectively induced growth arrest in rhabdomyosarcoma cells, which was concurrent with inhibition of Akt and Erk signaling. Studies of ligand-induced phosphorylation of Erk and Akt in rhabdomyosarcoma cells showed that insulin-like growth factor-1 is a potent activator, which can be blocked by treatment with sorafenib. In vivo sorafenib treatment of rhabdomyosarcoma xenografts had a significant inhibitory effect on tumor growth, which was associated with inhibited vascularization and enhanced necrosis in the adjacent tumor stroma. Our results demonstrate that in vitro and in vivo growth of rhabdomyosarcoma can be suppressed by treatment with sorafenib, and suggests the possibilities of using sorafenib as a potential adjuvant therapy for the treatment of rhabdomyosarcoma.Keywords: soft tissue sarcoma, kinase inhibitors, targeted therapy, vascularization

Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers.

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Iacobazzi, Rosa Maria; Porcelli, Letizia; Lopedota, Angela Assunta; Laquintana, Valentino; Lopalco, Antonio; Cutrignelli, Annalisa; Altamura, Emiliano; Di Fonte, Roberta; Azzariti, Amalia; Franco, Massimo; Denora, Nunzio

2017-08-07

Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R. Copyright © 2017 Elsevier B.V. All rights reserved.

Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

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Ferrari Stefano

2009-12-01

Full Text Available Abstract Background Osteosarcoma (OS is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006 in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

Extraordinary radiation super-sensitivity accompanying with sorafenib combination therapy: what lies beneath?

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Lee, Ja Young; Lee, Ju Hye; Yoon, Han Bin; Lee, Ho Jeong; Jeon, Ho Sang; Nam, Ji Ho [Dept. of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan (Korea, Republic of)

2017-06-15

Primary liver tumor, especially hepatocellular carcinoma (HCC), is a common cause of cancer death worldwide. The incidence is generally higher in Asian countries than in western countries. Carcinogenesis of HCC is often associated with hepatitis viral infections. Current standard treatment of HCC is surgical resection or transplantation in patients with early stage disease. However, the patient with advanced stage disease, surgical resection is often limited. Sorafenib or other treatment modalities are not so effective as well. We report a case of unusual radiation super-sensitivity in advanced stage HCC, and review the literature.

New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation

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Branka Zorc

2012-01-01

Full Text Available Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a–e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1, 4-chloro-pyridine-2-carboxamides 2a–e, 4-(4-aminophenoxy-pyridine-2-carboxamides 3a–e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethylphenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a–e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a–e (IC50 = 1-4.3 μmol·L−1. Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.

Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways

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Weibo Chen

2014-01-01

Full Text Available Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.

Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report

International Nuclear Information System (INIS)

Casadei Gardini, Andrea; Chiadini, Elisa; Faloppi, Luca; Marisi, Giorgia; Delmonte, Angelo; Scartozzi, Mario; Loretelli, Cristian; Lucchesi, Alessandro; Oboldi, Devil; Dubini, Alessandra; Frassineti, Giovanni Luca; Ulivi, Paola

2016-01-01

Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients

Clinical observation of transcatheter arterial chemoembolization combined with sorafenib on intermediate-advanced hepatocellular carcinoma

International Nuclear Information System (INIS)

Wei Zhaoguang; Lu Ligong; Shao Peijian; Hu Baoshan; Li Yong; Zhang Lei; He Xu; Yu Xianyi; Luo Xiaoning

2012-01-01

Objective: To evaluate the treatment effect and security of transcatheter arterial chemoembolization (TACE) combined with sorafenib for intermediate-advanced hepatocellular carcinoma. Methods: From July 2008 to November 2010,the treatment effects of two groups of patients with advanced hepatocellular carcinoma were retrospectively analyzed and compared, including 44 patients treated by sorafenib combined with TACE (test group) and the other 44 patients treated only with TACE (control group). To assess the treatment effect based on mRECIST, the time for patients' tumor progression (TTP), overall survival (OS) time and adverse events were recorded. Survival rate were analyzed using Kaplan-Meier method and Log-rank analysis in SPSS 18.0. Results: Till January 2011, 24 patients (54.5%) survived and 20 patients (include patients lost to visit) died (45.5%) among the test group, 13 patients survived (29.5 %) and 31 patients (include patients lost to visit) died (70.5 %) among the control group. No complete remission condition was observed in all patients. Among the test group, 1 patient got partial remission, 24 ones remain stable and 19 patients got progression. While among the control group, conditions remained stable in 21 patients and progressed in rest 23 ones. The disease control rate (DCR) in the test group and control group were 56.8% (25/44) and 47.7% (21/44) respectively, with no statistical significance (χ 2 =0.729, P=0.393). The median overall survival time (mOS) of test group and control group were 21.0 (95% CI: 14.9-27.1)months and 10.0 (95% CI: 6.4-13.6) months respectively, and the difference reached statistical significance (χ 2 =7.436, P=0.006). The median time to tumor progression (mTTP) of test group and control group was 11.0 (95% CI: 8.7-13.3) and 6.0 (95% CI: 3.9-8.1) months respectively, and the difference had statistical significance (χ 2 =10.437, P=0.001). The adverse events of test group mainly included hand-foot skin reaction, loss of

Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells.

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Lo Re, Oriana; Panebianco, Concetta; Porto, Stefania; Cervi, Carlo; Rappa, Francesca; Di Biase, Stefano; Caraglia, Michele; Pazienza, Valerio; Vinciguerra, Manlio

2018-02-01

Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use. © 2017 Wiley Periodicals, Inc.

Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma

OpenAIRE

Kissel, Maria; Berndt, Sandra; Fiebig, Lukas; Kling, Simon; Ji, Qunsheng; Gu, Qingyang; Lang, Tina; Hafner, Frank-Thorsten; Teufel, Michael; Zopf, Dieter

2017-01-01

The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib ...

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

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Mathew, Nimitha R; Baumgartner, Francis; Braun, Lukas; O'Sullivan, David; Thomas, Simone; Waterhouse, Miguel; Müller, Tony A; Hanke, Kathrin; Taromi, Sanaz; Apostolova, Petya; Illert, Anna L; Melchinger, Wolfgang; Duquesne, Sandra; Schmitt-Graeff, Annette; Osswald, Lena; Yan, Kai-Li; Weber, Arnim; Tugues, Sonia; Spath, Sabine; Pfeifer, Dietmar; Follo, Marie; Claus, Rainer; Lübbert, Michael; Rummelt, Christoph; Bertz, Hartmut; Wäsch, Ralph; Haag, Johanna; Schmidts, Andrea; Schultheiss, Michael; Bettinger, Dominik; Thimme, Robert; Ullrich, Evelyn; Tanriver, Yakup; Vuong, Giang Lam; Arnold, Renate; Hemmati, Philipp; Wolf, Dominik; Ditschkowski, Markus; Jilg, Cordula; Wilhelm, Konrad; Leiber, Christian; Gerull, Sabine; Halter, Jörg; Lengerke, Claudia; Pabst, Thomas; Schroeder, Thomas; Kobbe, Guido; Rösler, Wolf; Doostkam, Soroush; Meckel, Stephan; Stabla, Kathleen; Metzelder, Stephan K; Halbach, Sebastian; Brummer, Tilman; Hu, Zehan; Dengjel, Joern; Hackanson, Björn; Schmid, Christoph; Holtick, Udo; Scheid, Christof; Spyridonidis, Alexandros; Stölzel, Friedrich; Ordemann, Rainer; Müller, Lutz P; Sicre-de-Fontbrune, Flore; Ihorst, Gabriele; Kuball, Jürgen; Ehlert, Jan E; Feger, Daniel; Wagner, Eva-Maria; Cahn, Jean-Yves; Schnell, Jacqueline; Kuchenbauer, Florian; Bunjes, Donald; Chakraverty, Ronjon; Richardson, Simon; Gill, Saar; Kröger, Nicolaus; Ayuk, Francis; Vago, Luca; Ciceri, Fabio; Müller, Antonia M; Kondo, Takeshi; Teshima, Takanori; Klaeger, Susan; Kuster, Bernhard; Kim, Dennis Dong Hwan; Weisdorf, Daniel; van der Velden, Walter; Dörfel, Daniela; Bethge, Wolfgang; Hilgendorf, Inken; Hochhaus, Andreas; Andrieux, Geoffroy; Börries, Melanie; Busch, Hauke; Magenau, John; Reddy, Pavan; Labopin, Myriam; Antin, Joseph H; Henden, Andrea S; Hill, Geoffrey R; Kennedy, Glen A; Bar, Merav; Sarma, Anita; McLornan, Donal; Mufti, Ghulam; Oran, Betul; Rezvani, Katayoun; Shah, Omid; Negrin, Robert S; Nagler, Arnon; Prinz, Marco; Burchert, Andreas; Neubauer, Andreas; Beelen, Dietrich; Mackensen, Andreas; von Bubnoff, Nikolas; Herr, Wolfgang; Becher, Burkhard; Socié, Gerard; Caligiuri, Michael A; Ruggiero, Eliana; Bonini, Chiara; Häcker, Georg; Duyster, Justus; Finke, Jürgen; Pearce, Erika; Blazar, Bruce R; Zeiser, Robert

2018-03-01

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-γ + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

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

Synthesis of thermosensitive magnetic nanocarrier for controlled sorafenib delivery

Energy Technology Data Exchange (ETDEWEB)

Heidarinasab, Amir [Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Ahmad Panahi, Homayon [Department of Chemistry, Central Tehran Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Faramarzi, Mehdi, E-mail: faramarzi.iaug@gmail.com [Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Farjadian, Fatemeh [Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz (Iran, Islamic Republic of)

2016-10-01

Allyl glycidyl ether/N-isopropylacrylamide-grafted magnetic nanoparticles were prepared using silica-coated magnetic nanoparticles as a substrate for radical copolymerization of allyl glycidyl ether and N-isopropylacrylamide. Chitosan was coupled with the prepared nanoparticles by opening the epoxy ring of the allyl glycidyl ether. The thermosensitive magnetic nanocarrier (TSMNC) obtained can be applied as a potent drug carrier. The TSMNC structure was characterized using Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, vibrating sample magnetometer, and elemental analysis. Its morphology and size were investigated using field emission scanning electron microscopy, transmission electron microscopy and dynamic light scattering. The feasibility of employing the TSMNC for adsorption and in vitro controlled release of the chemotherapeutic agent sorafenib was tested. The effect of the adsorption parameters of pH, temperature, and loading time of sorafenib onto TSMNC was evaluated. The adsorption data was fitted to the Langmuir and Freundlich isotherms and the relevant parameters derived. The drug release profile indicated that 88% of the adsorbed drug was released within 35 h at 45 °C and drug release was Fickian diffusion-controlled. The results confirmed that the TSMNC has a high adsorption capacity at low temperature and good controlled release in a slow rate at a high temperature and could be developed for further application as a drug nanocarrier. - Graphical abstract: Magnetic nanoparticles were functionalized with chitosan and N-isopropylacrylamide. It was evaluated for sorafenib (SFB) adsorption and tested as a controlled-release system in response to changes in temperature. The TSMNC showed superparamagnetic properties with a high adsorption capacity and desirable controlled release at below and above LCST. Display Omitted - Highlights: • A TSMNC was synthesized for controlled

Research advances in sorafenib combined with orthotopic liver transplantation, radiofrequency ablation, and transarterial chemoembolization in treatment of hepatocellular carcinoma

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ZHANG Mingjuan

2014-08-01

Full Text Available Hepatocellular carcinoma (HCC is one of the most common malignant tumors worldwide, and traditional surgery and chemotherapy provide limited benefit. Sorafenib, a multikinase inhibitor, was proved effective for advanced HCC in phase III clinical trial, which was a breakthrough in the treatment of HCC. In recent years, the studies on sorafenib combined with other therapies in the treatment of HCC have been conducted around the world, and inspiring results have been seen. The research advances in sorafenib combined with orthotopic liver transplantation, radiofrequency ablation, and transarterial chemoembolization in the treatment of HCC are summarized. It is thought that sorafenib combined with other anticancer therapies is expected to become a new approach of targeted therapy of HCC.

The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

International Nuclear Information System (INIS)

Schult, Catrin; Boldt, Sonja; Wolkenhauer, Olaf; Neri, Luca Maria; Freund, Mathias; Junghanss, Christian; Dahlhaus, Meike; Ruck, Sabine; Sawitzky, Mandy; Amoroso, Francesca; Lange, Sandra; Etro, Daniela; Glass, Aenne; Fuellen, Georg

2010-01-01

Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells

Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.

Science.gov (United States)

Chung, Chih-Ling; Wang, Shih-Wei; Sun, Wei-Chih; Shu, Chih-Wen; Kao, Yu-Chen; Shiao, Meng-Shin; Chen, Chun-Lin

2018-04-18

Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response.

Science.gov (United States)

Zhang, Conggang; Liu, Zeyu; Bunker, Eric; Ramirez, Adrian; Lee, Schuyler; Peng, Yinghua; Tan, Aik-Choon; Eckhardt, S Gail; Chapnick, Douglas A; Liu, Xuedong

2017-09-08

Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m -chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma.

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Malarvizhi, Giridharan Loghanathan; Retnakumari, Archana Payickattu; Nair, Shantikumar; Koyakutty, Manzoor

2014-11-01

Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer. Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation.

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Gedaly, Roberto; Angulo, Paul; Hundley, Jonathan; Daily, Michael F; Chen, Changguo; Evers, B Mark

2012-08-01

Deregulated Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PKI-587 and sorafenib as single agents or in combination on HCC (Huh7 cell line) proliferation. (3)H-thymidine incorporation and MTT assay were used to assess Huh7 cell proliferation. Phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways was detected by Western blot. We found that PKI-587 is a more potent PI3K/mTOR inhibitor than PI-103. Combination of PKI-587 and sorafenib was a more effective inhibitor of Huh7 proliferation than the combination of PI-103 and sorafenib. Combination of PKI-587 and sorafenib synergistically inhibited epidermal growth factor (EGF)-stimulated Huh7 proliferation compared with monodrug therapy. EGF increased phosphorylation of Ras/Raf downstream signaling proteins MEK and ERK; EGF-stimulated activation was inhibited by sorafenib. However, sorafenib, as a single agent, increased AKT (Ser473) phosphorylation. EGF-stimulated AKT (ser473) activation was inhibited by PKI-587. PKI-587 is a potent inhibitor of AKT (Ser473), mTOR (Ser2448), and S6K (Thr389) phosphorylation; in contrast, rapamycin stimulated mTOR complex 2 substrate AKT(Ser473) phosphorylation although it inhibited mTOR complex 1 substrate S6K phosphorylation. PKI-587, as a single agent, stimulated MEK and ERK phosphorylation. However, when PKI-587 and sorafenib were used in combination, they inhibited all the tested kinases in the Ras/Raf /MAPK and PI3K/AKT/mTOR pathways. The combination of PKI-587 and sorafenib has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure

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M. Klein

2008-06-01

Full Text Available Inhibition of tyrosine kinases can reverse pulmonary hypertension but little is known about the role of serine-/threonine kinases in vascular and myocardial remodeling. We investigated the effects of sorafenib, an inhibitor of the tyrosine kinases VEGFR, PDGFR and c-kit as well as the serine-/threonine kinase Raf-1, in pulmonary hypertension and right ventricular (RV pressure overload. In monocrotaline treated rats, sorafenib (10 mg·kg–1·d–1 p.o. reduced pulmonary arterial pressure, pulmonary artery muscularization and RV hypertrophy, and improved systemic hemodynamics (table 1. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of downstream signaling pathways (Erk 1/2. After pulmonary banding, sorafenib, but not the PDGFR/c-KIT/ABL-inhibitor imatinib reduced RV mass and RV filling pressure significantly. Congruent with these results, sorafenib only prevented ERK phosphorylation and vasopressin induced hypertrophy of the cardiomyocyte cell line H9c2 dose dependently (IC50 = 300 nM. Combined inhibition of tyrosine and serine-/threonine kinases by sorafenib prevents vascular and cardiac remodeling in pulmonary hypertension, which is partly mediated via inhibition of the Raf kinase pathway.

Orthotopic liver transplantation after the combined use of locoregional therapy and sorafenib for advanced hepatocellular carcinoma

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Yoo EJ

2013-06-01

Full Text Available Eun Jin Yoo,1,* Hye Sun Shin,1,* Seung Up Kim,1,2,7 Dong Jin Joo,3,4 Jun Yong Park,1,2,7 Gi Hong Choi,3 Do Young Kim,1,2,7 Sang Hoon Ahn,1,2,7 Jinsil Seong,5 Myung Joo Koh,6 Kwang-Hyub Han,1,2,7 Chae Yoon Chon1,2,7 1Department of Internal Medicine, 2Institute of Gastroenterology, 3Department of Surgery, 4Research Institute for Transplantation, 5Department of Radiation Oncology, 6Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea; 7Liver Cirrhosis Clinical Research Center, Seoul, South Korea *These authors contributed equally to this work Abstract: We herein report a patient with advanced hepatitis B virus-related hepatocellular carcinoma (HCC beyond the Milan criteria. He underwent orthotopic liver transplantation after successful HCC downstaging that satisfied the University of California, San Francisco criteria, using concurrent chemoradiation therapy with a combination of repeated hepatic arterial infusion chemotherapy (HAIC and sorafenib. A 52-year-old male was diagnosed with advanced hepatitis B virus-related HCC beyond the Milan criteria. He underwent concurrent chemoradiation therapy (50 Gy with 20 fractions over 5 weeks with HAIC using 5-fluorouracil at a dose of 500 mg/day, which was administered during the first and fifth weeks of radiation therapy as an initial treatment modality. This was followed by the combined use of HAIC using 5-fluorouracil (500 mg/m2 for 5 hours on days 1–3 and cisplatin (60 mg/m2 for 2 hours on day 2 every 4 weeks (twelve cycles and sorafenib (from the third to the twelfth cycle of HAIC to treat the remaining HCC. Because a remarkable decrease in the tumor burden that satisfied the University of California, San Francisco criteria was observed after these combination treatments, the patient underwent orthotopic liver transplantation with curative aim and survived for 11 months without evidence of HCC recurrence. Keywords: hepatocellular carcinoma, liver transplantation

Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

OpenAIRE

Rigalli, Juan Pablo; Ciriaci, Nadia; Arias, Agostina; Ceballos, Mar?a Paula; Villanueva, Silvina Stella Maris; Luquita, Marcelo Gabriel; Mottino, Aldo Domingo; Ghanem, Carolina In?s; Catania, Viviana Alicia; Ruiz, Mar?a Laura

2015-01-01

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of t...

Advanced inoperable type B3 thymoma: monitoring of a novel therapeutic approach with radio-chemotherapy and sorafenib by FDG-PET and CT

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Winder, T.; Gasser, K.; Schuster, A.; Becherer, A.; Vries, A. de; Gruber-Moesenbacher, U.; Muendlein, A.; Drexel, H.; Lang, A.

2010-01-01

This report highlights the benefit of radio-chemotherapy followed by sorafenib in a 55 years old woman, diagnosed with an inoperable type B3 thymoma and illustrates the potential usefulness of 18 F-FDG in monitoring treatment with sorafenib. (orig.)

Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients?

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Brandi, Giovanni; de Rosa, Francesco; Calzà, Laura; Girolamo, Stefania Di; Tufoni, Manuel; Ricci, Carmen Serena; Cirignotta, Fabio; Caraceni, Paolo; Biasco, Guido

2013-03-01

Sorafenib is the standard treatment of advanced hepatocarcinoma (HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine-kinase (TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK-related pathways and by inhibiting angiogenesis. The aim of this study was to investigate whether sorafenib administration can be associated to metabolic encephalopathy in patients with cirrhosis. We retrospectively reviewed medical records of all cirrhotic patients treated with sorafenib for HCC afferent at our Department from January 2009 to December 2011. Among 62 patients, we identified 10 patients with clinically significant cognitive impairment. Seven of these were clearly diagnosed with overt hepatic encephalopathy (HE), one with brain metastases and two with drug-related toxic-metabolic encephalopathy. These last two cases were characterized by severe cognitive impairment, mood alteration and memory deficit. Clinical exam, blood tests and brain CT excluded organic causes of encephalopathy and precipitating factors of HE. Sorafenib discontinuation was associated with complete reversal of the syndrome, which recurred on drug re-administration in one case. Our study suggests that sorafenib may be a precipitating factor of metabolic encephalopathy in cirrhotic patients with advanced HCC. This neurological syndrome appears to be not responsive to the conventional treatment for HE, but it is fully reversible by drug discontinuation. It can be speculated that the potential direct neuronal action of sorafenib may represent a trigger for the onset of metabolic encephalopathy in a subset of cirrhotic patients. © 2012 John Wiley & Sons A/S.

PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation.

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Gedaly, Roberto; Galuppo, Roberto; Musgrave, Yolanda; Angulo, Paul; Hundley, Jonathan; Shah, Malay; Daily, Michael F; Chen, Changguo; Cohen, Donald A; Spear, Brett T; Evers, B Mark

2013-11-01

Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM (P PKI-587 at 0.1 μM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12). LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation. Copyright © 2013 Elsevier Inc. All rights reserved.

Differential modulatory effects of GSK-3β and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis in melanoma

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Mier James W

2011-09-01

Full Text Available Abstract Background GSK-3β phosphorylates numerous substrates that govern cell survival. It phosphorylates p53, for example, and induces its nuclear export, HDM2-dependent ubiquitination, and proteasomal degradation. GSK-3β can either enhance or inhibit programmed cell death, depending on the nature of the pro-apoptotic stimulus. We previously showed that the multikinase inhibitor sorafenib activated GSK-3β and that this activation attenuated the cytotoxic effects of the drug in various BRAF-mutant melanoma cell lines. In this report, we describe the results of studies exploring the effects of GSK-3β on the cytotoxicity and antitumor activity of sorafenib combined with the HDM2 antagonist MI-319. Results MI-319 alone increased p53 levels and p53-dependent gene expression in melanoma cells but did not induce programmed cell death. Its cytotoxicity, however, was augmented in some melanoma cell lines by the addition of sorafenib. In responsive cell lines, the MI-319/sorafenib combination induced the disappearance of p53 from the nucleus, the down modulation of Bcl-2 and Bcl-xL, the translocation of p53 to the mitochondria and that of AIF to the nuclei. These events were all GSK-3β-dependent in that they were blocked with a GSK-3β shRNA and facilitated in otherwise unresponsive melanoma cell lines by the introduction of a constitutively active form of the kinase (GSK-3β-S9A. These modulatory effects of GSK-3β on the activities of the sorafenib/MI-319 combination were the exact reverse of its effects on the activities of sorafenib alone, which induced the down modulation of Bcl-2 and Bcl-xL and the nuclear translocation of AIF only in cells in which GSK-3β activity was either down modulated or constitutively low. In A375 xenografts, the antitumor effects of sorafenib and MI-319 were additive and associated with the down modulation of Bcl-2 and Bcl-xL, the nuclear translocation of AIF, and increased suppression of tumor angiogenesis

Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

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Mark Schrader

2012-09-01

Full Text Available Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR. A putative mechanism allowing prostate cancer (PCa cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD. Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma.

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Jeannot, Victor; Busser, Benoit; Vanwonterghem, Laetitia; Michallet, Sophie; Ferroudj, Sana; Cokol, Murat; Coll, Jean-Luc; Ozturk, Mehmet; Hurbin, Amandine

2016-01-01

Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G 2 /M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for

Synthesis and conformational analysis of new arylated-diphenylurea derivatives related to sorafenib drug via Suzuki-Miyaura cross-coupling reaction

Science.gov (United States)

Al-Masoudi, Najim A.; Essa, Ali Hashem; Alwaaly, Ahmed A. S.; Saeed, Bahjat A.; Langer, Peter

2017-10-01

Sorafenib, is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. The development of new sorafenib analogues offers the possibility of generating structures of increased potency. To this end, a series of arylated-diphenylurea analogues 17-31 were synthesized via Suzuki-Miyaura coupling reaction, related to sorafenib by treatment of three diarylureas 2-4 having 3-bromo, 4-chloro and 2-iodo groups with various arylboronic acids. Conformational analysis of the new arylated urea analogues has been investigated using MOPAC 2016 of semi empirical PM7 Hamiltonian computational method. Our results showed that all compounds preferred the trans-trans conformations. Compound 17 has been selected to calculate the torsional energy profiles for rotation around the urea bonds and found to be existed predominantly in the trans-trans conformation with only very minimal fluctuation in conformation.

Sorafenib-induced defective autophagy promotes cell death by necroptosis

OpenAIRE

Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Bj?rklund, Ann-Charlotte; Zhivotovsky, Boris; Grand?r, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

2015-01-01

Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencin...

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

Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766 in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma

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Roberta Schmieder

2013-10-01

Full Text Available OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK. BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.

Intracranial Metastasis in a Patient with Hepatocellular Carcinoma and Gastric Cancer

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Akinobu Tawada

2014-03-01

Full Text Available A 76-year-old man was referred to our hospital with visual disturbance, weakness of the left upper and lower limbs, and gait disturbance. He had previously received transarterial chemoembolization for hepatocellular carcinoma (HCC 3 and 10 years ago. When he had received radiofrequency ablation for HCC recurrence 2 years ago, total gastrectomy was also performed for his gastric cancer. Subsequently, sorafenib had been administrated for concomitant lung metastatic tumors. On admission, MRI revealed an intra-axial tumor with perifocal edema. The level of carcinoembryonic antigen, but not alpha-fetoprotein, markedly increased. The tumor was successfully removed by craniotomy and pathological examination revealed that it was composed of adenocarcinoma, which was consistent with the primary gastric cancer. After surgery, his neurological disturbances rapidly resolved. Additional gamma-knife treatment was also performed for another small brain metastasis detected after craniotomy. Subsequently, sorafenib administration was discontinued and S-1 was administered postoperatively. Successful treatment of intracranial metastasis of gastric cancer is important and meaningful, even in patients with multiple primary malignancies.

A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

Energy Technology Data Exchange (ETDEWEB)

Hu, Bo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Sun, Ding [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Department of Hepatobiliary Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Sun, Chao; Sun, Yun-Fan; Sun, Hai-Xiang [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Zhu, Qing-Feng [The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology, Baltimore, MD, 21205 (United States); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Yang, Xin-Rong [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Gao, Ya-Bo [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032 (China); Tang, Wei-Guo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Fan, Jia [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Maitra, Anirban [The Sol Goldman Pancreatic Cancer Research Center, Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States); and others

2015-12-25

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and

A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

International Nuclear Information System (INIS)

Hu, Bo; Sun, Ding; Sun, Chao; Sun, Yun-Fan; Sun, Hai-Xiang; Zhu, Qing-Feng; Yang, Xin-Rong; Gao, Ya-Bo; Tang, Wei-Guo; Fan, Jia; Maitra, Anirban

2015-01-01

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and

Inhibition of Cell Proliferation in an NRAS Mutant Melanoma Cell Line by Combining Sorafenib and α-Mangostin.

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Yun Xia

Full Text Available α-Mangostin is a natural product commonly used in Asia for cosmetic and medicinal applications including topical treatment of acne and skin cancer. Towards finding new pharmacological strategies that overcome NRAS mutant melanoma, we performed a cell proliferation-based combination screen using a collection of well-characterized small molecule kinase inhibitors and α-Mangostin. We found that α-Mangostin significantly enhances Sorafenib pharmacological efficacy against an NRAS mutant melanoma cell line. The synergistic effects of α-Mangostin and Sorafenib were associated with enhanced inhibition of activated AKT and ERK, induced ER stress, and reduced autophagy, eventually leading to apoptosis. The structure of α-Mangostin resembles several inhibitors of the Retinoid X receptor (RXR. MITF expression, which is regulated by RXR, was modulated by α-Mangostin. Molecular docking revealed that α-Mangostin can be accommodated by the ligand binding pocket of RXR and may thereby compete with RXR-mediated control of MITF expression. In summary, these data demonstrate an unanticipated synergy between α-Mangostin and sorafenib, with mechanistic actions that convert a known safe natural product to a candidate combinatorial therapeutic agent.

Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion and growth in vitro

Science.gov (United States)

Carr, Brian Irving; D’Alessandro, Rosalba; Refolo, Maria Grazia; Iacovazzi, Palma Aurelia; Lippolis, Catia; Messa, Caterina; Cavallini, Aldo; Correale, Mario; Di Carlo, Antonio

2012-01-01

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multi-kinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1–1µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multi-kinase inhibitor concentrations thus modulate several aspects of HCC cell biology. PMID:23169148

Targeted therapy for human hepatic carcinoma cells using folate-functionalized polymeric micelles loaded with superparamagnetic iron oxide and sorafenib in vitro

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Zhang L

2013-04-01

Full Text Available Lei Zhang,1 Faming Gong,2 Fang Zhang,3 Jing Ma,1 Peidong Zhang,1 Jun Shen3 1Department of Hepatobiliary and Pancreatic Surgery, 2PCFM Laboratory of Ministry of Education, School of Chemistry and Chemical Engineering, 3Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China Background: The purpose of this study was to evaluate the inhibitory effect of targeted folate-functionalized micelles containing superparamagnetic iron oxide nanoparticles (SPIONs and sorafenib on human hepatic carcinoma (HepG2 cells in vitro, and to observe the feasibility of surveillance of this targeting therapeutic effect by magnetic resonance imaging. Methods: Sorafenib and SPIONs were loaded into polymeric micelles. The targeted nanocarrier was synthesized by functionalizing the micelles with folate. Folate-free micelles loaded with sorafenib and SPIONs were used as control (nontargeted micelles. Uptake of the nanocarrier by cells was assessed using Prussian blue staining after 1 hour of incubation with the polymeric micelles. The inhibitory effect of the targeted micelles on HepG2 cell proliferation at various concentrations of sorafenib was assessed in vitro using the methyl thiazolyl tetrazolium (MTT assay and apoptotic analysis using flow cytometry. Magnetic resonance imaging using a clinical 1.5 T scanner was performed to detect changes in the signal intensity of cells after incubation with the targeted micelles. Results: Prussian blue staining showed significantly more intracellular SPIONs in cells incubated with the targeted micelles than those incubated with nontargeted micelles. The MTT assay showed that the average inhibitory ratio in the targeted group was significantly higher than that in the nontargeted group (38.13% versus 22.54%, P = 0.028. The mean apoptotic rate in the targeted cells, nontargeted cells, and untreated cells was 17.01%, 11.04%, and 7.89%, respectively. The apoptotic rate in the

Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs

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Wenjing Ye

2017-10-01

Full Text Available Using a highly effective binuclear Cu complex as the catalyst, the 1,3-dipolar cycloaddition reactions between 16 alkynes and two azides were successfully performed and resulted in the production of 25 new triazole-containing sorafenib analogs. Several compounds were evaluated as potent antitumor agents. Among them, 4-(4-(4-(3-fluorophenyl-1H-1,2,3-triazol-1-ylphenoxy-N-methylpicolinamide (8f potently suppressed the proliferation of HT-29 cancer cells by inducing apoptosis and almost completely inhibited colony formation at a low micromolar concentration.

The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing

NARCIS (Netherlands)

Tesori, V.; Piscaglia, A.C.; Samengo, D.; Barba, M.; Bernardini, C.; Scatena, R.; Pontoglio, A.; Castellini, L.; Spelbrink, H.; Maulucci, G.; Puglisi, M.A.; Pani, G.; Gasbarrini, A.

2015-01-01

Although the only effective drug against primary hepatocarcinoma, the multikinase inhibitor Sorafenib (SFB) usually fails to eradicate liver cancer. Since SFB targets mitochondria, cell metabolic reprogramming may underlie intrinsic tumor resistance. To characterize cancer cell metabolic response to

Fluoro-sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence and recovery

Science.gov (United States)

Carr, Brian I.; Cavallini, Aldo; Lippolis, Catia; D’Alessandro, Rosalba; Messa, Caterina; Refolo, Maria Grazia; Tafaro, Angela

2015-01-01

To evaluate the growth-inhibitory properties of the potent multi-kinase antagonist Regorafenib (Fluoro-Sorafenib), which was synthesized as a more potent Sorafenib, a Raf inhibitor and to determine whether similar mechanisms were involved, human hepatoma cell lines were grown in the presence or absence of Regorafanib and examined for growth inhibition. Western blots were performed for Raf targets, for apoptosis and autophagy. Regorafenib inhibited growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner. Multiple signaling pathways were altered, including MAP kinases phospho-ERK and phospho-JNK and its target phospho-c-Jun. There was evidence for apoptosis by FACS, cleavage of caspases and increased Bax levels; as well as induction of autophagy, as judged by increased Beclin-1 and LC3 (II) levels. Prolonged drug exposure resulted in cell quiescence. Full growth recovery occurred after drug removal, unlike with doxorubicin chemotherapy. Regorafenib is a potent inhibitor of cell growth. Cells surviving Regorafenib treatment remain viable, but quiescent and capable of regrowth following drug removal. The reversibility of tumor cell growth suppression after drug removal may have clinical implications. PMID:22777740

Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway.

Science.gov (United States)

Lin, Ming-Te; Lin, Chia-Liang; Lin, Tzu-Yu; Cheng, Chun-Wen; Yang, Shun-Fa; Lin, Chu-Liang; Wu, Chih-Chien; Hsieh, Yi-Hsien; Tsai, Jen-Pi

2016-05-01

Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

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Archibald M

2016-01-01

Full Text Available Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs, sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

Effective prevention of sorafenib-induced hand–foot syndrome by dried-bonito broth

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Kamimura K

2018-04-01

Full Text Available Kenya Kamimura,1 Yoko Shinagawa-Kobayashi,1 Ryo Goto,1 Kohei Ogawa,1 Takeshi Yokoo,1 Akira Sakamaki,1 Satoshi Abe,1 Hiroteru Kamimura,1 Takeshi Suda,2 Hiroshi Baba,3 Takayuki Tanaka,4 Yoshizu Nozawa,5 Naoto Koyama,6 Masaaki Takamura,1 Hirokazu Kawai,1 Satoshi Yamagiwa,1 Yutaka Aoyagi,1 Shuji Terai1 1Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; 2Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata Medical and Dental Hospital, Minami-Uonuma, Niigata, Japan; 3Division of Anesthesiology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; 4Uonuma Eye Clinic, Uonuma, Niigata, Japan; 5Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan; 6Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan Background: Sorafenib (SOR is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC. Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand–foot syndrome (HFS is the most common, occurring in 30%–50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms. Materials and methods: To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB, which was reported to improve peripheral blood flow, on the prevention of the symptom was

Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner.

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Lohmeyer, J; Nerreter, T; Dotterweich, J; Einsele, H; Seggewiss-Bernhardt, R

2018-03-24

Natural killer (NK) cells play a major role in host immunity against leukaemia and lymphoma. However, clinical trials applying NK cells have not been as efficient as hoped for. Patients treated with rapidly accelerated fibrosarcoma (RAF) inhibitors exhibit increased tumour infiltration by immune cells, suggesting that a combination of RAF inhibitors with immunotherapy might be beneficial. As mitogen-activated protein kinases (MAPKs) such as raf-1 proto-oncogene, serine/threonine kinase (CRAF) regulate NK cell functions, we performed an in-vitro investigation on the potential of clinically relevant short-acting tyrosine kinase inhibitors (TKIs) as potential adjuvants for NK cell therapy: NK cells from healthy human blood donors were thus treated with sorafenib, sunitinib or the pan-RAF inhibitor ZM336372 during ex-vivo expansion. Functional outcomes assessed after washout of the drugs included cytokine production, degranulation, cytotoxicity, apoptosis induction and signal transduction with/without target cell contact. Paradoxically, sorafenib enhanced NK cell effector functions in a time- and dose-dependent manner by raising the steady-state activation level. Of note, this did not lead to NK cell exhaustion, but enhanced activity against target cells such as K562 or Daudis mediated via the RAS/RAF/extracellular-regulated kinase (ERK) pathway, but not via protein kinase B (AKT). Our data will pave the path to develop a rationale for the considered use of RAF inhibitors such as sorafenib for pre-activation in NK cell-based adoptive immune therapy. © 2018 British Society for Immunology.

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

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Jeannot V

2016-11-01

apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for treating patients with mutant KRAS resistant to other treatments. Keywords: targeted therapy, combined treatments, non-small cell lung cancer, hepatocarcinoma

Tumor Molecular Profiling for an Individualized Approach to the Treatment of Hepatocellular Carcinoma: A Patient Case Study

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Kristine Posadas

2018-04-01

Full Text Available Hepatocellular carcinoma (HCC is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA, may produce clinical benefits to a limited extent. Systemic chemotherapy has been shown to produce a modest response, but there is no clinically valid biomarker that can be used to predict which patients may benefit. In this case study, we present two patients with metastatic HCC, they received systemic treatment using capecitabine, oxaliplatin, and either bevacizumab or sorafenib. The tumor response to treatment was determined by the progression-free survival (PFS. Molecular profiling of the tumors showed differential expression of biochemical markers and different mutational status of the TP53 and β-catenin (CTNNB1 genes. We hypothesize that the PFS correlates with the tumor molecular profiles, which may be predictive of the therapeutic response to systemic chemotherapy. Further investigation is indicated to correlate tumor biomarkers and treatment responses, with the objective of personalizing the therapies for patients with advanced HCC.

Is phenytoin contraindicated in patients receiving cranial irradiation?

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Borg, M.F. [Royal Adelaide Hospital, SA (Australia); Probert, J.C. [Auckland Hospital, Auckland (New Zealand). Dept. of Radiation Oncology; Zwi, L.J. [Auckland Univ. (New Zealand). Dept. of Medicine and Surgery

1995-02-01

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation. 21 refs., 2 tabs., 3 figs.

Is phenytoin contraindicated in patients receiving cranial irradiation?

International Nuclear Information System (INIS)

Borg, M.F.; Probert, J.C.; Zwi, L.J.

1995-01-01

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation. 21 refs., 2 tabs., 3 figs

Patient satisfaction after receiving dental treatment among patients ...

African Journals Online (AJOL)

Background: Patient satisfaction is one of the indicators of the quality of care. Therefore it is one of the tools for evaluating the quality of care. Aim: To determine patient satisfaction after receiving dental treatment among patients attending public dental clinics in Dar-Es-Salaam. Material and methods: Five public dental clinics ...

Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.

Science.gov (United States)

Ukon, Naoyuki; Zhao, Songji; Yu, Wenwen; Shimizu, Yoichi; Nishijima, Ken-Ichi; Kubo, Naoki; Kitagawa, Yoshimasa; Tamaki, Nagara; Higashikawa, Kei; Yasui, Hironobu; Kuge, Yuji

2016-12-01

Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl- 3 H(N)]-3'-fluoro-3'-deoxythythymidine ([ 3 H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [ 18 F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [ 18 F]FLT. The dynamic pattern of [ 18 F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [ 18 F]FLT phosphorylation (k 3 ) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [ 18 F]FLT forward transport (K 1 ) to reverse transport (k 2 ), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group). Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic

The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

International Nuclear Information System (INIS)

Pignochino, Ymera; Dell’Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M

2015-01-01

Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. ERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM. The online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users

Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.

Science.gov (United States)

Pal, Harish C; Diamond, Ariana C; Strickland, Leah R; Kappes, John C; Katiyar, Santosh K; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

2016-01-12

Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.

Nutritional survey of neoplasm patients receiving radiotherapy

International Nuclear Information System (INIS)

Li Xinli; Zhu Shengtao

2001-01-01

Objective: In order to know the nutriture of neoplasm patients receiving radiotherapy and give nutritional guidance properly, the authors make the following survey. Methods: A dietary survey of twenty-four-hour retrospective method was used; The patients' activity was recorded and their twenty-four hours caloric consumption was calculated. Results: Of all the patients, the intake of protein is more than recommended, percentage of calorific proportion is about 15%-19% of gross caloric. A larger portion of patients' caloric intake, especially female patients, is lower than caloric consumption. Among all the patients, the intake of vegetables is not enough; The consumption of milk and milky products is lower; it is common and serious that neoplasm patients receiving radiotherapy have vitamine and mineral's scarcity. Conclusions: Nutriture of neoplasm patients is not optimistic, it is imperative to improve their nutriture

Hypersensitivity reactions in patients receiving hemodialysis.

Science.gov (United States)

Butani, Lavjay; Calogiuri, Gianfranco

2017-06-01

To describe hypersensitivity reactions in patients receiving maintenance hemodialysis. PubMed search of articles published during the past 30 years with an emphasis on publications in the past decade. Case reports and review articles describing hypersensitivity reactions in the context of hemodialysis. Pharmacologic agents are the most common identifiable cause of hypersensitivity reactions in patients receiving hemodialysis. These include iron, erythropoietin, and heparin, which can cause anaphylactic or pseudoallergic reactions, and topical antibiotics and anesthetics, which lead to delayed-type hypersensitivity reactions. Many hypersensitivity reactions are triggered by complement activation and increased bradykinin resulting from contact system activation, especially in the context of angiotensin-converting enzyme inhibitor use. Several alternative pharmacologic preparations and dialyzer membranes are available, such that once an etiology for the reaction is established, recurrences can be prevented without affecting the quality of care provided to patients. Although hypersensitivity reactions are uncommon in patients receiving hemodialysis, they can be life-threatening. Moreover, considering the large prevalence of the end-stage renal disease population, the implications of such reactions are enormous. Most reactions are pseudoallergic and not mediated by immunoglobulin E. The multiplicity of potential exposures and the complexity of the environment to which patients on dialysis are exposed make it challenging to identify the precise cause of these reactions. Great diligence is needed to investigate hypersensitivity reactions to avoid recurrence in this high-risk population. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia.

Science.gov (United States)

Miners, John O; Chau, Nuy; Rowland, Andrew; Burns, Kushari; McKinnon, Ross A; Mackenzie, Peter I; Tucker, Geoffrey T; Knights, Kathleen M; Kichenadasse, Ganessan

2017-04-01

Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug-drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC 50 values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were enzyme identified to date. In vitro-in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely. Copyright © 2017 Elsevier Inc. All rights reserved.

First- and Second-Line Targeted Systemic Therapy in Hepatocellular Carcinoma—An Update on Patient Selection and Response Evaluation

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Johann von Felden

2016-11-01

Full Text Available Advanced hepatocellular carcinoma (HCC with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI sorafenib is the only proven active substance in systemic HCC therapy for first-line treatment. In this review, we summarize current aspects in patient selection and management of side effects, and provide an update on response evaluation during first-line sorafenib therapy. Since second-line treatment options have been improved with the successful completion of the RESORCE trial, demonstrating a survival benefit for second-line treatment with the TKI regorafenib, response monitoring during first-line therapy will be critical to deliver optimal systemic therapy in HCC. To this regard, specific side effects, in particular worsening of arterial hypertension and diarrhea, might suggest treatment response during first-line sorafenib therapy; however, clear predictive clinical markers, as well as laboratory test or serum markers, are not established. Assessment of radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST is helpful to identify patients who do not benefit from sorafenib treatment.

Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation

Energy Technology Data Exchange (ETDEWEB)

Watkins, E.B.; Findlay, P.; Gelmann, E.; Lane, H.C.; Zabell, A.

1987-09-01

The oropharynx and hypopharynx are common sites of involvement in AIDS patients with mucocutaneous Kaposi's sarcoma. The radiotherapist is often asked to intervene with these patients due to problems with pain, difficulty in swallowing, or impending airway obstruction. We have noted an unexpected decrease in normal tissue tolerance of the oropharyngeal mucosa to irradiation in AIDS patients treated in our department. Data on 12 patients with AIDS and Kaposi's sarcoma receiving oropharyngeal irradiation are presented here. Doses ranged from 1000 cGy to 1800 cGy delivered in 150-300 cGy fractions. Seven of eight patients receiving doses of 1200 cGy or more developed some degree of mucositis, four of these developed mucositis severe enough to require termination of treatment. All patients in this study received some form of systemic therapy during the course of their disease, but no influence on mucosal response to irradiation was noted. Four patients received total body skin electron treatments, but no effect on degree of mucositis was seen. Presence or absence of oral candidiasis was not an obvious factor in the radiation response of the oral mucosa in these patients. T4 counts were done on 9 of the 12 patients. Although the timing of the T4 counts was quite variable, no correlation with immune status and degree of mucositis was found. The degree of mucositis seen in these patients occurred at doses much lower than expected based on normal tissue tolerances seen in other patient populations receiving head and neck irradiations. We believe that the ability of the oral mucosa to repair radiation damage is somehow altered in patients with AIDS.

Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation

International Nuclear Information System (INIS)

Watkins, E.B.; Findlay, P.; Gelmann, E.; Lane, H.C.; Zabell, A.

1987-01-01

The oropharynx and hypopharynx are common sites of involvement in AIDS patients with mucocutaneous Kaposi's sarcoma. The radiotherapist is often asked to intervene with these patients due to problems with pain, difficulty in swallowing, or impending airway obstruction. We have noted an unexpected decrease in normal tissue tolerance of the oropharyngeal mucosa to irradiation in AIDS patients treated in our department. Data on 12 patients with AIDS and Kaposi's sarcoma receiving oropharyngeal irradiation are presented here. Doses ranged from 1000 cGy to 1800 cGy delivered in 150-300 cGy fractions. Seven of eight patients receiving doses of 1200 cGy or more developed some degree of mucositis, four of these developed mucositis severe enough to require termination of treatment. All patients in this study received some form of systemic therapy during the course of their disease, but no influence on mucosal response to irradiation was noted. Four patients received total body skin electron treatments, but no effect on degree of mucositis was seen. Presence or absence of oral candidiasis was not an obvious factor in the radiation response of the oral mucosa in these patients. T4 counts were done on 9 of the 12 patients. Although the timing of the T4 counts was quite variable, no correlation with immune status and degree of mucositis was found. The degree of mucositis seen in these patients occurred at doses much lower than expected based on normal tissue tolerances seen in other patient populations receiving head and neck irradiations. We believe that the ability of the oral mucosa to repair radiation damage is somehow altered in patients with AIDS

Use of Ultrasmall Superparamagnetic Iron Oxide Enhanced Susceptibility Weighted Imaging and Mean Vessel Density Imaging to Monitor Antiangiogenic Effects of Sorafenib on Experimental Hepatocellular Carcinoma

Directory of Open Access Journals (Sweden)

Shuohui Yang

2017-01-01

Full Text Available We investigated effectiveness of ultrasmall superparamagnetic iron oxide enhanced susceptibility weighted imaging (USPIO-enhanced SWI and mean vessel density imaging (Q in monitoring antiangiogenic effects of Sorafenib on orthotopic hepatocellular carcinoma (HCC. Thirty-five HCC xenografts were established. USPIO-enhanced SWI and Q were performed on a 1.5 T MR scanner at baseline, 7, 14, and 21 days after Sorafenib treatment. Intratumoral susceptibility signal intensity (ITSS and Q were serially measured and compared between the treated (n = 15 and control groups (n = 15. Both ITSS and Q were significantly lower in the treated group at each time point (P < 0.05. Measurements in the treated group showed that ITSS persisted at 7 days (P = 0.669 and increased at 14 and 21 days (P < 0.05, while Q significantly declined at 7 days (P = 0.028 and gradually increased at 14 and 21 days. In the treated group, significant correlation was found between Q and histologic microvessel density (MVD (r = 0.753, P < 0.001, and ITSS correlated well with MVD (r = 0.742, P = 0.002 after excluding the data from baseline. This study demonstrated that USPIO-enhanced SWI and Q could provide novel biomarkers for evaluating antiangiogenic effects of Sorafenib on HCC.

Osteoporosis prophylaxis in patients receiving chronic glucocorticoid therapy

International Nuclear Information System (INIS)

Ali, Mir Sadat; AlElq, Abdulmohsen H.; AlShafei, Badar A.; AbuJubarac, Mohammed A.; AlTurki, Haifa A.

2009-01-01

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, yet few patients receive proper measures to prevent its development. We retrospectively searched prescription records to determine if patients receiving oral prednisolone were receiving prophylaxis or treatment for osteopenia and osteoporosis. Patients who were prescribed greater or equal to 7.5 milligrams of prednisolone for 6 months or longer during a 6- month period were identified through the prescription monitoring system. Demographic and clinical data were extracted from the patient records, and dual energy x-ray absorptiometry (DEXA) scans were retrieved, when available. Use of oral calcium, vitamin D and anti-resorptives was recorded. One hundred males and 65 females were receiving oral prednisolone for a mean (SD) duration of 40.4 (29.9) months in males and 41.2 (36.4) months in females. Twenty-one females (12.7%) and 5 (3%) males had bone mineral density measured by DEXA. Of those, 10 (47.6%) females and 3 (50%) males were osteoporotic and 11(52.4%) females and 2 (40%) males were osteopenic. Calcium and vitamin D were prescribed to the majority of patients (60% to 80%), but none were prescribed antiresorptive/anabolic therapy. Patients in this study were neither investigated properly nor treated according to the minimum recommendations for the management of GIOP. Physician awareness about the prevention and treatment of GIOP should be a priority for the local health care system. (author)

Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.

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Abbattista, Maria R; Jamieson, Stephen M F; Gu, Yongchuan; Nickel, Jennifer E; Pullen, Susan M; Patterson, Adam V; Wilson, William R; Guise, Christopher P

2015-01-01

PR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. This dinitrobenzamide mustard is reduced to activated DNA cross-linking metabolites (hydroxylamine PR-104H and amine PR-104M) under hypoxia by one-electron reductases and independently of hypoxia by the 2-electron reductase aldo-keto reductase 1C3 (AKR1C3). High expression of AKR1C3, along with extensive hypoxia, suggested the potential of PR-104 for treatment of hepatocellular carcinoma (HCC). However, a phase IB trial with sorafenib demonstrated significant toxicity that was ascribed in part to reduced PR-104A clearance, likely reflecting compromised glucuronidation in patients with advanced HCC. Here, we evaluate the activity of PR-104 in HCC xenografts (HepG2, PLC/PRF/5, SNU-398, Hep3B) in mice, which do not significantly glucuronidate PR-104A. Cell line differences in sensitivity to PR-104A in vitro under aerobic conditions could be accounted for by differences in both expression of AKR1C3 (high in HepG2 and PLC/PRF/5) and sensitivity to the major active metabolite PR-104H, to which PLC/PRF/5 was relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity and reductive metabolism was greatest in the low-AKR1C3 SNU-398 and Hep3B lines. Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the range seen in 21 human HCC specimens. PR-104 monotherapy elicited significant reductions in growth of Hep3B and HepG2 xenografts, and the combination with sorafenib was significantly active in all 4 xenograft models. The results suggest that better-tolerated analogs of PR-104, without a glucuronidation liability, may have the potential to exploit AKR1C3 and/or hypoxia in HCC in humans.

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

NARCIS (Netherlands)

Mathew, N.R.; Baumgartner, F.; Braun, L.; O'Sullivan, D.; Thomas, S.; Waterhouse, M.; Muller, T.A.; Hanke, K.; Taromi, S.; Apostolova, P.; Illert, A.L.; Melchinger, W.; Duquesne, S.; Schmitt-Graeff, A.; Osswald, L.; Yan, K.L.; Weber, A; Tugues, S.; Spath, S.; Pfeifer, D.; Follo, M.; Claus, R.; Lubbert, M.; Rummelt, C.; Bertz, H.; Wasch, R.; Haag, J.; Schmidts, A.; Schultheiss, M.; Bettinger, D.; Thimme, R.; Ullrich, E.; Tanriver, Y.; Vuong, G.L.; Arnold, R.; Hemmati, P.; Wolf, D.; Ditschkowski, M.; Jilg, C.; Wilhelm, K.; Leiber, C.; Gerull, S.; Halter, J.; Lengerke, C.; Pabst, T.; Schroeder, T.; Kobbe, G.; Rosler, W.; Doostkam, S.; Meckel, S.; Stabla, K.; Metzelder, S.K.; Halbach, S.; Brummer, T.; Hu, Z; Dengjel, J.; Hackanson, B.; Schmid, C.; Holtick, U.; Scheid, C.; Spyridonidis, A.; Stolzel, F.; Ordemann, R.; Muller, L.P.; Sicre-de-Fontbrune, F.; Ihorst, G.; Kuball, J.; Ehlert, J.E.; Feger, D.; Wagner, E.M.; Cahn, J.Y.; Schnell, J.; Kuchenbauer, F.; Bunjes, D.; Chakraverty, R.; Richardson, S.; Gill, S.; Kroger, N.; Ayuk, F.; Vago, L.; Ciceri, F.; Muller, A.M.; Kondo, T.; Teshima, T.; Klaeger, S.; Kuster, B.; Kim, D.D.H.; Weisdorf, D.; Velden, W.J. van der; Dorfel, D.; Bethge, W.; Hilgendorf, I.; Hochhaus, A.; Andrieux, G.; Borries, M.; Busch, H.; Magenau, J.; Reddy, P.; Labopin, M.; Antin, J.H., et al.

2018-01-01

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a

8. Prevalence of Epistaxis among Patients Receiving ...

African Journals Online (AJOL)

user

The aim of this study was thus to determine the prevalence, aetiology and treatment modalities of epistaxis among patients receiving otorhinolaryngology services at MNH and MOI. Materials and Methods: A cross-sectional, hospital based study was done to 427 patients at Muhimbili. National Hospital (MNH) and Muhimbili.

Economic Evaluation of a Patient-Directed Music Intervention for ICU Patients Receiving Mechanical Ventilatory Support.

Science.gov (United States)

Chlan, Linda L; Heiderscheit, Annette; Skaar, Debra J; Neidecker, Marjorie V

2018-05-04

Music intervention has been shown to reduce anxiety and sedative exposure among mechanically ventilated patients. Whether music intervention reduces ICU costs is not known. The aim of this study was to examine ICU costs for patients receiving a patient-directed music intervention compared with patients who received usual ICU care. A cost-effectiveness analysis from the hospital perspective was conducted to determine if patient-directed music intervention was cost-effective in improving patient-reported anxiety. Cost savings were also evaluated. One-way and probabilistic sensitivity analyses determined the influence of input variation on the cost-effectiveness. Midwestern ICUs. Adult ICU patients from a parent clinical trial receiving mechanical ventilatory support. Patients receiving the experimental patient-directed music intervention received a MP3 player, noise-canceling headphones, and music tailored to individual preferences by a music therapist. The base case cost-effectiveness analysis estimated patient-directed music intervention reduced anxiety by 19 points on the Visual Analogue Scale-Anxiety with a reduction in cost of $2,322/patient compared with usual ICU care, resulting in patient-directed music dominance. The probabilistic cost-effectiveness analysis found that average patient-directed music intervention costs were $2,155 less than usual ICU care and projected that cost saving is achieved in 70% of 1,000 iterations. Based on break-even analyses, cost saving is achieved if the per-patient cost of patient-directed music intervention remains below $2,651, a value eight times the base case of $329. Patient-directed music intervention is cost-effective for reducing anxiety in mechanically ventilated ICU patients.

Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition.

Science.gov (United States)

Sun, Danni; Liu, Hongchun; Dai, Xiaoyang; Zheng, Xingling; Yan, Juan; Wei, Rongrui; Fu, Xuhong; Huang, Min; Shen, Aijun; Huang, Xun; Ding, Jian; Geng, Meiyu

2017-10-10

Aspirin is associated with a reduced risk of cancer and delayed progression of malignant disease. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mTOR signaling is believed to partially contribute to these anticancer effects, although the mechanism is unclear. In this study, we revealed the mechanism underlying the effects of aspirin on AMPK-mTOR signaling, and described a mechanism-based rationale for the use of aspirin in cancer therapy. We found that aspirin inhibited mTORC1 signaling through AMPK-dependent and -independent manners. Aspirin inhibited the AMPK-TSC pathway, thus resulting in the suppression of mTORC1 activity. In parallel, it directly disrupted the mTOR-raptor interaction. Additionally, the combination of aspirin and sorafenib showed synergetic effects via inhibiting mTORC1 signaling and the PI3K/AKT, MAPK/ERK pathways. Aspirin and sorafenib showed synergetic anticancer efficacy in the SMMC-7721 model. Our study provides mechanistic insights and a mechanism-based rationale for the roles of aspirin in cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Anxiety and depression in patients receiving radiotherapy. Prospective study

International Nuclear Information System (INIS)

Chaturvedi, S.K.; Chandra, P.S.; Channabasavanna, S.M.; Anantha, N.; Reddy, B.K.M.; Sharma, S.

1994-01-01

The objective of this study was to detect the prevalence of anxiety and depressive disorders using the Hospital Anxiety and Depression Scale (HADS) prospectively in patients receiving Radiotherapy (RT) during and after treatment. 140 consecutive cancer patients referred for radiotherapy and their care givers were included. All patients were administered the Hospital Anxiety and Depression Scale (HADS) conducted at intake, just before starting RT, after finishing the course of RT, and at 3-4 months follow-up. Anxiety and depression are detected frequently in patients receiving RT both prior to treatment and later during follow-up

A pilot study to assess feasibility of value based pricing in Cyprus through pharmacoeconomic modelling and assessment of its operational framework: sorafenib for second line renal cell cancer.

Science.gov (United States)

Petrou, Panagiotis; Talias, Michael A

2014-01-01

The continuing increase of pharmaceutical expenditure calls for new approaches to pricing and reimbursement of pharmaceuticals. Value based pricing of pharmaceuticals is emerging as a useful tool and possess theoretical attributes to help health system cope with rising pharmaceutical expenditure. To assess the feasibility of introducing a value-based pricing scheme of pharmaceuticals in Cyprus and explore the integrative framework. A probabilistic Markov chain Monte Carlo model was created to simulate progression of advanced renal cell cancer for comparison of sorafenib to standard best supportive care. Literature review was performed and efficacy data were transferred from a published landmark trial, while official pricelists and clinical guidelines from Cyprus Ministry of Health were utilised for cost calculation. Based on proposed willingness to pay threshold the maximum price of sorafenib for the indication of second line renal cell cancer was assessed. Sorafenib value based price was found to be significantly lower compared to its current reference price. Feasibility of Value Based Pricing is documented and pharmacoeconomic modelling can lead to robust results. Integration of value and affordability in the price are its main advantages which have to be weighed against lack of documentation for several theoretical parameters that influence outcome. Smaller countries such as Cyprus may experience adversities in establishing and sustaining essential structures for this scheme.

Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.

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Pal, Harish Chandra; Baxter, Ronald D; Hunt, Katherine M; Agarwal, Jyoti; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

2015-09-29

Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.

Palliative care for patients with cancer: do patients receive the care they consider important? A survey study.

Science.gov (United States)

Heins, Marianne; Hofstede, Jolien; Rijken, Mieke; Korevaar, Joke; Donker, Gé; Francke, Anneke

2018-04-17

In many countries, GPs and home care nurses are involved in care for patients with advanced cancer. Given the varied and complex needs of these patients, providing satisfactory care is a major challenge for them. We therefore aimed to study which aspects of care patients, GPs and home care nurses consider important and whether patients receive these aspects. Seventy-two Dutch patients with advanced cancer, 87 GPs and 26 home care nurses rated the importance of support when experiencing symptoms, respect for patients' autonomy and information provision. Patients also rated whether they received these aspects. Questionnaires were based on the CQ index palliative care. Almost all patients rated information provision and respect for their autonomy as important. The majority also rated support when suffering from specific symptoms as important, especially support when in pain. In general, patients received the care they considered important. However, 49% of those who considered it important to receive support when suffering from fatigue and 23% of those who wanted to receive information on the expected course of their illness did not receive this or only did so sometimes. For most patients with advanced cancer, the palliative care that they receive matches what they consider important. Support for patients experiencing fatigue may need more attention. When symptoms are difficult to control, GPs and nurses may still provide emotional support and practical advice. Furthermore, we recommend that GPs discuss patients' need for information about the expected course of their illness.

Post-operative neuromuscular function of patients receiving non ...

African Journals Online (AJOL)

Objectives: To determine the number of patients whose non-depolarising muscle relaxation is adequately reversed. To define factors that contribute to reversal. Design: A cross sectional study. Setting: Universitas Hospital recovery room over a 2 month period. Subjects: Patients that received non-depolarising muscle ...

Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.

Science.gov (United States)

Hammami, Muhammad M; Duaiji, Najla; Mutairi, Ghazi; Aklabi, Sabah; Qattan, Nasser; Abouzied, Mohei El-Din M; Sous, Mohamed W

2015-09-09

Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer. An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies. Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione

Patient-reported distress and survival among patients receiving definitive radiation therapy

Directory of Open Access Journals (Sweden)

Yacob Habboush, MD

2017-04-01

Conclusions: PRD before or during RT is a prognostic factor associated with decreased survival. Distress screening guidelines and interventions should be implemented for patients receiving definitive RT.

Prevalence of major depressive disorder in patients receiving beta-blocker therapy versus other medications.

Science.gov (United States)

Carney, R M; Rich, M W; teVelde, A; Saini, J; Clark, K; Freedland, K E

1987-08-01

Depression is believed to be a common side effect in patients receiving beta-blocker therapy. However, diagnoses of depression defined by current diagnostic criteria may not be more common in patients receiving beta-blockers than in patients with the same medical disorder receiving other medications. Seventy-seven patients undergoing elective cardiac catheterization for evaluation of chest pain received a semi-structured diagnostic psychiatric interview. Twenty-one percent of the patients receiving beta-blockers and 33 percent of the patients receiving medications other than beta-blockers met the current American Psychiatric Association criteria for major depressive disorder (DSM-III) (p = NS). The mean heart rate and state anxiety scores for patients taking beta-blockers were significantly lower than those measured in patients taking medications other than beta-blockers. No other medical or demographic differences were observed between the two groups. Despite the methodologic limitations of the study, there does not appear to be a difference in the point prevalence of depression between patients receiving beta-blockers and those receiving other medications.

Where Do Patients With Cancer in Iowa Receive Radiation Therapy?

Science.gov (United States)

Ward, Marcia M.; Ullrich, Fred; Matthews, Kevin; Rushton, Gerard; Tracy, Roger; Goldstein, Michael A.; Bajorin, Dean F.; Kosty, Michael P.; Bruinooge, Suanna S.; Hanley, Amy; Jacobson, Geraldine M.; Lynch, Charles F.

2014-01-01

Purpose: Multiple studies have shown survival benefits in patients with cancer treated with radiation therapy, but access to treatment facilities has been found to limit its use. This study was undertaken to examine access issues in Iowa and determine a methodology for conducting a similar national analysis. Patients and Methods: All Iowa residents who received radiation therapy regardless of where they were diagnosed or treated were identified through the Iowa Cancer Registry (ICR). Radiation oncologists were identified through the Iowa Physician Information System (IPIS). Radiation facilities were identified through IPIS and classified using the Commission on Cancer accreditation standard. Results: Between 2004 and 2010, 113,885 invasive cancers in 106,603 patients, 28.5% of whom received radiation treatment, were entered in ICR. Mean and median travel times were 25.8 and 20.1 minutes, respectively, to the nearest facility but 42.4 and 29.1 minutes, respectively, to the patient's chosen treatment facility. Multivariable analysis predicting travel time showed significant relationships for disease site, age, residence location, and facility category. Residents of small and isolated rural towns traveled nearly 3× longer than urban residents to receive radiation therapy, as did patients using certain categories of facilities. Conclusion: Half of Iowa patients could reach their nearest facility in 20 minutes, but instead, they traveled 30 minutes on average to receive treatment. The findings identified certain groups of patients with cancer who chose more distant facilities. However, other groups of patients with cancer, namely those residing in rural areas, had less choice, and some had to travel considerably farther to radiation facilities than urban patients. PMID:24443730

Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth

Energy Technology Data Exchange (ETDEWEB)

Yang, Hao [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Institute of Pharmacology and Toxicology, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222000, Jiangsu (China); Wang, Juan [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Fan, Jin-hong; Zhang, Ya-qi; Zhao, Jun-xian [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Dai, Xiao-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Liu, Qi; Shen, Yan-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Liu, Chang [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Sun, Wei-dong, E-mail: zyykjc@sina.com [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Sun, Yun, E-mail: ysun@yzu.edu.cn [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China)

2017-01-15

Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth. - Highlights: • Ilexgenin A exerts anti-inflammatory and anti-angiogenesis effects in hepatoma. • Ilexgenin A may exert these effects through inhibition of STAT3 and PI3K pathways. • Ilexgenin A exhibits synergistic effects with Sorafenib on hepatoma growth

[Management of patients with bronchial asthma received general anesthesia and surgical intervention].

Science.gov (United States)

To, Masako; Tajima, Makoto; Ogawa, Cyuhei; Otomo, Mamoru; Suzuki, Naohito; Sano, Yasuyuki

2002-01-01

Stimulation to bronchial mucosa is one of the major risk factor of asthma attack. When patients receive surgical intervention and general anesthesia, they are always exposed to stimulation to bronchial mucosa. Prevention method of bronchial asthma attack during surgical intervention is not established yet. We investigated that clinical course of patients with bronchial asthma who received general anesthesia and surgical intervention. Seventy-six patients with bronchial asthma were received general anesthesia and surgical intervention from 1993 to 1998. Twenty-four patients were mild asthmatic patients, 39 were moderate asthmatic patients and 13 were severe asthmatic patients. Preoperative treatment for preventing asthma attack was as follows; Eight patients were given intravenous infusion of aminophylline before operation. Fifty-two patients were given intravenous infusion of aminophylline and hydrocortisone before operation. Three patients were given intravenous infusion of hydrocortisone for consecutive 3 days before operation. Thirteen patients were given no treatment for preventing asthma attack. One patient was suffered from asthma attack during operation. She was given no preventing treatment for asthma attack before operation. Three patients were suffered from asthma attack after operation. No wound dehiscence was observed in all patients. To prevent asthma attack during operation, intravenous infusion of steroid before operation is recommended, when patients with asthma receive general anesthesia and surgical intervention.

Plasma Aluminum Concentrations in Pediatric Patients Receiving Long-Term Parenteral Nutrition.

Science.gov (United States)

Courtney-Martin, Glenda; Kosar, Christina; Campbell, Alison; Avitzur, Yaron; Wales, Paul W; Steinberg, Karen; Harrison, Debra; Chambers, Kathryn

2015-07-01

Patients receiving long-term parenteral nutrition (PN) are at increased risk of aluminium (Al) toxicity because of bypass of the gastrointestinal tract during PN infusion. Complications of Al toxicity include metabolic bone disease (MBD), Al-associated encephalopathy in adults, and impaired neurological development in preterm infants. Unlike the United States, there are no regulations regarding Al content of large- and small-volume parenterals in Canada. We, therefore, aimed to present our data on plasma Al concentration and Al intake from our cohort of pediatric patients receiving long-term PN. Plasma Al concentration was retrospectively gathered from the patient charts of all 27 patients with intestinal failure (IF) receiving long-term PN at The Hospital for Sick Children, Toronto, Canada, and compared with age- and sex-matched controls recruited for comparison. In addition, Al concentration was measured in PN samples collected from 10 randomly selected patients with IF and used to determine their Al intake. The plasma Al concentration of patients with IF receiving long-term PN was significantly higher than that of control participants (1195 ± 710 vs 142 ± 63 nmol/L; P Parenteral and Enteral Nutrition.

Iodine Supplementation for Pediatric Patients Receiving Long-Term Parenteral Nutrition.

Science.gov (United States)

Santoro, Jonathan D; Nespor, Colleen; Poole, Robert L; Kerner, John A

2016-04-01

Patients dependent on parenteral nutrition (PN) are among a group at risk of developing iodine deficiency. Supplementation with iodine in this population has been debated in a number of studies, resulting in variable clinical practices. The Committee on Clinical Practice Issues of the American Society for Clinical Nutrition recommends a dose of 1 mcg/kg/d of parenteral iodine for patients receiving PN. At our institution, PN trace elements do not include iodine, although this is not the case internationally. Our study sought to assess iodine levels and thyroid function in a cohort of PN-dependent pediatric patients. A retrospective analysis studied 32 pediatric patients with a variety of medical diagnoses who received PN as a primary means of nutrition for 6 months or longer. Patients received variable proportions of their total caloric intake as PN, which ranged from 14%-100%. Iodine and thyroid function levels were obtained by serum sampling. No patient in our cohort of 32 demonstrated thyroid dysfunction or developed iodine deficiency. The length of time on PN and the percentage of total nutrition intake as PN were not associated with iodine levels (P Parenteral and Enteral Nutrition.

The Views Of Cancer Patients On Receiving Bad News

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Hatice Bostanoglu Fesci

2011-06-01

Full Text Available AIM: This study was performed in a descriptive matter to determine the views of inpatients at an oncology state hospital on receiving bad news. METHOD: The study sample consisted of 237 inpatients (155 females, 82 males at an oncology state hospital between October and November 2008 who were determined using the random sampling method and accepted participating in the study. The data collection tool used was a survey form that consisted of 24 questions related to the sociodemographic features and views on receiving bad news. RESULTS: The mean age of the study subjects was 53.1±13.9 (min.=18, max.=83. The patients were undergoing the treatment process in 84% and the diagnostic process in 16%. The bad news had been given by the physician in 87.8% and while in the physician's room in 74.8%. The patients had been told while receiving the bad news that 'there is a mass/problem/lesion/tumor and you will undergo surgery' in 47.7% while 24.9% had been told that they had cancer directly. The patients stated that they froze, fainted, were shocked, felt their life was shattered and experienced emotions such as sadness, fear, hopelessness, sorrow, disappointment, desperation, etc. at a rate of 93.7%. We found that 58.2% of the patients had not been given an opportunity to express their emotions when they received the bad news, 67.4% preferred to have a relative with them at the time, 40.9% felt that the bad news should be given in a special environment, 30% wanted the bad news to be given as soon as the diagnosis was known while 36.7% preferred being told everything about the disease when receiving the bad news CONCLUSION: Taking into account the information content, family participation, and the individual preferences of the patients regarding time and place when giving bad news and encouraging them to ask questions and express themselves may make it easier for the patients to cope with bad news. [TAF Prev Med Bull 2011; 10(3.000: 319-326

Factors predicting hyperkalemia in patients with cirrhosis receiving spironolactone

International Nuclear Information System (INIS)

Abbas, Z.; Mumtaz, K.; Salam, A.; Jafri, W.

2003-01-01

Objective: To evaluate the factors leading to hyperkalemia in patients with cirrhosis receiving spironolactone. Results: Patients with hyperkalemia (K>5 mmol/l) had higher blood urea nitrogen, serum creatinine and bilirubin levels (p=0.004, 0.001 and 0.044 respectively). Their serum sodium and albumin levels were lower (p=0.000 and 0.017 respectively). They had advanced cirrhosis with high Pugh score (p=0.003). These patients were on higher dose of spironolactone (p=0.001). Multivariate analysis showed that dose of spironolactone > 100 mg/day, serum creatinine >1.3 mg/dl, persistence of ascites and edema, and female gender were important predictors of development of hyperkalemia. Conclusion: Patients with cirrhosis receiving high dose of the diuretic, having edema, ascites and high serum creatinine are at the greater risk of developing hyperkalemia during spironolactone therapy. (author)

An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving ...

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investigation was a prospective study that was conducted in cancer patients receiving Inj. Doxorubicin .... patients. Pre-Chem o. I - Cycle. II - Cycle III - Cycle. IV - Cycle. 0. 1. 2. 3. 4 .... vitamin E, vitamin C, vitamin A, antioxidant components.

Assessing Selenium, Manganese, and Iodine Status in Pediatric Patients Receiving Parenteral Nutrition.

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Johnsen, Jacob Clarke; Reese, Susan Anne; Mackay, Mark; Anderson, Collin R; Jackson, Daniel; Paul, Irasema Libertad

2017-08-01

Pediatric patients who are receiving parenteral nutrition (PN) unsupplemented with trace minerals can become deficient. Due to shortages in trace mineral products and the 2004 American Society for Parenteral and Enteral Nutrition report stating that individualized trace element supplementation may be warranted, a review was conducted concerning the trace minerals selenium (Se), manganese (Mn), and iodine (I). A retrospective review of pediatric patients receiving PN that contained Se and Mn was conducted to determine if a difference existed between them and patients receiving PN without Se and Mn. Statistical analysis was done to assess a difference between trace mineral levels and the time to deficiency between supplemented and unsupplemented patients. Unsupplemented I patients had urine I levels assessed to determine deficiencies in patients receiving PN. Plasma Se levels were measured at a mean of 20 days for supplemented patients (n = 131) and 19 days for nonsupplemented patients (n = 57) with no difference between groups ( P = .2973). Plasma Mn levels were measured at a mean of 28 days, showing no statistical difference ( P = .721). Of the 177 nonsupplemented I patients, 74% demonstrated I deficiencies without supplementation. Time to the development of a Se, Mn, or I deficiency is important to guide supplementation of exclusive PN in children when trace mineral products are short in supply. Our retrospective experience supports assessment of the trace minerals Se at 21 days and Mn at 30 days. It also suggests that some pediatric patients receiving PN are deficient in I.

Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation.

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Na, Gun Hyung; Hong, Tae Ho; You, Young Kyoung; Kim, Dong Goo

2016-07-07

To evaluated patterns and outcomes of hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT). From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54 (18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mTOR inhibitor. The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence < 12 mo (P = 0.048), multiple recurrences at HCC recurrence (P = 0.038), and palliative treatment for recurrent tumors (P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showed survival benefits in the palliative treatment group (P = 0.005). Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an mTOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group.

Quality of life of lung cancer patients receiving outpatient chemotherapy

OpenAIRE

MATSUDA, AYAKO; KOBAYASHI, MIKA; SAKAKIBARA, YUMI; TAMAOKA, MEIYO; FURUIYE, MASASHI; INASE, NAOHIKO; MATSUSHIMA, EISUKE

2011-01-01

An increasing number of cancer patients receive outpatient chemotherapy as an alternative to inpatient chemotherapy. The aim of this study was to investigate whether quality of life (QOL) during outpatient chemotherapy was better than QOL prior to hospital discharge, and to explore possible related factors prior to hospital discharge that affected the QOL of lung cancer patients who received outpatient chemotherapy. Lung cancer inpatients who were scheduled for outpatient chemotherapy were as...

Assessment of psychological responses in patients about to receive radiotherapy

International Nuclear Information System (INIS)

Karasawa, Kumiko; Horikawa, Naoshi; Kawase, Eri

2005-01-01

Radiotherapy is considered to be associated with psychological distress. We assessed the mental status, anxiety, and the factors associated with these in cancer patients about to receive radiotherapy. Hospitalized patients about to receive radiotherapy participated. Psychological status was assessed by a psychiatrist, based on interview about the type of anxiety related to cancer or radiotherapy as well as self-rating questionnaires. Eligible data were collected from 94 patients. The incidence of mental disorders was 20%. The total mood disturbance scores were significantly higher in patients with poor performance status. The most common type of anxiety regarding radiotherapy was acute adverse effect, and the predictors were palliative treatment and living alone. Mental disorders, mood disturbance, and anxiety in patients cannot be neglected in radiation oncology practice. Especially careful attention should be paid to patients with these predictive factors. (author)

Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia.

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Stankowicz, Matthew; Banaszynski, Megan; Crawford, Russell

2018-01-01

Cryptococcal infections are responsible for significant morbidity and mortality in immunocompromised patients. Reports of these infections in patients on small molecular kinase inhibitors have not been widely reported in clinical trials. We describe one case of cryptococcal meningoencephalitis and one case of cryptococcal pneumonia in two patients who were receiving ibrutinib for chronic lymphocytic leukemia. Despite different sites of cryptococcal infection, both patients had similar presentations of acute illness. Patient 1 was worked up for health care-associated pneumonia, as well as acute sinusitis prior to the diagnosis of cryptococcal meningoencephalitis. He also had a more complex past medical history than patient 2. Patient 2 developed atrial fibrillation from ibrutinib prior to admission for presumed health care-associated pneumonia. Cryptococcal antigen testing was done sooner in this patient due to patient receiving high-dose steroids for the treatment of underlying hemolytic anemia. We conclude that patients who develop acute illness while receiving ibrutinib should be considered for cryptococcal antigen testing.

An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving ...

African Journals Online (AJOL)

Background: Hepatic dysfunction in the cancer unit has a significant impact on patient outcomes. The therapeutic application of anthracycline antibiotics are limited by side‑effects mainly myelosuppression, chronic cardiotoxicity, and hepatotoxicity. Aim: To assess the risk of Hepatotoxicity in breast cancer patients receiving ...

Out-of-hospital mortality among patients receiving methadone for noncancer pain.

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Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Cooper, William O; Hall, Kathi; Stein, C Michael

2015-03-01

Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias. To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate. A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32 742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients' median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively. The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital. There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P = .046) relative to a comparable dose of morphine SR (methadone in this retrospective cohort study, even for low doses, supports recommendations that it should not be a drug of first choice for

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2.

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Sun, Shaofeng; He, Zuopeng; Huang, Mindong; Wang, Ningning; He, Zongzhong; Kong, Xiangkai; Yao, Jianwen

2018-04-03

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-Raf V600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-Raf V600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC 50 of 21 nM, 27 nM and 17 nM, B-Raf V600E with IC 50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC 50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay. Copyright © 2018 Elsevier Ltd. All rights reserved.

Medical treatment of hepatocellular carcinoma.

Science.gov (United States)

Granito, Alessandro; Bolondi, Luigi

2009-12-16

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and the third leading cause of cancer-related deaths worldwide. Cirrhosis, most often due to viral hepatitis, is the predominant risk factors for HCC and geographical differences in both risk factors and incidence are largely due to epidemiological variations in hepatitis B and C infection. Hepatic function is a relevant parameter in selecting therapy in HCC. The current clinical classification of HCC split patients into 5 stages, with a specific treatment schedule for any stage. As patients with early stages can receive curative treatments, such as surgical resection, liver transplantation or local ablation, surveillance program in high-risk populations has become mandatory. Sorafenib, a multikinase inhibitor, has recently shown survival benefits in patients at advanced stage of disease. Hopefully, new molecular targeted therapies and their combination with sorafenib or interventional and surgical procedures, should expand the therapeutic armamentarium against HCC.

A new patient-focused approach to the treatment of metastatic renal cell carcinoma: establishing customized treatment options.

Science.gov (United States)

Bellmunt, Joaquim; Eisen, Tim; Szczylik, Cezary; Mulders, Peter; Porta, Camillo

2011-04-01

What's known on the subject? and What does the study add? • Six targeted agents--sorafenib, sunitinib, pazopanib, bevacizumab, temsirolimus and everolimus--have been approved for the treatment of advanced renal cell carcinoma (RCC) based on evidence from large randomized controlled trials (RCTs). However, no head-to-head trials have been conducted to evaluate the relative efficacy of these agents in this setting. • Patient populations included in clinical trials do not accurately reflect the wider population of patients with RCC, as certain subgroups, such as the elderly or those with co-morbidities, are typically under-represented. • The optimum choice of therapy should be based on patient characteristics, nature of disease, and history and aims of therapy; however, there is currently no clear guidance for physicians in this decision-making process. • A patient-focussed schema has been developed that acknowledges nine different patient-, disease-, and treatment-related factors relevant to clinical decision-making, and provides a visual indication of the strength of evidence with which a particular agent can be recommended for use in specific subgroups. • To demonstrate the applicability of this tool, a review of all available evidence (published articles, congress presentations and personal communications) for sorafenib in RCC was conducted by a panel of experts, findings from which showed that sorafenib can be recommended for use in various subgroups of differing age, prognosis, performance status, tumour burden and distribution, treatment history and co-morbidity. • This patient-focussed approach has broad application and can be used to assess other agents and tumour types. Randomized controlled trials (RCTs) show that six targeted agents--sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib--improve outcome in advanced renal cell carcinoma (RCC). The populations enrolled in the pivotal phase III studies differed, and, to date

Fosaprepitant-induced phlebitis: a focus on patients receiving doxorubicin/cyclophosphamide therapy.

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Leal, A D; Kadakia, K C; Looker, S; Hilger, C; Sorgatz, K; Anderson, K; Jacobson, A; Grendahl, D; Seisler, D; Hobday, T; Loprinzi, Charles L

2014-05-01

The purpose of this study was to investigate the incidence of fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin/cyclophosphamide (AC) chemotherapy. A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC from January 2011 to April 2012. Data collected included baseline demographics, antiemetic regimen, documentation of ISAEs, and type of intravenous (IV) access. Descriptive statistics (mean and standard deviation or percentages) were summarized overall, by type of IV access and initial antiemetic given. Among the 148 patients included in this analysis, 98 initially received fosaprepitant and 44 received aprepitant. The incidence of ISAEs associated with fosaprepitant administration was 34.7 % (n=34), while the incidence of aprepitant-associated ISAEs was 2.3 % (n=1). All ISAEs were associated with peripheral IV access. The most commonly reported ISAEs were infusion site pain (n=26), erythema (n=22), swelling (n=12), superficial thrombosis (n=8), infusion site hives (n=5), and phlebitis/thrombophlebitis (n=5). Twenty-six patients experienced more than one type of ISAE. The incidence and severity of ISAEs associated with fosaprepitant administration among a group of patients receiving AC chemotherapy are significant and appreciably higher than what has been previously reported.

Sugammadex Improves Neuromuscular Function in Patients Receiving Perioperative Steroids.

Science.gov (United States)

Ozer, A B; Bolat, E; Erhan, O L; Kilinc, M; Demirel, I; Toprak, G Caglar

2018-02-01

Sugammadex has steroid-encapsulating effect. This study was undertaken to assess whether the clinical efficacy of sugammadex was altered by the administration of steroids. Sixty patients between 18 and 60 years of age with the American Society of Anesthesiologists I-IV and undergoing elective direct laryngoscopy/biopsy were included in this study. Patients were assigned to two groups based on the intraoperative steroid use: those who received steroid (Group S) and who did not (Group C). After standard general anesthesia, patients were monitored with the train of four (TOF) monitoring. The preferred steroid and its dose, timing of steroid administration, and TOF value before and after sugammadex as well as the time to recovery (TOF of 0.9) were recorded. SPSS software version 17.0 was used for statistical analysis. There is no statistically significant difference between groups in terms of age, gender, preoperative medication use, and TOF ratio just before administering sugammadex. The reached time to TOF 0.9 after sugammadex administration was significantly shorter in Group S than Group C (P sugammadex as well as the dose of sugammadex in those who received prednisolone; time to TOF 0.9 was higher in prednisolone receivers as compared to dexamethasone receivers (P sugammadex was found, in contrast with what one expect. Further studies are required to determine the cause of this effect which is probably due to a potential interaction between sugammadex and steroids.

Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A treatment

Science.gov (United States)

We sought to determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A. DESIGN: Randomized, controlled, double-masked trial of 225 nonsmoking patients, aged 18 to 60 years, evaluated over a 4-year interval. Patients received ...

Increased Bowel Toxicity in Patients Treated With a Vascular Endothelial Growth Factor Inhibitor (VEGFI) After Stereotactic Body Radiation Therapy (SBRT)

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Barney, Brandon M., E-mail: barney.brandon@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Markovic, Svetomir N. [Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Laack, Nadia N.; Miller, Robert C.; Sarkaria, Jann N. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Macdonald, O. Kenneth [Therapeutic Radiologists Incorporated, Kansas City, Kansas (United States); Bauer, Heather J.; Olivier, Kenneth R. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

2013-09-01

Purpose: Gastrointestinal injury occurs rarely with agents that affect the vascular endothelial growth factor receptor and with abdominal stereotactic body radiation therapy (SBRT). We explored the incidence of serious bowel injury (SBI) in patients treated with SBRT with or without vascular endothelial growth factor inhibitor (VEGFI) therapy. Methods and Materials: Seventy-six patients with 84 primary or metastatic intra-abdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Of the patients, 20 (26%) received VEGFI within 2 years after SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The incidence of SBI (Common Terminology Criteria for Adverse Events, version 4.0, grade 3-5 ulceration or perforation) after SBRT was obtained, and the relationship between SBI and VEGFI was examined. Results: In the combined population, 7 patients (9%) had SBI at a median of 4.6 months (range, 3-17 months) from SBRT. All 7 had received VEGFI before SBI and within 13 months of completing SBRT, and 5 received VEGFI within 3 months of SBRT. The 6-month estimate of SBI in the 26 patients receiving VEGFI within 3 months of SBRT was 38%. No SBIs were noted in the 63 patients not receiving VEGFI. The log–rank test showed a significant correlation between SBI and VEGFI within 3 months of SBRT (P=.0006) but not between SBI and radiation therapy bowel dose (P=.20). Conclusions: The combination of SBRT and VEGFI results in a higher risk of SBI than would be expected with either treatment independently. Local therapies other than SBRT may be considered if a patient is likely to receive a VEGFI in the near future.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Malignancies.

Science.gov (United States)

Varughese, Tilly; Taur, Ying; Cohen, Nina; Palomba, M Lia; Seo, Susan K; Hohl, Tobias M; Redelman-Sidi, Gil

2018-03-02

Ibrutinib is a Bruton's tyrosine kinase inhibitor that is used for the treatment of lymphoid malignancies, including chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia and mantle cell lymphoma (MCL). Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. We reviewed the electronic medical records of patients with lymphoid malignancies at Memorial Sloan Kettering Cancer Center who received ibrutinib during a five-year period from January 1, 2012 to December 31, 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by univariate and multivariate analyses. 378 patients with lymphoid malignancies who received ibrutinib were analyzed. The most common underlying malignancies were CLL and MCL. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Of these, 23 (53.5%) developed invasive bacterial infections, and 16 (37.2%) developed invasive fungal infections (IFI). The majority of those who developed IFI on ibrutinib therapy (62.5%) lacked classical clinical risk factors for fungal infection (i.e., neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in six of the 43 patients (14%). Patients with lymphoid malignancies receiving ibrutinib treatment are at risk for serious infections, including IFI.

Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment.

Science.gov (United States)

Riley, Philip; McCabe, Martin G; Glenny, Anne-Marie

2016-10-01

In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT).

[Cognitive plasticity in Alzheimer's disease patients receiving cognitive stimulation programs].

Science.gov (United States)

Zamarrón Cassinello, Ma Dolores; Tárraga Mestre, Luis; Fernández-Ballesteros, Rocío

2008-08-01

The main purpose of this article is to examine whether cognitive plasticity increases after cognitive training in Alzheimer's disease patients. Twenty six patients participated in this study, all of them diagnosed with mild Alzheimer's disease, 17 of them received a cognitive training program during 6 months, and the other 9 were assigned to the control group. Participants were assigned to experimental or control conditions for clinical reasons. In order to assess cognitive plasticity, all patients were assessed before and after treatment with three subtests from the "Bateria de Evaluación de Potencial de Aprendizaje en Demencias" [Assessment Battery of Learning Potential in Dementia] (BEPAD). After treatment, Alzheimer's disease patients improved their performance in all the tasks assessing cognitive plasticity: viso-spatial memory, audio-verbal memory and verbal fluency. However, the cognitive plasticity scores of the patients in the control group decreased. In conclusion, this study showed that cognitive stimulation programs can improve cognitive functioning in mildly demented patients, and patients who do not receive any cognitive interventions may reduce their cognitive functioning.

Anxiety, depression in patients receiving chemotherapy for solid tumors

International Nuclear Information System (INIS)

Mansoor, S.; Jehangir, S.

2015-01-01

To determine the frequency of anxiety and depression in patients undergoing chemotherapy for solid tumors using Hospital Anxiety Depression Scale (HADS). Study Design: Cross sectional descriptive study. Place and Duration of Study: Out-patient department of Armed Forces Institute of Mental Health, Rawalpindi from June 2011 to December 2011. Methodology: Consecutive non probability sampling technique was used to select patients of age (25-70 years), male or female, who had received atleast 03 cycles of chemotherapy for solid tumors. Those with history of prior psychiatric illness, current use of psychotropic medication or psychoactive substance use, and any major bereavement in past one year were excluded from the study. After taking informed consent, relevant socio- demographic data was collected and HADS was administered. HADS-A cut off score of 7 was taken as significant anxiety while a HADS-D cut off score of 7 was taken as significant depression. Results: The total number of participants was 209. The mean age of patients was 42.9 years, with 55.5% males and 44.5% females. Overall 33/209 (15.8%) patients had anxiety while 56/209 (26.8%) were found to have depression. There was a higher frequency of anxiety and depression in younger patients (less than age 40 years), females, patients who were single or divorced, and patients receiving chemotherapy for pancreatic carcinoma. Conclusion: Patients undergoing chemotherapy suffer from considerable levels of anxiety and depression, thus highlighting the need for specialized interventions. (author)

Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy.

Science.gov (United States)

Kunka, Megan E; Cady, Elizabeth A; Woo, Heejung C; Thompson Bastin, Melissa L

2015-01-01

Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours), which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient's actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure.

Alcohol in Primary Care. Differential characteristics between alcohol-dependent patients who are receiving or not receiving treatment.

Science.gov (United States)

Barrio, Pablo; Miquel, Laia; Moreno-España, Jose; Martínez, Alicia; Ortega, Lluisa; Teixidor, Lidia; Manthey, Jakob; Rehm, Jürgen; Gual, Antoni

2016-03-02

primary health care services for other reasons. The aim of the present study is to describe the differential characteristics of AD patients in primary care, distinguishing between those who receive treatment and those who do not, and their reasons for not seeking it. In a cross-sectional study patients were evaluated by their general practitioner (GP) and interviewed by a member of the research team. Sociodemographic, diagnostic and clinical data were collected. From 1,372 patients interviewed in Catalonia, 118 (8.6%) were diagnosed as AD. These patients showed a lower socioeconomic status (48.3% vs 33.3%, odds ratio 2.02), higher unemployment rates (32.2% vs 19.2 %, odds ratio 2.11), and greater psychological distress and disability. Patients with AD receiving treatment (16.9%), were older (44 vs 36 years of age), reported higher unemployment rates (66% vs 25.5%, odds ratio 6.32) and higher daily alcohol consumption (61.5 vs 23.7 grams), suggesting a more advanced disease. Patients with AD in general showed a higher degree of comorbidity compared to other patients, with patients in treatment showing the most elevated level. The main reasons given for not seeking treatment were shame, fear of giving up drinking and barriers to treatment. Taken together, the data suggest the need to implement earlier strategies for the detection and treatment of AD.

Evaluation of the efficiency of combination palliative treatment in patients with metastatic clear-cell renal cell carcinoma

Directory of Open Access Journals (Sweden)

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.

Peptic ulcer disease and other complications in patients receiving dexamethasone palliation for brain metastasis

International Nuclear Information System (INIS)

Penzner, R.D.; Lipsett, J.A.

1982-01-01

A retrospective analysis was done of 106 patients who received radiation therapy for brain metastasis. Dexamethasone therapy was instituted in 97 patients. Peptic ulcer disease developed in 5 of 89 patients (5.6 percent) who received a dosage of at least 12 mg a day, but did not occur in patients who received a lower dose or in those who did not receive steroids. The interval between institution of dexamethasone therapy and the development of peptic ulcer disease ranged from three to nine weeks. Two patients had perforated ulcers, one of whom required surgical resection. Peptic ulcer disease contributed to the general deterioration and death of three of the five patients. Overall, in 14 of the 89 patients (15.7 percent) a complication of steroid therapy developed in the form of peptic ulcer disease, steroid myopathy or diabetes mellitus (or a combination of these)

Thalidomide for control delayed vomiting in cancer patients receiving chemotherapy

International Nuclear Information System (INIS)

Han, Z.; Sun, X.; Du, X.

2016-01-01

To explore the efficacy and safety of thalidomide for the treatment of delayed vomiting, induced by chemotherapy in cancer patients. Study Design: Randomized, double-blind controlled study. Place and Duration of Study: The Oncology Department of Affiliated Hospital of Xuzhou Medical University, Jiangsu Xuzhou, China, from January 2012 to January 2014. Methodology: A total of 78 cancer patients, who had delayed vomiting observed from 24 hours to 1 week after chemotherapy, were included in the study. Patients were divided in a treatment group (40 patients, 51.28%) and a control group (38 patients, 48.71%). The treatment group received thalidomide at an oral dose of 100 mg per night; 50 mg was added daily up to a dose of 200 mg per night, if the curative effect was suboptimal and the medicine was tolerated. Both the treatment and the control groups received a drip of 10 mg azasetron 30 minutes before chemotherapy. The control group only proportions of antiemetic effects and adverse reactions were compared using the ?2 test. Antiemetic effects and adverse reactions were assessed from Odds Ratios (OR) with 95% Confidence Intervals(95% CI). Results: The effective control rate of delayed vomiting in the treatment group was significantly higher than that in the control group (?2=5.174, p=0.023). No significant difference was found between the two groups in other adverse effects of chemotherapy. Karnofsky scores or the overall self-evaluation of the patients (p>0.05). Conclusion: Thalidomide can effectively control the delayed vomiting of cancer patients receiving chemotherapy and the adverse reactions of the agent can be tolerated.

Impact on survival of warfarin in patients with pulmonary arterial hypertension receiving subcutaneous treprostinil.

Science.gov (United States)

Ascha, Mona; Zhou, Xuan; Rao, Youlan; Minai, Omar A; Tonelli, Adriano R

2017-10-01

Anticoagulation is a common treatment modality in patients with pulmonary arterial hypertension (PAH). Further studies are needed to appropriately assess the risk/benefit ratio of anticoagulation, particularly in PAH patients receiving PAH-specific therapies. We use observational long-term data on PAH patients treated with subcutaneous (SQ) treprostinil from a large open-label study. Patients were followed for up to 4 years. The use of warfarin and bleeding events were recorded. At total of 860 patients (age [mean±SD] 46±15 years, 76% female, 83% Caucasian, 49% idiopathic PAH, and 76% New York Heart Association [NYHA] functional class III) were included. All patients received SQ treprostinil (15% also other pulmonary hypertension [PH]-therapies) and 590 (69%) received warfarin during the study. The proportions of women, African American, and idiopathic pulmonary hypertension (IPAH) patients were higher in the group receiving warfarin. A higher proportion of patients with congenital heart disease and portopulmonary hypertension did not receive warfarin. There were no differences in unadjusted long-term survival between PAH patients receiving warfarin or not (log-rank test, P value=.69), even when only considering idiopathic PAH (P=.32). In addition, no difference was found in adjusted long-term survival both in PAH (P=.84) and idiopathic PAH patients (P=.44) based on the use of warfarin. Furthermore, no survival difference based on the use of warfarin were noted between propensity score-matched PAH patients (P=.37). Long-term anticoagulation with warfarin was not associated with any significant effect on survival in PAH or idiopathic PAH patients treated with SQ treprostinil. © 2017 John Wiley & Sons Ltd.

Metabolic Profiling of Impaired Cognitive Function in Patients Receiving Dialysis

OpenAIRE

Kurella Tamura, Manjula; Chertow, Glenn M.; Depner, Thomas A.; Nissenson, Allen R.; Schiller, Brigitte; Mehta, Ravindra L.; Liu, Sai; Sirich, Tammy L.

2016-01-01

Retention of uremic metabolites is a proposed cause of cognitive impairment in patients with ESRD. We used metabolic profiling to identify and validate uremic metabolites associated with impairment in executive function in two cohorts of patients receiving maintenance dialysis. We performed metabolic profiling using liquid chromatography/mass spectrometry applied to predialysis plasma samples from a discovery cohort of 141 patients and an independent replication cohort of 180 patients partici...

Antibiotic dosing in critically ill patients receiving CRRT: underdosing is overprevalent.

Science.gov (United States)

Lewis, Susan J; Mueller, Bruce A

2014-01-01

Published CRRT drug dosing algorithms and other dosing guidelines appear to result in underdosed antibiotics, leading to failure to attain pharmacodynamic targets. High mortality rates persist with inadequate antibiotic therapy as the most important risk factor for death. Reasons for unintended antibiotic underdosing in patients receiving CRRT are many. Underdosing may result from lack of the recognition that better hepatic function in AKI patients yields higher nonrenal antibiotic clearance compared to ESRD patients. Other factors include the variability in body size and fluid composition of patients, the serious consequence of delayed achievement of antibiotic pharmacodynamic targets in septic patients, potential subtherapeutic antibiotic concentrations at the infection site, and the influence of RRT intensity on antibiotic concentrations. Too often, clinicians weigh the benefits of overcautious antibiotic dosing to avoid antibiotic toxicity too heavily against the benefits of rapid attainment of therapeutic antibiotic concentrations in critically ill patients receiving CRRT. We urge clinicians to prescribe antibiotics aggressively for these vulnerable patients. © 2014 Wiley Periodicals, Inc.

Regorafenib for the treatment of unresectable hepatocellular carcinoma.

Science.gov (United States)

Rimassa, Lorenza; Pressiani, Tiziana; Personeni, Nicola; Santoro, Armando

2017-07-01

Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC) and well preserved liver function. However, until recent approval of regorafenib by the Food and Drug Administration (FDA), no effective therapeutic options were available for patients resistant to sorafenib. Areas covered: The present article reviews the preclinical and clinical data of regorafenib, putting them into the context of current and future landscape of treatment options for patients with HCC. Recently, the randomized, placebo-controlled, Phase III RESORCE trial, demonstrated a statistically and clinically significant increase in overall survival from 7.8 months with placebo to 10.6 months with regorafenib in patients progressing on sorafenib. Furthermore, the study showed a significant improvement in all the other efficacy endpoints. Main adverse events were hypertension, hand-foot skin reaction, fatigue and diarrhea, with no negative impact on quality of life. Expert commentary: Regorafenib is a recently approved treatment option for HCC patients who have been previously treated with sorafenib. The RESORCE trial demonstrates the beneficial effect of a sequential approach involving two multikinase inhibitors, namely sorafenib and regorafenib, whose antitumor activity extends beyond their antiangiogenic functions.

Identification of a unique hepatocellular carcinoma line, Li-7, with CD13(+) cancer stem cells hierarchy and population change upon its differentiation during culture and effects of sorafenib.

Science.gov (United States)

Yamada, Takeshi; Abei, Masato; Danjoh, Inaho; Shirota, Ryoko; Yamashita, Taro; Hyodo, Ichinosuke; Nakamura, Yukio

2015-04-11

Cancer stem cell (CSC) research has highlighted the necessity of developing drugs targeting CSCs. We investigated a hepatocellular carcinoma (HCC) cell line that not only has CSC hierarchy but also shows phenotypic changes (population changes) upon differentiation of CSC during culture and can be used for screening drugs targeting CSC. Based on a hypothesis that the CSC proportion should decrease upon its differentiation into progenitors (population change), we tested HCC cell lines (HuH-7, Li-7, PLC/PRF/5, HLF, HLE) before and after 2 months culture for several markers (CD13, EpCAM, CD133, CD44, CD90, CD24, CD166). Tumorigenicity was tested using nude mice. To evaluate the CSC hierarchy, we investigated reconstructivity, proliferation, ALDH activity, spheroid formation, chemosensitivity and microarray analysis of the cell populations sorted by FACS. Only Li-7 cells showed a population change during culture: the proportion of CD13 positive cells decreased, while that of CD166 positive cells increased. The high tumorigenicity of the Li-7 was lost after the population change. CD13(+)/CD166(-) cells showed slow growth and reconstructed the bulk Li-7 populations composed of CD13(+)/CD166(-), CD13(-)/CD166(-) and CD13(-)/CD166(+) fractions, whereas CD13(-)/CD166(+) cells showed rapid growth but could not reproduce any other population. CD13(+)/CD166(-) cells showed high ALDH activity, spheroid forming ability and resistance to 5-fluorouracil. Microarray analysis demonstrated higher expression of stemness-related genes in CD166(-) than CD166(+) fraction. These results indicated a hierarchy in Li-7 cells, in which CD13(+)/CD166(-) and CD13(-)/CD166(+) cells serve as slow growing CSCs and rapid growing progenitors, respectively. Sorafenib selectively targeted the CD166(-) fraction, including CD13(+) CSCs, which exhibited higher mRNA expression for FGF3 and FGF4, candidate biomarkers for sorafenib. 5-fluorouracil followed by sorafenib inhibited the growth of bulk Li-7

Antidepressant Medication Management among Older Patients Receiving Home Health Care

Science.gov (United States)

Bao, Yuhua; Shao, Huibo; Bruce, Martha L.; Press, Matthew J.

2014-01-01

Objective Antidepressant management for older patients receiving home health care (HHC) may occur through two pathways: nurse-physician collaboration (without patient visits to the physician) and physician management through office visits. This study examines the relative contribution of the two pathways and how they interplay. Methods Retrospective analysis was conducted using Medicare claims of 7,389 depressed patients 65 or older who received HHC in 2006–7 and who possessed antidepressants at the start of HHC. A change in antidepressant therapy (vs. discontinuation or refill) was the main study outcome and could take the form of a change in dose, switch to a different antidepressant, or augmentation (addition of a new antidepressant). Logistic regressions were estimated to examine how use of home health nursing care, patient visits to physicians, and their interactions predict a change in antidepressant therapy. Results About 30% of patients experienced a change in antidepressants versus 51% who refilled and 18% who discontinued. Receipt of mental health specialty care was associated with a statistically significant, 10–20 percentage-point increase in the probability of antidepressant change; receipt of primary care was associated with a small and statistically significant increase in the probability of antidepressant change among patients with no mental health specialty care and above-average utilization of nursing care. Increased home health nursing care in absence of physician visits was not associated with increased antidepressant change. Conclusions Active antidepressant management resulting in a change in medication occurred on a limited scale among older patients receiving HHC. Addressing knowledge and practice gaps in antidepressant management by primary care providers and home health nurses and improving nurse-physician collaboration will be promising areas for future interventions. PMID:25158915

Validating Appetite Assessment Tools among Patients Receiving Hemodialysis

Science.gov (United States)

Molfino, Alessio; Kaysen, George A.; Chertow, Glenn M.; Doyle, Julie; Delgado, Cynthia; Dwyer, Tjien; Laviano, Alessandro; Fanelli, Filippo Rossi; Johansen, Kirsten L.

2016-01-01

Objective To test the performance of appetite assessment tools among patients receiving hemodialysis. Design Cross-sectional. Setting Seven dialysis facilities in Northern California. Subjects 221 patients receiving hemodialysis. Intervention We assessed five appetite assessment tools [self-assessment of appetite, subjective assessment of appetite, visual analogue scale (VAS), Functional Assessment of Anorexia/Cachexia Therapy (FAACT) score and the Anorexia Questionnaire (AQ)]. Main outcome measures Reported food intake, normalized protein catabolic rate (nPCR), and change in body weight were used as criterion measures, and we assessed associations among the appetite tools and biomarkers associated with nutrition and inflammation. Patients were asked to report their appetite and the percentage of food eaten (from 0% to 100%) during the last meal compared to usual intake. Results Fifty-eight (26%) patients reported food intake ≤50% (defined as poor appetite). The prevalence of anorexia was 12% by self-assessment of appetite, 6% by subjective assessment of appetite, 24% by VAS, 17% by FAACT score, and 12% by AQ. All tools were significantly associated with food intake ≤50% (pappetite. The FAACT score and the VAS had the strongest association with food intake ≤50% (c-statistic 0.80 and 0.76). Patients with food intake ≤50% reported weight loss more frequently than patients without low intake (36% vs 22%) and weight gain less frequently (19% vs 35%; p=0.03). nPCR was lower among anorexic patients based on the VAS (1.1 ± 0.3 vs 1.2 ± 0.3, p=0.03). Ln IL-6 correlated inversely with food intake (p=0.03), but neither IL-6 nor CRP correlated with any of the appetite tools. Furthermore, only the self-assessment of appetite was significantly associated with serum albumin (p=0.02), prealbumin (p=0.02) and adiponectin concentrations (p=0.03). Conclusions Alternative appetite assessment tools yielded widely different estimates of the prevalence of anorexia in

Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy.

Science.gov (United States)

Dangsuwan, Penkae; Manchana, Tarinee

2010-03-01

To compare the incidence of repeated red blood cell (RBC) transfusion in anemic gynecologic cancer patients receiving platinum-based chemotherapy comparing intravenous and oral iron. Forty-four anemic gynecologic cancer patients (hemoglobin level below 10 mg/dl) who required RBC transfusion were stratified and randomized according to baseline hemoglobin levels and chemotherapy regimen. Study group received 200 mg of intravenous iron sucrose and control group received oral ferrous sulphate 600 mg/day. RBC transfusion requirement in the consecutive cycle of chemotherapy was the primary outcome. Quality of life was evaluated by validated Thai version of the Functional Assessment of Cancer Therapy-Anemia (FACT-An). In a total of the 44 patients, there were 22 patients in each group. Five patients (22.7%) in the study group and 14 patients (63.6%) in the control group required RBC transfusion in consecutive cycle of chemotherapy (p=0.01). No significant difference in baseline hemoglobin and hematocrit levels was demonstrated in both groups. Significantly higher mean hemoglobin and hematocrit levels after treatment were reported in the study group (10.0+/-0.8 g/dl and 30.5+/-2.4%) than the control group (9.5+/-0.9 g/dl and 28.4+/-2.7%). No significant change of total FACT-An scores was noted between before and after treatment in both groups. No serious adverse events were reported and there was no significant difference among adverse events between both groups. Intravenous iron is an alternative treatment for anemic gynecologic cancer patients receiving platinum-based chemotherapy and reduces the incidence of RBC transfusion without serious adverse events.

Symptomatic burden of COPD for patients receiving dual or triple therapy

Directory of Open Access Journals (Sweden)

Chen S

2018-04-01

Full Text Available Stephanie Chen,1 Mark Small,2 Leandro Lindner,3 Xiao Xu1,4 1Health Economics and Payer Analytics, AstraZeneca, Gaithersburg, MD, USA; 2Respiratory, Adelphi Real World, Bollington, UK; 3Global Payer Evidence and Pricing, AstraZeneca, Cambridge, UK; 4Global Payer Evidence and Pricing, AstraZeneca, Gaithersburg, MD, USA Background: COPD is associated with a large disease burden. The use of dual (two maintenance treatments and triple (combination of any three treatments therapy has shown efficacy for symptom relief; however, some patients with COPD remain symptomatic despite these therapies. This study assessed the scope and magnitude of the symptomatic burden for patients with COPD receiving dual or triple therapy. Patients and methods: Cross-sectional data from three Adelphi COPD surveys (2013–2016 conducted in the USA, Europe, Japan, and China were analyzed for patients with COPD and forced expiratory volume in 1 second ≤65% receiving dual or triple therapy for ≥3 months. Physicians completed clinical and disease characteristic forms for identified patients. Corresponding patients completed questionnaires that included validated survey instruments to assess adherence and symptom impact. Descriptive statistics are reported. Results: Our analysis included 690 patients (mean age 68.2 years; 73.3% male; 41.4% and 58.6% were receiving dual and triple therapy, respectively. Most patients had dyspnea with substantial disability (modified Medical Research Council dyspnea scale rating ≥2, 56.3%; large health status impairment from symptoms, COPD Assessment Test score >20, 64.4%. A large symptom burden was observed, even for patients highly adherent to treatment (Morisky Medication Adherence Scale 8, 30.3% [185/612], of whom 62.1% still had a COPD Assessment Test score >20. Sensitivity analyses of patients regardless of their forced expiratory volume in 1 second status and of those receiving treatment for >6 months both reported similar results

Plaque, caries level and oral hygiene habits in young patients receiving orthodontic treatment

DEFF Research Database (Denmark)

Martignon, S; Ekstrand, K R; Lemos, M I

2010-01-01

To assess plaque, caries, and oral hygiene habits amongst patients receiving fixed-orthodontic treatment at the Dental-Clinic, Universidad-El-Bosque, Bogotá, Colombia.......To assess plaque, caries, and oral hygiene habits amongst patients receiving fixed-orthodontic treatment at the Dental-Clinic, Universidad-El-Bosque, Bogotá, Colombia....

Prevalence and Contents of Advance Directives of Patients with ESRD Receiving Dialysis.

Science.gov (United States)

Feely, Molly A; Hildebrandt, Daniel; Edakkanambeth Varayil, Jithinraj; Mueller, Paul S

2016-12-07

ESRD requiring dialysis is associated with increased morbidity and mortality rates, including increased rates of cognitive impairment, compared with the general population. About one quarter of patients receiving dialysis choose to discontinue dialysis at the end of life. Advance directives are intended to give providers and surrogates instruction on managing medical decision making, including end of life situations. The prevalence of advance directives is low among patients receiving dialysis. Little is known about the contents of advance directives among these patients with advance directives. We retrospectively reviewed the medical records of all patients receiving maintenance in-center hemodialysis at a tertiary academic medical center between January 1, 2007 and January 1, 2012. We collected demographic data, the prevalence of advance directives, and a content analysis of these advance directives. We specifically examined the advance directives for instructions on management of interventions at end of life, including dialysis. Among 808 patients (mean age of 68.6 years old; men =61.2%), 49% had advance directives, of which only 10.6% mentioned dialysis and only 3% specifically addressed dialysis management at end of life. Patients who had advance directives were more likely to be older (74.5 versus 65.4 years old; Phydration (34.3%), and pain management (43.4%) than dialysis (10.6%). Although one-half of the patients receiving dialysis in our study had advance directives, end of life management of dialysis was rarely addressed. Future research should focus on improving discernment and documentation of end of life values, goals, and preferences, such as dialysis-specific advance directives, among these patients. Copyright © 2016 by the American Society of Nephrology.

Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy

Directory of Open Access Journals (Sweden)

Megan E. Kunka

2015-01-01

Full Text Available Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours, which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient’s actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure.

Genetic and Non-genetic Factors Associated WithConstipation in Cancer Patients Receiving Opioids

OpenAIRE

Laugsand, Eivor Alette; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-01-01

Objectives: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Methods: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation a...

[Pharmaceutical care of patients with rheumatoid and psoriatic arthritis receiving etanercept].

Science.gov (United States)

Romero Crespo, I; Antón Torres, R; Borrás Blasco, J; Navarro Ruiz, A

2005-01-01

To evaluate a pharmaceutical care protocol for patients with rheumatoid arthritis (RA) or psoriatic arthritis who begin treatment with etanercept with the objective of identifying potential medication-related problems and implementing therapeutic measures to improve the way this drug is used. An observational, prospective, 3-month study of patients with RA receiving etanercept therapy from March to December 2003 was conducted and a pharmaceutical care protocol was set up. During the first visit, a pharmacotherapeutic record was initiated for each patient, including socio-demographic data, personal history, diagnosis, DMARDs (disease-modifying anti-rheumatic drugs) previously received, and concomitant therapies for other underlying conditions. Patients were briefed on dosage, administration route, and potential adverse events both orally and in writing. Correct drug administration and preservation were verified during the second visit, where potential adverse effects were identified, treatment adherence was confirmed, and, if needed, potential drug interactions with other ongoing medications were disclosed. During the third visit, adherence was assessed, adverse events were recorded, and patients evaluated their response to treatment. Fifty patients were included, 40 with a diagnosis of rheumatoid arthritis (80%) and 10 diagnosed with psoriatic arthritis (20%). In all, 72% had received previous treatment with methotrexate (MTX), 40% with leflunomide, 20% with infliximab, 56% with corticoids, 2% with analgesics, 56% with NSAIDs, and 30% with other DMARDs. No significant drug interactions were found. Regarding adherence to treatment, 7.7% of patients skipped one or more doses, with travelling being the most common reason. Adverse events reported included: injection site reaction (27%), headache (7.7%) and nausea (7.7%). At 3 months after treatment onset, a reduction of MTX doses was seen in 18% of patients, of leflunomide dosage in 8%, of corticoids in 18%, of

Management of hepatitis B reactivation in patients receiving cancer chemotherapy

OpenAIRE

Huang, Yi-Wen; Chung, Raymond T.

2012-01-01

Hepatitis B virus (HBV) reactivation is well documented in previously resolved or inactive HBV carriers who receive cancer chemotherapy. The consequences of HBV reactivation range from self-limited conditions to fulminant hepatic failure and death. HBV reactivation also leads to premature termination of chemotherapy or delay in treatment schedules. This review summarizes current knowledge of management of HBV reactivation in patients receiving cancer chemotherapy. HBV surface antigen (HBsAg) ...

A model for predicting skin dose received by patients from an x-ray ...

African Journals Online (AJOL)

Patient dosimetry has raised concern on quality assurance in hospitals. Several organisations and research groups have been advocating ways of minimising radiation dose received by patients in hospitals. In this paper we have shown that it is possible to obtain in a simple way a reasonable estimate of skin dose received ...

Long-term outcomes of patients receiving a massive transfusion after trauma.

Science.gov (United States)

Mitra, Biswadev; Gabbe, Belinda J; Kaukonen, Kirsi-Maija; Olaussen, Alexander; Cooper, David J; Cameron, Peter A

2014-10-01

Resuscitation of patients presenting with hemorrhagic shock after major trauma has evolved to incorporate multiple strategies to maintain tissue perfusion and oxygenation while managing coagulation disorders. We aimed to study changes across time in long-term outcomes in patients with major trauma. A retrospective observational study in a single major trauma center in Australia was conducted. We included all patients with major trauma and massive blood transfusion within the first 24 h during a 6-year period (from 2006 to 2011). The main outcome measures were Glasgow Outcome Score-Extended (GOSE) and work capacity at 6 and 12 months. There were 5,915 patients with major trauma of which 365 (6.2%; 95% confidence interval [95% CI], 5.6 - 6.8) received a massive transfusion. The proportion of major trauma patients receiving a massive transfusion decreased across time from 8.2% to 4.4% (P GOSE at 6 months, and 44% unfavorable GOSE at 12 months. Massive transfusion was independently associated with unfavorable outcomes at 6 months after injury (adjusted odds ratio, 1.56; 95% CI, 1.05 - 2.31) but not at 12 months (adjusted odds ratio, 0.85; 95% CI, 0.72 - 1.01). A significant reduction in massive transfusion rates was observed. Unfavorable long-term outcomes among patients receiving a massive transfusion after trauma were frequent with a substantial proportion of survivors experiencing poor functional status 1 year after injury.

Occupational Therapy and Physiotherapy in Acute Stroke: Do Rural Patients Receive Less Therapy?

Directory of Open Access Journals (Sweden)

Josie Merchant

2016-01-01

Full Text Available Objective. To assess whether acute stroke patients in rural hospitals receive less occupational therapy and physiotherapy than those in metropolitan hospitals. Design. Retrospective case-control study of health data in patients ≤10 days after stroke. Setting. Occupational therapy and physiotherapy services in four rural hospitals and one metropolitan hospital. Participants. Acute stroke patients admitted in one health district. Main Outcome Measures. Frequency and duration of face-to-face and indirect therapy sessions. Results. Rural hospitals admitted 363 patients and metropolitan hospital admitted 378 patients. Mean age was 73 years. Those in rural hospitals received more face-to-face (p>0.0014 and indirect (p=0.001 occupational therapy when compared to those in the metropolitan hospital. Face-to-face sessions lasted longer (p=0.001. Patients admitted to the metropolitan hospital received more face-to-face (p>0.000 and indirect (p>0.000 physiotherapy when compared to those admitted to rural hospitals. Face-to-face sessions were shorter (p>0.000. Almost all were seen within 24 hours of referral. Conclusions. Acute stroke patients in Australian rural hospital may receive more occupational therapy and less physiotherapy than those in metropolitan hospitals. The dose of therapy was lower than recommended, and the referral process may unnecessarily delay the time from admission to a patient’s first therapy session.

Incidence and predictors of Lhermitte’s sign among patients receiving mediastinal radiation for lymphoma

International Nuclear Information System (INIS)

Youssef, Bassem; Shank, JoAnn; Reddy, Jay P.; Pinnix, Chelsea C.; Farha, George; Akhtari, Mani; Allen, Pamela K.; Fanale, Michelle A.; Garcia, John A.; Horace, Patricia H.; Milgrom, Sarah; Smith, Grace Li; Nieto, Yago; Arzu, Isadora; Wang, He; Fowler, Nathan; Rodriguez, Maria Alma; Dabaja, Bouthaina

2015-01-01

To prospectively examine the risk of developing Lhermitte’s sign (LS) in patients with lymphoma treated with modern-era chemotherapy followed by consolidation intensity-modulated radiation therapy. We prospectively interviewed all patients with lymphoma who received irradiation to the mediastinum from July 2011 through April 2014. We extracted patient, disease, and treatment-related variables from the medical records of those patients and dosimetric variables from treatment-planning systems and analyzed these factors to identify potential predictors of LS with Pearson chi-square tests. During the study period 106 patients received mediastinal radiation for lymphoma, and 31 (29 %) developed LS. No correlations were found between LS and any of the variables examined, including total radiation dose, maximum point dose to the spinal cord, volume receiving 105 % of the dose, and volumes receiving 5 or 15 Gy. In this group of patients, treatment with chemotherapy followed by intensity-modulated radiation therapy led to 29 % developing LS; this symptom was independent of radiation dose and seemed to be an idiosyncratic reaction. This relatively high incidence could have resulted from prospective use of a structured interview

The management of metastatic radioiodine-refractory differentiated thyroid cancer requires an integrated approach including both directed and systemic therapies.

Science.gov (United States)

Cooray, Shamil D; Topliss, Duncan J

2017-01-01

A 58-year-old man with metastatic radioiodine-refractory differentiated thyroid cancer (DTC) presented with left thigh and right flank numbness. He had known progressive and widespread bony metastases, for which he received palliative radiotherapy, and multiple bilateral asymptomatic pulmonary metastases. CT scan and MRI of the spine revealed metastases at right T10-L1 vertebrae with extension into the central canal and epidural disease at T10 and T11 causing cord displacement and canal stenosis but retention of spinal cord signal. Spinal surgery was followed by palliative radiotherapy resulting in symptom resolution. Two months later, sorafenib received approval for use in Australia and was commenced and up-titrated with symptomatic management of mild adverse effects. Follow-up CT scan three months after commencement of sorafenib revealed regression of pulmonary metastases but no evident change in most bone metastases except for an advancing lesion eroding into the right acetabulum. The patient underwent a right total hip replacement, intra-lesional curettage and cementing. After six months of sorafenib therapy, CT scanning showed enlarging liver lesions with marked elevation of serum thyroglobulin. Lenvatinib was commenced and sorafenib was ceased. He now has stable disease with a falling thyroglobulin more than 5 years after metastatic radioiodine-refractory DTC was diagnosed. In DTC, 5% of distant metastases become radioiodine-refractory, resulting in a median overall survival of 2.5-3.5 years. Tyrosine kinase inhibitor (TKI) therapy has recently been demonstrated to increase progression-free survival in these patients but poses some unique management issues and is best used as part of an integrated approach with directed therapy. Directed therapies may have greater potential to control localised disease and related symptoms when compared to systemic therapies.Consider TKI therapy in progressive disease where benefits outweigh risks.Active surveillance and

Study of Bacterial Infections Among Patients Receiving Kidney Transplant in Mashhad, Iran.

Science.gov (United States)

Mansury, Davood; Khaledi, Azad; Ghazvini, Kiarash; Sabbagh, Mahin Ghorban; Zare, Hosna; Rokni-Hosseini, Mohammad Hossein; Vazini, Hossein

2017-11-15

Over the past 2 decades, significant advances have been made in the management of infections after transplant; however, transplant recipients are still at high risk of infectious complications. This study aimed to evaluate the prevalence of bacterial infections and antimicrobial resistance patterns in kidney transplant recipients. This cross-sectional study included 356 patients who received kidney transplants, regardless of the underlying disease, from 2013 to 2015 at the Montaserieh Transplant Hospital (Mashhad, Iran). Clinical samples collected from patients were sent to the microbiology laboratory for culture processing. Typing of bacteria was conducted, and susceptibility testing was performed according to the Clinical and Laboratory Standards Institute guideline by use the of disk diffusion agar method. Data were then analyzed by SPSS software (SPSS: An IBM Company, IBM Corporation, Armonk, NY, USA) using chi-square test. Among 356 kidney recipients (206 men and 150 women), 115 (32.3%) received transplants from living donors and 241 (67.7%) received transplants from deceased donors. Of 356 total patients, 112 patients (31.5%) had an infection at various times after transplant. The most common gram-negative and gram-positive isolated bacteria were Escherichia coli and coagulase-negative Staphylococcus, with prevalence rates of 66.1% and 48.6%. Most of the isolates were resistant against selected antibiotics. Because of the high prevalence of infection among transplant patients, infection prevention should receive more attention, and antibiotic susceptibility should be determined before treatment.

Pseudoneutropenia in lymphangioleiomyomatosis (LAM) patients receiving sirolimus: evaluation in a 100 patient cohort.

Science.gov (United States)

Gopalakrishnan, Vissagan; Jones, Amanda M; Julien-Williams, Patricia; Machado, Tania; Danner, Robert L; Swigris, Jeffrey J; Paine, Robert; Lozier, Jay N; Moss, Joel

2018-01-01

In lymphangioleiomyomatosis patients receiving sirolimus treatment, transient leukopenia in the morning may be due to circadian rhythm, with leukocyte counts recovering later in the day, indicating that a decrease in drug dose may not be warranted http://ow.ly/jPFz30iysgV.

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

Science.gov (United States)

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-06-18

To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (Pconstipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (Phospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model.

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Shinagawa-Kobayashi, Yoko; Kamimura, Kenya; Goto, Ryo; Ogawa, Kohei; Inoue, Ryosuke; Yokoo, Takeshi; Sakai, Norihiro; Nagoya, Takuro; Sakamaki, Akira; Abe, Satoshi; Sugitani, Soichi; Yanagi, Masahiko; Fujisawa, Koichi; Nozawa, Yoshizu; Koyama, Naoto; Nishina, Hiroshi; Furutani-Seiki, Makoto; Sakaida, Isao; Terai, Shuji

2018-02-05

Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow. Copyright © 2018 Elsevier Inc. All rights reserved.

Characteristic patients with oral mucositis receiving 5-FU chemotherapy at Hasan Sadikin Hospital Bandung

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Syarifah Fatimah

2016-11-01

Full Text Available Introduction: Oral mucositis is an inflammatory reaction of oral mucous membrane that often appears in cancer patients due to the chemotherapeutic agents, such as 5-fluorouracil (5-FU. The aim of this study was to describe the characteristic patients who receive 5-FU and had oral mucositis. Methods: This study was conducted on 41 patients with cancer receiving 5-FU chemotherapy at Dr Hasan Sadikin Hospital Bandung. The data was retrieved through interviews to find out patient’s characteristic; nutritional status examination by using body mass index measurement; and oral examination. Severity level was determined by using National Cancer Institute’s Common Toxicity Criteria scale, and the level of pain was measured by Numeric Pain Intensity Rating scale. Results: This research have shown 60,98% patient with cancer had received 5-FU chemotherapy treatment, and 44% with poor nutritional status (underweight. Oral mucositis was only found at non-keratinised mucous. The finding of this study was patients that receiving 5-FU chemotherapy treatment diagnosed with oral mucositis was on the 1st stadium (52% and the 2nd stadium (44% with the level of pain was on the mild level (48% and moderate level (32%.Conclusion: Oral mucositis was found on patients with cancer that received 5-FU chemotherapy with a variety of characteristics, nutritional statuses, locations, levels of severity and pain.

Effects of astrogaloside on the inflammation and immunity of renal failure patients receiving maintenance dialysis.

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Sun, Renlian; Ren, Haiwei; Wei, Jianxin

2018-03-01

Chronic renal failure is a type of clinical syndrome originating from chronic renal diseases. The aim of the study was to investigate the effect of astrogaloside on the inflammation and immunity of renal failure patients receiving maintenance dialysis. We randomly selected 92 renal failure patients receiving maintenance dialysis who were admitted to hospital for treatment between May, 2015 and April, 2016. Patients were randomly divided into the control (n=46) and observation (n=46) groups. Patients in the control group received the regular dialysis plus the basic treatment in Western medicine, while in the observation group, patients additionally received astrogaloside via intravenous injection as treatment. We compared the clinical efficacy of patients between the two groups, residual renal function (RRF), changes in urine volume, variations in inflammatory indicators [C-reaction protein (CRP), interleukin-6 (IL-6), IL-17, and tumor necrosis factor-α (TNF-α)] before and after treatment, and the levels of the thymus-dependent lymphocyte (T cells) subgroup (CD3 + , CD4 + , CD8 + and CD4 + /CD8 + ) in the immune system of patients after treatment. In the observation group, the total effective rate was significantly higher than that in the control group (Prenal failure patients receiving the maintenance dialysis, ameliorate the inflammatory responses, and enhance the immune function, thereby increasing the disease resistance of patients and improving the clinical symptoms.

Fentanyl sublingual spray for breakthrough cancer pain in patients receiving transdermal fentanyl.

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Alberts, David S; Smith, Christina Cognata; Parikh, Neha; Rauck, Richard L

2016-10-01

To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 µg). Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse event included nausea (9%) and peripheral edema (9%). FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850.

Comparative Evaluation of Serotonin Toxicity among Veterans Affairs Patients Receiving Linezolid and Vancomycin

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Patel, N.; Rivera, A.; Tristani, L.; Lazariu, V.; Vandewall, H.; McNutt, L. A.

2013-01-01

Despite the theoretical risk of serotonin toxicity (ST) with linezolid, “real-world” clinical evaluations of the risk of ST in patients receiving linezolid have been limited to case reports and noncomparator studies. An observational, matched-cohort study was conducted to evaluate the risk of ST among hospitalized patients who received linezolid or vancomycin at the Upstate New York Veterans Affairs Healthcare Network (Veterans Integrated Service Network 2 [VISN-2]). Matching criteria included VISN-2 hospital, hospital ward, prior hospital length of stay, age, and baseline platelet counts. The patients' electronic medical records were evaluated for symptoms consistent with ST and the Hunter serotonin toxicity criteria (HSTC) using an intensive, natural word search algorithm. The study included 251 matched pairs. Demographics and comorbidities were similar between groups. Over half of the study population received at least one concurrent medication with serotonergic activity. Receipt of agents with serotonergic activity was more pronounced in the vancomycin group, and the higher frequency was due to concomitant antihistamine and antiemetic use. Antidepressant use, including selective serotonin reuptake inhibitors (SSRIs), was similar between groups. No patients in either group were found to meet the criteria using the word search algorithm for ST. Fewer linezolid patients than vancomycin patients met the HSTC overall (3.2% versus 8.8%) and when stratified by receipt of a concurrent serotonergic agent (4.3% versus 12.4%). Of the patients meeting the HSTC, most had past or present comorbidities that may have contributed to or overlapped the HSTC. This study of hospitalized patients revealed comparably low frequencies of adverse events potentially related to ST among patients who received linezolid or vancomycin. PMID:24041888

[Clinical evaluation of bedridden patients with pneumonia receiving home health care].

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Fukuyama, Hajime; Ishida, Tadashi; Tachibana, Hiromasa; Iga, Chiya; Nakagawa, Hiroaki; Ito, Akihiro; Ubukata, Satoshi; Yoshioka, Hiroshige; Arita, Machiko; Hashimoto, Toru

2010-12-01

Pneumonia which develops in patients while living in their own home is categorized as community-acquired pneumonia (CAP), even if these patients are bedridden and receiving home health care. However, because of the differences in patient backgrounds, we speculated that the clinical outcomes and pathogens of bedridden patients with pneumonia who are receiving home health care would be different from those of CAP. We conducted a prospective study of patients with CAP who were hospitalized at our hospital from April 2007 through September 2009. We compared home health care bedridden pneumonia (performance status 4, PS4-CAP) with non-PS4-CAP in a total of 505 enrolled patients in this study. Among these, 66 had PS4-CAP, mostly associated with aspiration. Severity scores, mortality rate, recurrence rate and length of hospital stay of those with PS4-CAP were significantly higher than those with non-PS4-CAP. Drug resistant pathogens were more frequently isolated from patients with PS4-CAP than from those of non-PS4-CAP. The results of patients with PS4-CAP were in agreement with those of previous health care-associated pneumonia (HCAP) reports. The present study suggested home health care bedridden pneumonia should be categorized as HCAP, not CAP.

Retrospective chart review of elderly patients receiving electroconvulsive therapy in a tertiary general hospital

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Mosam Phirke

2015-01-01

Full Text Available Background: Electroconvulsive therapy (ECT is the one of the oldest and effective treatments in psychiatry today. It has been used in a wide variety of psychiatric disorders in both young and old patients. Aims of the study: The present study is a retrospective chart review of geriatric patients receiving ECT as a treatment option in a tertiary care general hospital psychiatry setting. Methodology: The study evaluated ECT records over a 5-year period between the years 2010 and 2014, and it was observed that 23 elderly patients (aged ≥60 years had received ECT. Results: The patients received modified bitemporal ECT using a brief pulse ECT machine and had no major complications. A total of 184 ECT treatments were administered at an average of 8 treatments per case. The major diagnoses of patients were schizophrenia and major depression. The main indications of ECT were intolerance to medication, suicidal behavior and aggression. Out of the 23 elderly patients, 18 (78.26% showed a good response to ECT. The only complication noted was memory loss and confusion in 3 cases. Patients with medical illnesses like hypertension, diabetes and both together received ECT without any complications. Conclusions: This study adds to the scarce database on the use of ECT in elderly patients in India and adds evidence to the fact that ECT is a safe and effective treatment in the elderly.

Skeletal mass in patients receiving chronic anticonvulsant therapy

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Zanzi, I.; Roginsky, M.S.; Rosen, A.; Cohn, S.H.

1981-01-01

The technique of in vivo total body neutron activation analysis was used to measure total body calcium (TBCa), a sensitive and precise index of skeletal mass, expressed as the Ca ratio (TBCa observed/TBCa predicted). 23 unselected, ambulatory, noninstitutionalized, adult epileptic patients under long-term anticonvulsant therapy were studied. Ca ratio was normal in 20 of the patients, low in only 2 and borderline in 1 patient. Plasma alkaline phosphatase values were elevated in half the subjects. Plasma Ca (uncorrected) was in the normal range in all. Serum 25-hydroxvitamin D (25-OHD) was low in 67% of the subjects, but only 1 patient had a value below 5 ng/ml. There was no correlation between the Ca ratio and the alkaline phosphatase or 25-OHD values. No radiographic or other evidences of osteomalacia were observed. This study does not support the notion of a prevalence of osteopenia in ambulatory, noninstitutionalized, adult epileptic patients receiving chronic anticonvulsant therapy in this geographical area despite the frequent findings of biochemical abnormalities.

Plasma levels of gastrointestinal regulatory peptides in patients receiving maintenance hemodialysis

International Nuclear Information System (INIS)

Hegbrant, J.; Thysell, H.; Ekmann, R.

1991-01-01

The fasting plasma levels of nine gastrointestinal regulatory peptides were measured by radioimmunoassay in 13 stable patients with chronic renal failure, receiving hemodialysis treatment regularly and compared with those of ten healthy controls. The plasma concentrations of gastrin-releasing peptide, motilin, neurotensin, pancreatic polypeptide, peptide YY, somatostatin, substance P, and vasoactive intestinal peptide were increased. The plasma level of gastrin was not statistically different from that of the control (p=0.077). It is concluded that patients with chronic renal failure, receiving hemodialysis treatment regularly, have increased concentrations of eight of nine measured gastrointestinal regulatory peptides. The elevated levels of gastrointestinal peptides in patients with chronic renal failure may contribute to uremic gastrointestinal symptoms and dysfunctions. It is necessary to make a renal function evaluation before interpreting measured plasma levels of gastrointestinal regulatory peptides. 62 refs., 2 tabs

APPETITE PREDICTS INTAKE AND NUTRITIONAL STATUS IN PATIENTS RECEIVING PERITONEAL DIALYSIS.

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Young, Valerie; Balaam, Sarah; Orazio, Linda; Bates, Annerley; Badve, Sunil V; Johnson, David W; Campbell, Katrina L

2016-06-01

Sub-optimal nutrition status is common amongst patients receiving peritoneal dialysis (PD) and leads to poor clinical outcome. This population experiences multi-factorial challenges to achieving optimal nutritional status, particularly driven by inadequate intake. The aim of this investigation was to identify factors associated with inadequate protein intake and sub-optimal nutritional status in patients undergoing PD. This was a cross-sectional study of 67 adult patients receiving PD (mean age 59 ± 14 years; 57% male) within a single centre. Participants were consecutively recruited and interviewed by renal dietitians, collecting: Subjective Global Assessment (SGA); quality of life (using EQ-5D); dietary intake (via dietary interview); and appetite (using Appetite and Diet Assessment Tool). Participant demographics were obtained via survey or medical charts. Main outcome measures were inadequate dietary protein intake (anorexia) was reported in 62% (18/29) of participants with inadequate protein malnourished patients reported anorexia versus 12 (23%) of the well-nourished patients (p = 0.0001). Anorexia was a key risk factor for inadequate protein intake and malnutrition in patients undergoing PD. These findings highlight a need to closely monitor patients with appetite disturbances. © 2016 European Dialysis and Transplant Nurses Association/European Renal Care Association.

Risk factors for death in HIV-infected adult African patients receiving anti-retroviral therapy.

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Siika, A M; Wools-Kaloustian, K; Mwangi, A W; Kimaiyo, S N; Diero, L O; Ayuo, P O; Owino-Ong'or, W D; Sidle, J E; Einterz, R M; Yiannoutsos, C T; Musick, B; Tierney, W M

2010-11-01

To determine risk factors for death in HIV-infected African patients on anti-retroviral therapy (ART). Retrospective Case-control study. The MOH-USAID-AMPATH Partnership ambulatory HIV-care clinics in western Kenya. Between November 2001 and December 2005 demographic, clinical and laboratory data from 527 deceased and 1054 living patients receiving ART were compared to determine independent risk factors for death. Median age at ART initiation was 38 versus 36 years for the deceased and living patients respectively (p100/mm3 (HR=1.553. 95% CI (1.156, 2.087), p<0.003). Patients attending rural clinics had threefold higher risk of dying compared to patients attending clinic at a tertiary referral hospital (p<0.0001). Two years after initiating treatment fifty percent of non-adherent patients were alive compared to 75% of adherent patients. Male gender, WHO Stage and haemoglobin level <10 grams% were associated with time to death while age, marital status, educational level, employment status and weight were not. Profoundly immunosuppressed patients were more likely to die early in the course of treatment. Also, patients receiving care in rural clinics were at greater risk of dying than those receiving care in the tertiary referral hospital.

Immunological Evaluation of -Thalassemia Major Patients Receiving Oral Iron Chelator Deferasirox

International Nuclear Information System (INIS)

Aleem, A.; Alsaleh, K.; Algahtani, F.; Momen, A. A.; Shakoor, Z.; Iqbal, Z.

2014-01-01

Objective: To determine the immune abnormalities and occurrence of infections in transfusion-dependent -thalassemia major patients receiving oral iron chelator deferasirox (DFX). Study Design: An observational study. Place and Duration of Study: Hematology Clinics, King Khalid University Hospital, Riyadh, Saudi Arabia, from July to December 2010. Methodology: Seventeen patients with -thalassemia major (12 females, median age 26 years) receiving deferasirox (DFX) for a median duration of 27 months were observed for any infections and had their immune status determined. Immune parameters studied included serum immunoglobulins and IgG subclasses, serum complement (C3 and C4) and anti-nuclear antibody (ANA) level, total B and T-lymphocytes, CD4+ and CD8+ counts, CD4+/CD8+ ratio, and natural killer (NK) cells. Immunological parameters of the patients were compared with age, gender, serum ferritin level and splenectomy status. Lymphocyte subsets were also compared with age and gender matched normal controls. Results: A considerable reduction in serum ferritin was achieved by DFX from a median level of 2528 to 1875 mol/l. Serum IgG levels were increased in 7 patients. Low C4 levels were found in 9 patients. Total B and T-lymphocytes were increased in 14 patients each, while CD4+, CD8+ and NK cells were increased in 13, 12 and 11 patients respectively. Absolute counts for all lymphocyte subsets were significantly higher compared to the normal controls (p=0.05 for all parameters). Raised levels of IgG were associated with older age, female gender, splenectomized status and higher serum ferritin levels but this did not reach statistical significance except for the higher ferritin levels (p=0.044). Increased tendency to infections was not observed. Conclusion: Patients with -thalassemia major receiving DFX exhibited significant immune abnormalities. Changes observed have been described previously, but could be related to DFX. The immune abnormalities were not associated with

Difference between received and expected knowledge of patients undergoing knee or hip replacement in seven European countries.

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Klemetti, Seija; Leino-Kilpi, Helena; Cabrera, Esther; Copanitsanou, Panagiota; Ingadottir, Brynja; Istomina, Natalja; Katajisto, Jouko; Papastavrou, Evridiki; Unosson, Mitra; Valkeapää, Kirsi

2015-12-01

The purpose of the study was to examine received and expected knowledge of patients with knee/hip arthroplasty in seven European countries. The goal was to obtain information for developing empowering patient education. The data were collected (during 2009-2012) from patients (n = 943) with hip/knee arthroplasty prior to scheduled preoperative education and before discharge with the Received Knowledge of hospital patient scale (RKhp) and Expected Knowledge of hospital patient scale (EKhp). Patients' knowledge expectations were high but the level of received knowledge did not correspond to expectations. The difference between received and expected knowledge was higher in Greece and Sweden compared with Finland (p European countries. © The Author(s) 2014.

CEFTRIAXONE EFFICIENCY AMONG PATIENTS, SUFFERING FROM JUVENILE ARTHRITIS AND RECEIVING IMMUNOSUPPRESSIVE THERAPY

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A.M. Chomakhidze

2007-01-01

Full Text Available The article is dedicated to diagnostics and treatment of infectious complications among children with juvenile rheumatoid arthritis, receiving immunosuppressive therapy. The research involves 92 children with different variants of the illness run, who received immunosuppressive therapy. All the patients showed development of the systemic inflammatory response manifestations. The researchers used the definition of the procalcytonine levels as a marker for the bacterial infectiondevelopment. All the patients showed it higher than 0,5 ng/ml, while 7 patients — higher than 10 ng/ml. keeping in mind several courses of the antibacterial therapy in the anamnesis and presence of the combined bacterial infection, ceftriaxone was prescribed to all the children. As a result of the ceftriaxone based therapy, reduction of the clinical and laboratory manifestations of the bacterial infection was noted among more than 90% of patients. The development of the allergic reaction was noted in 1 case, and leukopenia was also found in 1 patient.Key words: children, juvenile rheumatoid arthritis, ceftriaxone.

Exposure-response relationship of regorafenib efficacy in patients with hepatocellular carcinoma.

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Solms, Alexander; Reinecke, Isabel; Fiala-Buskies, Sabine; Keunecke, Anne; Drenth, Henk-Jan; Bruix, Jordi; Meinhardt, Gerold; Cleton, Adriaan; Ploeger, Bart

2017-11-15

To explore the relationship between regorafenib exposure and efficacy in patients with hepatocellular carcinoma (HCC) who had disease progression during sorafenib treatment (RESORCE). Exposure-response (ER) analyses for regorafenib were performed using data from a phase 3, randomized, placebo-controlled trial (RESORCE). Patients received 160mg regorafenib or placebo once daily (3weeks on/1week off in a 4-week cycle) with best supportive care until disease progression, death, or unacceptable toxicity. Kaplan-Meier analyses for overall survival (OS) and time-to-progression (TTP) were performed in which regorafenib-treated patients were grouped into four categories according to their estimated average exposure over 4weeks in cycle 1. While this analysis primarily focused on efficacy, a potential correlation between exposure and treatment-emergent adverse events (TEAEs) was also evaluated. If any differences were observed between Kaplan-Meier plots, the ER analysis continued with a multivariate Cox regression analysis to evaluate the correlation between exposure quartile categories and the efficacy and safety parameters while taking into consideration the effect of the predefined clinically relevant demographic and baseline covariates. The functional form of the ER relationship within the regorafenib treatment group was subsequently evaluated. Based on visual assessment of the Kaplan-Meier plots, no meaningful relationship between the exposure categories and TEAEs were observed, although median OS and TTP tended to be longer in the higher exposure categories. Further ER analyses, which considered the effects of predefined covariates and the different shapes of the ER relationship, focused on efficacy. The baseline risk factors Eastern Cooperative Oncology Group (ECOG) performance status ≥1, alpha-fetoprotein levels ≥400ng/ml, and aspartate transaminase or alanine transaminase levels >3×upper limit of normal were significantly associated with OS (Pregorafenib

Control of Nausea and Vomiting in Patients Receiving Anthracycline/Cyclophosphamide Chemotherapy for Breast Cancer.

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Nawa-Nishigaki, Minako; Kobayashi, Ryo; Suzuki, Akio; Hirose, Chiemi; Matsuoka, Rie; Mori, Ryutaro; Futamura, Manabu; Sugiyama, Tadashi; Yoshida, Kazuhiro; Itoh, Yoshinori

2018-02-01

Chemotherapy-induced nausea and vomiting (CINV) is one of most distressing adverse events during cancer chemotherapy. In breast cancer patients receiving anthracycline and cyclophosphamide (AC) chemotherapy, CINV is poorly controlled. The prevalence of guideline-consistent antiemetic medication and control of CINV were investigated retrospectively in breast cancer patients receiving the first cycle of AC chemotherapy. Risks for CINV were analyzed by the multivariate logistic regression analysis. The effect of olanzapine added to the standard antiemetic medication on the incidence of CINV was subsequently evaluated in separate patients who received the first cycle of AC chemotherapy. Although the guideline-consistent antiemetic medication was performed in all subjects, the control rate of nausea (32%), but not vomiting (78%) was low. Risk analysis indicated that age younger than 55-year-old was a significant factor that reduces the control of both nausea and vomiting. Olanzapine (5 mg/day for 5 days), when added to the standard three-drug antiemetic medication, significantly improved the control of nausea and complete response. CINV was poorly controlled in breast cancer patients receiving AC chemotherapy, in which age younger than 55-year-old was a significant risk for both nausea and vomiting. Olanzapine was effective for improvement of the control of CINV associated with AC chemotherapy. Therefore, care should be taken to prevent CINV in young patients receiving AC chemotherapy by adding olanzapine to the standard three-drug antiemetic medication. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The information needs of patients receiving procedural sedation in a hospital emergency department.

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Revell, Sue; Searle, Judy; Thompson, Shona

2017-07-01

This research investigated the information needs of patients receiving ED procedural sedation to determine the best format to consistently deliver key information in a way acceptable to all involved. Of particular interest was the question concerning patients' need for receiving written information. A descriptive exploratory study gathered qualitative data through face-to-face interviews and focus groups involving patients, nurses and medical staff. Individual interviews were conducted with eight adult patients following procedural sedation. They identified very few gaps in terms of specific information they needed pertaining to procedural sedation and rejected the need for receiving information in a written format. Their information needs related to a central concern for safety and trust. Focus groups, reflecting on the findings from patients, were conducted with five ED nurses and four emergency medicine consultants/registrars who regularly provided procedural sedation. Themes that emerged from the analysis of data from all three groups identified the issues concerning patient information needs as being: competence and efficiency of staff; explanations of procedures and progress; support person presence; and medico-legal issues. The research confirms that the quality of the patient's ED experience, specifically related to procedural sedation, is enhanced by ED staff, especially nurses, providing them with ongoing and repeated verbal information relevant to their circumstances. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prevention of blood transfusion with intravenous iron in gynecologic cancer patients receiving platinum-based chemotherapy.

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Athibovonsuk, Punnada; Manchana, Tarinee; Sirisabya, Nakarin

2013-12-01

To compare the efficacy of intravenous iron and oral iron for prevention of blood transfusions in gynecologic cancer patients receiving platinum-based chemotherapy. Sixty-four non anemic gynecologic cancer patients receiving adjuvant platinum-based chemotherapy were stratified and randomized according to baseline hemoglobin levels and chemotherapy regimen. The study group received 200mg of intravenous iron sucrose immediately after each chemotherapy infusion. The control group received oral ferrous fumarate at a dose of 200mg three times a day. Complete blood count was monitored before each chemotherapy infusion. Blood transfusions were given if hemoglobin level was below 10mg/dl. There were 32 patients in each group. No significant differences in baseline hemoglobin levels and baseline characteristics were demonstrated between both groups. Nine patients (28.1%) in the study group and 18 patients (56.3%) in the control group required blood transfusion through 6 cycles of chemotherapy (p=0.02). Fewer median number of total packed red cell units were required in the study group compared to the control group (0 and 0.5 unit, respectively, p=0.04). Serious adverse events and hypersensitivity reactions were not reported. However, constipation was significantly higher in the control group (3.1% and 40.6%, p=gynecologic cancer patients receiving platinum-based chemotherapy, associated with less constipation than the oral formulation. © 2013 Elsevier Inc. All rights reserved.

Descriptive Study of Patients Receiving Excision and Radiotherapy for Keloids

International Nuclear Information System (INIS)

Speranza, Giovanna; Sultanem, Khalil M.D.; Muanza, Thierry

2008-01-01

Purpose: To review and describe our institution's outcomes in patients treated with external beam radiotherapy after keloid excision. Methods and Materials: This was a retrospective study. Patients who received radiotherapy between July 1994 and January 2004 after keloid excision were identified. A questionnaire was mailed regarding sociodemographic factors, early and late radiation toxicities, the need for additional therapy, and satisfaction level. All patients had received a total of 15 Gy in three daily 5-Gy fractions. Treatment started within 24 h after surgery and was delivered on a Siemens orthovoltage machine. The data were analyzed using the STATA statistical package. Results: A total of 234 patients were approached. The response rate was 41%, and 75% were female. The mean age was 36.5 years (range, 16-69 years). The patients were mainly of European (53.1%) or African (19.8%) descent. For early toxicity outcomes, 54.2% reported skin redness and 24% reported skin peeling. For late toxicity outcomes, 27% reported telangiectasia and 62% reported permanent skin color changes. No association was found with gender, skin color, or age for the late toxicity outcomes. Of the patients responding, 14.6% required adjuvant treatment. On a visual scale of 1-10 for the satisfaction level, 60% reported a satisfaction level of ≥8. Telangiectasia was the most significant predictor of a low satisfaction level (≤3, p < 0.005). Conclusion: The results of our study have shown that orthovoltage-based radiotherapy after surgical excision for keloids is a good method for the prevention of relapse. It is well tolerated, causes little toxicity, and leads to a high patient satisfaction level

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids

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Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-01-01

Objectives: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Methods: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). Results: The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini–Hochberg criterion for a 10% false discovery rate. Conclusions: Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment. PMID:26087058

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

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Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

2014-01-01

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

Effectiveness of cognitive behavioral therapy for depression in patients receiving disability benefits: a systematic review and individual patient data meta-analysis.

Directory of Open Access Journals (Sweden)

Shanil Ebrahim

Full Text Available To systematically summarize the randomized trial evidence regarding the relative effectiveness of cognitive behavioural therapy (CBT in patients with depression in receipt of disability benefits in comparison to those not receiving disability benefits.All relevant RCTs from a database of randomized controlled and comparative studies examining the effects of psychotherapy for adult depression (http://www.evidencebasedpsychotherapies.org, electronic databases (MEDLINE, EMBASE, PSYCINFO, AMED, CINAHL and CENTRAL to June 2011, and bibliographies of all relevant articles. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTION: Adult patients with major depression, randomly assigned to CBT versus minimal/no treatment or care-as-usual.Three teams of reviewers, independently and in duplicate, completed title and abstract screening, full text review and data extraction. We performed an individual patient data meta-analysis to summarize data.Of 92 eligible trials, 70 provided author contact information; of these 56 (80% were successfully contacted to establish if they captured receipt of benefits as a baseline characteristic; 8 recorded benefit status, and 3 enrolled some patients in receipt of benefits, of which 2 provided individual patient data. Including both patients receiving and not receiving disability benefits, 2 trials (227 patients suggested a possible reduction in depression with CBT, as measured by the Beck Depression Inventory, mean difference [MD] (95% confidence interval [CI] = -2.61 (-5.28, 0.07, p = 0.06; minimally important difference of 5. The effect appeared larger, though not significantly, in those in receipt of benefits (34 patients versus not receiving benefits (193 patients; MD (95% CI = -4.46 (-12.21, 3.30, p = 0.26.Our data does not support the hypothesis that CBT has smaller effects in depressed patients receiving disability benefits versus other patients. Given that the confidence interval is wide, a

Evaluation of electrolyte imbalance among tuberculosis patients receiving treatments in Southwestern Nigeria

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Adebimpe Wasiu Olalekan

2015-09-01

Conclusion: Hyponatraemia, hyperkalaemia, and hypochloremia characterized some of the electrolyte imbalance among TB patients receiving treatments. The raised level of bicarbonate may be attributed to overcorrection of respiratory acidosis often found in patients with tuberculosis. Monitoring electrolytes is therefore an important component of TB management.

Reversible Encephalopathy and Delirium in patients with chronic renalfailure who had received Ciprofloxacin

International Nuclear Information System (INIS)

Al-Ghamdi, S.M.J.

2002-01-01

We describe four patients with chronic renal failure (CRF) who developedsignificant neurotoxicity after receiving short-term ciprofloxacin. Three ofthem had developed encephalopathy with myoclonic jerks and one patient haddelirium. All patients had advanced chronic renal failure (mean estimatedcreatinine clearance 16+-6 ml/min), although they were not yet on renalreplacement therapy). The mean received dose of ciprofloxacin was 2150+-1300mg and symptoms started to appear after the first 24 hours of drug intake.Investigations ruled out other possible causes of these neurologicalpresentations and withdrawal of ciprofloxacin was followed by completeresolution, after a mean of 8.5+- 4 days. Advanced renal failure in allpatients and underlying neurologic disease in two patients may havepredisposed them to the neurotoxicity. The report of these cases should helpto draw the attention of clinicians to the potential occurrence of theseadverse effects in patients with CRF. (author)

The effect of geriatric intervention in frail elderly patients receiving chemotherapy for colorectal cancer

DEFF Research Database (Denmark)

Lund, C M; Vistisen, K K; Dehlendorff, C

2017-01-01

patients are offered inclusion and are then randomized to two groups (the intervention group and the control group). Patients in the intervention group receive a full geriatric assessment of comorbidity, medication, psycho-cognitive function, physical, functional and nutrition status, and interventions......BACKGROUND: Better surgical techniques, chemotherapy and biological therapy have improved survival in patients with colorectal cancer (CRC), most markedly in younger patients. About half of patients over 70 years receive dose reductions or early treatment discontinuation of the planned adjuvant...... or first-line treatment due to side effects. The Comprehensive Geriatric Assessment (CGA) is a multidisciplinary evaluation of an elderly individual's health status. This assessment in older patients with cancer can predict survival, chemotherapy toxicity and morbidity. METHODS: This randomized phase II...

Phase II Study of Bevacizumab in Patients With HIV-Associated Kaposi's Sarcoma Receiving Antiretroviral Therapy

Science.gov (United States)

Uldrick, Thomas S.; Wyvill, Kathleen M.; Kumar, Pallavi; O'Mahony, Deirdre; Bernstein, Wendy; Aleman, Karen; Polizzotto, Mark N.; Steinberg, Seth M.; Pittaluga, Stefania; Marshall, Vickie; Whitby, Denise; Little, Richard F.; Yarchoan, Robert

2012-01-01

Purpose Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti–VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS. Patients and Methods Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately. Results Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T1), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). Conclusion Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients. PMID:22430271

Prevalence of cirrhosis in patients with thrombocytopenia who receive bone marrow biopsy.

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Sheikh, Muhammad Y; Raoufi, Rahim; Atla, Pradeep R; Riaz, Muhammad; Oberer, Chad; Moffett, Michael J

2012-01-01

Thrombocytopenia is a common finding in patients with cirrhosis and may lead to unnecessary referral for bone marrow (BM) biopsy. To date, the prevalence of cirrhosis in patients with thrombocytopenia who receive BM biopsy is largely unknown. Between fiscal years 2006-2010, 744 patients (≥18 years) who underwent BM biopsies for thrombocytopenia at our hospital were identified retrospectively. 541 patients were excluded who had hematologic malignancies and received chemotherapy. Remaining 203 patients with predominant isolated thrombocytopenia were included in the study. Of 203 patients, 136 (67%) had a normal and 67 (33%) had an abnormal BM examination. Prevalence of cirrhosis in the study population was 35% (95% CI: 28.4-41.9). 51% patients with normal BM were found to have cirrhosis compared to 3% of patients with abnormal BM exam (P < 0.0001). Common causes of cirrhosis were nonalcoholic steatohepatitis (NASH) (47%), followed by alcohol and Hepatitis C virus infection. Idiopathic thrombocytopenia and myelodysplastic syndrome were most frequent causes of thrombocytopenia in patients without cirrhosis. Patients with NASH had higher body mass index (BMI) (33.4 vs. 25.8, P < 0.001) and lower MELD scores (11.1 vs. 16, P = 0.028) when compared to non-NASH patients with cirrhosis. Approximately, one third (35%) of patients with cirrhosis induced thrombocytopenia may undergo unwarranted BM biopsies. Clinical diagnosis of cirrhosis is still a challenge for many physicians, particularly with underlying NASH. We propose cirrhosis to be the prime cause of isolated thrombocytopenia.

Patient perspectives on care received at community acupuncture clinics: a qualitative thematic analysis.

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Tippens, Kimberly M; Chao, Maria T; Connelly, Erin; Locke, Adrianna

2013-10-29

Community acupuncture is a recent innovation in acupuncture service delivery in the U.S. that aims to improve access to care through low-cost treatments in group-based settings. Patients at community acupuncture clinics represent a broader socioeconomic spectrum and receive more frequent treatments compared to acupuncture users nationwide. As a relatively new model of acupuncture in the U.S., little is known about the experiences of patients at community acupuncture clinics and whether quality of care is compromised through this high-volume model. The aim of this study was to assess patients' perspectives on the care received through community acupuncture clinics. The investigators conducted qualitative, thematic analysis of written comments from an observational, cross-sectional survey of clients of the Working Class Acupuncture clinics in Portland, Oregon. The survey included an open-ended question for respondents to share comments about their experiences with community acupuncture. Comments were received from 265 community acupuncture patients. Qualitative analysis of written comments identified two primary themes that elucidate patients' perspectives on quality of care: 1) aspects of health care delivery unique to community acupuncture, and 2) patient engagement in health care. Patients identified unique aspects of community acupuncture, including structures that facilitate access, processes that make treatments more comfortable and effective and holistic outcomes including physical improvements, enhanced quality of life, and empowerment. The group setting, community-based locations, and low cost were highlighted as aspects of this model that allow patients to access acupuncture. Patients' perspectives on the values and experiences unique to community acupuncture offer insights on the quality of care received in these settings. The group setting, community-based locations, and low cost of this model potentially reduce access barriers for those who might not

The Effect of Consolidation Chemotherapy for LA-NSCLC Patients Receiving Concurrent Chemoradiotherapy

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Yelda Varol

2016-09-01

Full Text Available Aim: The efficacy and safety of consolidation chemotherapy (CCT following concurrent chemoradiotherapy are not adequately established for patients with locally advanced non-small-cell lung cancer (LA-NSCLC. In this context, the present study aims to evaluate the efficacy and toxicity of CCT.Material and Method: We retrospectively analyzed the overall survival (OS and progression-free survival (PFS of 83 LA-NSCLC patients treated with concurrent CRT as an initial treatment with (n:20 or without CCT (n:63. All patients were cytohistologically proven to have NSCLC and diagnosed with clinical Stage III (n:48 for IIIA and n:35 for IIIB according to the staging system published by the American Joint Committee on Cancer (AJCC in 2009. All patients received curative thoracic radiotherapy with concurrent platinum doublet chemotherapy. Results: The mean age of the lung cancer patients was 59 (±7.3; 89.2% were male (n:74,and there were only 9 female patients (10.8%.When we compared the outcome of LA-NSCLC patients treated with CCT (median 10.4 months to the patients treated without CCT (median 13.8 months, the log-rank analysis demonstrated a statistically significant difference for an inferior progression-free survival (p=0.046 in patients receiving CCT. However, no significant association was observed for overall survival (17.4, 21 months, respectively (p>0.05. Patients with CCT presented higher levels of hematological side effects compared with the patients without CCT (p

A Comparative Study of the Efficacy of IV Dexketoprofen, Lornoxicam, and Diclophenac Sodium on Postoperative Analgesia and Tramadol Consumption in Patients Receiving Patient-Controlled Tramadol.

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Kılıçkaya, Refika; Güleç, Ersel; Ünlügenç, Hakkı; Gündüz, Murat; Işık, Geylan

2015-06-01

This study was designed to compare the effects of dexketoprofen, lornoxicam, and diclophenac sodium on postoperative analgesia and tramadol consumption in patients receiving postoperative patient-controlled tramadol after a major abdominal surgery. Eighty patients were randomized to receive one of the four study drugs. Patients in group dexketoprofen (DT) received IV 50 mg dexketoprofen, group lornoxicam (LR) received IV 8 mg lornoxicam, group diclophenac sodium (DS) received 75 mg IV diclophenac sodium and group saline (S) received 0.9% saline in 2 mL syringes, 20 min before the end of anaesthesia. A standardized (1 mg kg(-1)) dose of tramadol was routinely administered to all patients as the loading dose at the end of surgery. Postoperatively, whenever patients requested, they were allowed to use a tramadol patient-controlled analgesia device giving a bolus dose (0.2 mg kg(-1)) of tramadol. Pain, discomfort, and sedation scores, cumulative tramadol consumption, supplemental meperidine requirement, and side effects were recorded. Visual rating scale and patient discomfort scores were significantly lower in DT, LR and DS groups compared to those in in group S (pdexketoprofen to patient-controlled tramadol resulted in lower pain scores, smaller tramadol consumption, less rescue supplemental analgesic requirement, and fewer side effects compared with the tramadol alone group.

The prognostic value of electrodiagnostic testing in patients with sciatica receiving physical therapy.

Science.gov (United States)

Savage, Nathan J; Fritz, Julie M; Kircher, John C; Thackeray, Anne

2015-03-01

To investigate the prognostic value of electrodiagnostic testing in patients with sciatica receiving physical therapy. Electrodiagnostic testing was performed on 38 patients with sciatica participating in a randomized trial comparing different physical therapy interventions. Patients were grouped and analyzed according to the presence or absence of radiculopathy based on electrodiagnostic testing. Longitudinal data analysis was conducted using multilevel growth modeling with ten waves of data collected from baseline through the treatment and post-treatment periods up to 6 months. The primary outcome measure was changes in low back pain-related disability assessed using the Roland and Morris disability questionnaire (RMDQ). Patients with radiculopathy (n = 19) had statistically significant and clinically meaningful improvements in RMDQ scores at every post-treatment follow-up occasion regardless of treatment received. The final multilevel growth model revealed improvements in RMDQ scores in patients with radiculopathy at the 6-week (-8.1, 95 % CI -12.6 to -2.6; P = 0.006) and 6-month (-4.1, 95 % CI -7.4 to -0.7; P = 0.020) follow-up occasions compared to patients without radiculopathy. Treatment group was not a significant predictive factor at any follow-up occasion. An interaction between electrodiagnostic status and time revealed faster weekly improvements in RMDQ scores in patients with radiculopathy at the 6-week (-0.72, 95 % CI -1.4 to -0.04; P = 0.040) through the 16-week (-0.30, 95 % CI, -0.57 to -0.04; P = 0.028) follow-up occasions compared to patients without radiculopathy. The presence of lumbosacral radiculopathy identified with electrodiagnostic testing is a favorable prognostic factor for recovery in low back pain-related disability regardless of physical therapy treatment received.

Metabolic Profiling of Impaired Cognitive Function in Patients Receiving Dialysis.

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Kurella Tamura, Manjula; Chertow, Glenn M; Depner, Thomas A; Nissenson, Allen R; Schiller, Brigitte; Mehta, Ravindra L; Liu, Sai; Sirich, Tammy L

2016-12-01

Retention of uremic metabolites is a proposed cause of cognitive impairment in patients with ESRD. We used metabolic profiling to identify and validate uremic metabolites associated with impairment in executive function in two cohorts of patients receiving maintenance dialysis. We performed metabolic profiling using liquid chromatography/mass spectrometry applied to predialysis plasma samples from a discovery cohort of 141 patients and an independent replication cohort of 180 patients participating in a trial of frequent hemodialysis. We assessed executive function with the Trail Making Test Part B and the Digit Symbol Substitution test. Impaired executive function was defined as a score ≥2 SDs below normative values. Four metabolites-4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline-were associated with impaired executive function at the false-detection rate significance threshold. After adjustment for demographic and clinical characteristics, the associations remained statistically significant: relative risk 1.16 (95% confidence interval [95% CI], 1.03 to 1.32), 1.39 (95% CI, 1.13 to 1.71), 1.24 (95% CI, 1.03 to 1.50), and 1.20 (95% CI, 1.05 to 1.38) for each SD increase in 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline, respectively. The association between 4-hydroxyphenylacetate and impaired executive function was replicated in the second cohort (relative risk 1.12; 95% CI, 1.02 to 1.23), whereas the associations for phenylacetylglutamine, hippurate, and prolyl-hydroxyproline did not reach statistical significance in this cohort. In summary, four metabolites related to phenylalanine, benzoate, and glutamate metabolism may be markers of cognitive impairment in patients receiving maintenance dialysis. Copyright © 2016 by the American Society of Nephrology.

Characteristics of Hemorrhagic Peptic Ulcers in Patients Receiving Antithrombotic/Nonsteroidal Antiinflammatory Drug Therapy

OpenAIRE

Nakamura, Kazuhiko; Akahoshi, Kazuya; Ochiai, Toshiaki; Komori, Keishi; Haraguchi, Kazuhiro; Tanaka, Munehiro; Nakamura, Norimoto; Tanaka, Yoshimasa; Kakigao, Kana; Ogino, Haruei; Ihara, Eikichi; Akiho, Hirotada; Motomura, Yasuaki; Kabemura, Teppei; Harada, Naohiko

2012-01-01

Background/Aims Antithrombotic/nonsteroidal antiinflammatory drug (NSAID) therapies increase the incidence of upper gastrointestinal bleeding. The features of hemorrhagic peptic ulcer disease in patients receiving antithrombotic/NSAID therapies were investigated. Methods We investigated the medical records of 485 consecutive patients who underwent esophagogastroduodenoscopy and were diagnosed with hemorrhagic gastroduodenal ulcers. The patients treated with antithrombotic agents/NSAIDs were c...

Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation

DEFF Research Database (Denmark)

Magnussen, Helgo; Watz, Henrik; Kirsten, Anne

2014-01-01

-controlled fashion, one group of patients continues to receive tiotropium, salmeterol and fluticasone, while the second group initiates stepwise withdrawal of fluticasone. The primary end point is time to first moderate or severe exacerbation following randomized treatment over 52 weeks. Lung function, symptoms...

Assessment of satisfaction with pharmaceutical services in patients receiving antiretroviral therapy in outpatient HIV treatment setting.

Science.gov (United States)

Agu, Kenneth Anene; Oqua, Dorothy; Agada, Peter; Ohiaeri, Samuel I; Adesina, Afusat; Abdulkareem, Mohammed Habeeb; King, Rosalyn C; Wutoh, Anthony K

2014-06-01

The patient's perception and satisfaction are increasingly considered as a useful factor in the assessment of competency of health care providers and quality of care. However, these patient focused assessments are largely ignored when assessing health care outcomes. The study assessed the perception and satisfaction of patients receiving antiretroviral therapy (ART) with pharmaceutical services received in outpatient HIV treatment settings. Seventeen HIV treatment centres in Nigeria. This cross-sectional survey included 2,700 patients randomly selected from 26,319 HIV patients on ART, who received pharmaceutical services in the study setting. A study-specific Likert-type instrument was administered to the participants at point of exit from the pharmacy. Midpoint of the 5-point scale was computed and scores above it were regarded as positive while below as negative. Chi-square was used for inferential statistics. All reported p values were 2-sided at 95 % confidence interval (CI). Patient satisfaction with pharmaceutical services. Of 2,700 patients sampled, data from 1,617 (59.9 %) were valid for analysis; 62.3 % were aged 26-40 years and 65.4 % were females. The participants had received pharmaceutical services for a mean duration of 25.2 (95 % CI 24.3-26.1) months. Perception of participants regarding the appearance of pharmacy was positive while that regarding the pharmacists' efforts to solve patients' medication related problems was negative. The participants' rating of satisfaction with the waiting time to access pharmaceutical services was negative; the satisfaction decreases with increasing waiting time. However, the satisfaction with the overall quality of pharmaceutical services received was rated as positive; 90.0 % reported that they got the kind of pharmaceutical services they wanted; 98.2 % would come back to the pharmacy if they were to seek help again and would recommend services to others. The level of satisfaction was found to be associated with

Pneumothorax as a complication of combination antiangiogenic therapy in children and young adults with refractory/recurrent solid tumors.

Science.gov (United States)

Interiano, Rodrigo B; McCarville, M Beth; Wu, Jianrong; Davidoff, Andrew M; Sandoval, John; Navid, Fariba

2015-09-01

Antiangiogenic agents show significant antitumor activity against various tumor types. In a study evaluating the combination of sorafenib, bevacizumab, and low-dose cyclophosphamide in children with solid tumors, an unexpectedly high incidence of pneumothorax was observed. We evaluated patient characteristics and risk factors for the development of pneumothorax in patients receiving this therapy. Demographics, clinical course, and radiographic data of 44 patients treated with sorafenib, bevacizumab and cyclophosphamide were reviewed. Risk factors associated with the development of pneumothorax were analyzed. Pneumothorax likely related to study therapy developed in 11 of 44 (25%) patients of whom 33 had pulmonary abnormalities. Median age of patients was 14.7 years (range, 1.08-24.5). Histologies associated with pneumothorax included rhabdoid tumor, synovial sarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, and renal cell carcinoma. Cavitation of pulmonary nodules in response to therapy was associated with pneumothorax development (Ppneumothorax was 5.7 weeks (range, 2.4-31). The development of cavitary pulmonary nodules in response to therapy is a risk factor for pneumothorax. As pneumothorax is a potentially life-threatening complication of antiangiogenic therapy in children with solid tumors, its risk needs to be evaluated when considering this therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

The effect of music therapy on physiological signs of anxiety in patients receiving mechanical ventilatory support.

Science.gov (United States)

Korhan, Esra Akin; Khorshid, Leyla; Uyar, Mehmet

2011-04-01

The aim of this study was to investigate if relaxing music is an effective method of reducing the physiological signs of anxiety in patients receiving mechanical ventilatory support. Few studies have focused on the effect of music on physiological signs of anxiety in patients receiving mechanical ventilatory support. A study-case-control, experimental repeated measures design was used. Sixty patients aged 18-70 years, receiving mechanical ventilatory support and hospitalised in the intensive care unit, were taken as a convenience sample. Participants were randomised to a control group or intervention group, who received 60 minutes of music therapy. Classical music was played to patients using media player (MP3) and headphones. Subjects had physiological signs taken immediately before the intervention and at the 30th, 60th and 90th minutes of the intervention. Physiological signs of anxiety assessed in this study were mean systolic and diastolic blood pressure, pulse rate, respiratory rate and oxygen saturation in blood measured by pulse oxymetry. Data were collected over eight months in 2006-2007. The music group had significantly lower respiratory rates, and systolic and diastolic blood pressure, than the control group. This decrease improved progressively in the 30th, 60th and 90th minutes of the intervention, indicating a cumulative dose effect. Music can provide an effective method of reducing potentially harmful physiological responses arising from anxiety. As indicated by the results of this study, music therapy can be supplied to allay anxiety in patients receiving mechanical ventilation. Nurses may include music therapy in the routine care of patients receiving mechanical ventilation. © 2011 Blackwell Publishing Ltd.

Use of complementary and alternative medicine among patients with cancer receiving outpatient chemotherapy in Taiwan.

Science.gov (United States)

Yang, Che; Chien, Li-Yin; Tai, Chen-Jei

2008-05-01

The objectives of this study were to describe the prevalence and types of complementary and alternative medicines (CAMs) used among patients with cancer receiving outpatient chemotherapy in Taiwan. This study was a cross-sectional survey. The study participants were 160 patients with cancer receiving outpatient chemotherapy at a medical center in northern Taiwan. The vast majority of the participants reported CAM use (n = 157, 98.1%). The two most common groups of CAM used were "biologically based therapies" (77.5%) and "mind-body interventions" (60.6%). Fifteen percent (15.3%) of patients took grapeseed and ginseng, which might affect the efficacy of some chemotherapy regimens. Fourteen percent (14.4%) of patients did not know the name of the herbs they took. The most commonly reported reasons for CAM use were to boost the immune system (55.4%) and relieve stress (53.5%). Approximately two thirds of patients (66.2%) had never informed their physicians of CAM use. This survey revealed a high prevalence of CAM use among patients with cancer receiving out-patient chemotherapy in Taiwan. The types of CAM used by patients with cancer in Taiwan differed from those in Western countries. Health professionals need to be cautious about the potential herb-drug interactions.

Implication of chemo-resistant memory T cells for immune surveillance in patients with sarcoma receiving chemotherapy.

Science.gov (United States)

Shibayama, Yuji; Tsukahara, Tomohide; Emori, Makoto; Murata, Kenji; Mizushima, Emi; Hirohashi, Yoshihiko; Kanaseki, Takayuki; Nakatsugawa, Munehide; Kubo, Terufumi; Yamashita, Toshihiko; Sato, Noriyuki; Torigoe, Toshihiko

2017-09-01

Chemotherapy has improved the prognosis of patients with sarcomas. However, it may suppress anti-tumor immunity. Recently, we reported a novel CD8 + memory T cell population with a chemo-resistance property, "young memory" T (T YM ) cells. In this study, we investigated the proportion and function of T YM cells in peripheral blood of healthy donors and sarcoma patients who received chemotherapy and those who did not. The proportion of T YM cells was significantly decreased in patients compared with that in healthy donors. In healthy donors, anti-EBV CTLs were induced using mixed lymphocyte peptide culture, from not only T YM cells but also T CM and T EM cells. No CTLs directed to tumor-associated antigens were induced. In sarcoma patients who did not receive chemotherapy, in addition to anti-EBV CTLs, CTLs directed to the tumor-associated antigen PBF were induced from T YM , T CM and T EM cells. In sarcoma patients who received chemotherapy, EBV-specific CTLs were induced from T YM cells but were hardly induced from T EM cells. Interestingly, CTLs directed to the anti-tumor-associated antigen PBF were induced from T YM cells but not from the T CM and T EM cells in sarcoma patients who received chemotherapy. The findings suggest that T YM cells are resistant to chemotherapy and can firstly recover from the nadir. T YM cells might be important for immunological memory, especially in sarcoma patients receiving chemotherapy. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Second-line therapy in diffuse large B-cell lymphoma (DLBCL): treatment patterns and outcomes in older patients receiving outpatient chemotherapy.

Science.gov (United States)

Danese, Mark D; Griffiths, Robert I; Gleeson, Michelle L; Dalvi, Tapashi; Li, Jingyi; Mikhael, Joseph R; Deeter, Robert; Dreyling, Martin

2017-05-01

Using SEER-Medicare linked data we identified elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL) between January 2000 and December 2007 who received second-line outpatient chemotherapy for relapsed or refractory disease. Second-line regimens were classified into three mutually exclusive groups: aggressive, conventional, and palliative. Of the 632 (426 relapsed, 206 refractory) patients in the cohort, 27.8% received aggressive second-line therapy, 39.1% received conventional therapy, and 33.1% received palliative therapy. There were no differences in survival by type of therapy received, either for relapsed or refractory patients, although the patient risk profile differed significantly. However, duration of remission, male gender, and anemia at diagnosis were important predictors in relapsed patients, and male gender, B-symptoms, comorbidity burden, and poverty status were important predictors in refractory patients. Survival in elderly patients receiving second-line therapy remains poor, and the 24-month cost of all care exceeds $97,000. Patients would benefit from improved treatment options.

Predictors of mortality in patients with extensively drug-resistant Acinetobacter baumannii pneumonia receiving colistin therapy.

Science.gov (United States)

Choi, Ik Sung; Lee, Yu Ji; Wi, Yu Mi; Kwan, Byung Soo; Jung, Kae Hwa; Hong, Woong Pyo; Kim, June Myong

2016-08-01

The ratio of the area under the free (unbound) concentration-time curve to minimum inhibitory concentration (fAUC/MIC) was proposed to be the pharmacokinetic/pharmacodynamic index most strongly linked to the antibacterial effect of colistin against Acinetobacter baumannii. A retrospective study of patients who received colistin to treat pneumonia caused by extensively drug-resistant (XDR) A. baumannii over a 4-year period was performed to assess the impact of the colistin MIC on mortality. A total of 227 patients were included in the analysis. The 7-day and 14-day mortality rates of patients with XDR A. baumannii pneumonia receiving colistin therapy were 15.0% and 23.8%, respectively. In the multivariate analysis, Acute Physiology and Chronic Health Evaluation (APACHE) II score, days from index culture to first dose of colistin, underlying tumour and septic shock at presentation were independent predictors of mortality in patients with XDR A. baumannii pneumonia receiving colistin therapy. In the univariate analysis, the colistin dose based on ideal body weight (IBW) correlated with patient outcome. Therefore, the use of IBW appeared to be more appropriate to calculate the colistin dosage. In addition, these results highlight the clinical significance of colistin MIC in patients with XDR A. baumannii pneumonia receiving colistin therapy. Although MICs were in the 'susceptible' range, patients infected with isolates with high colistin MICs showed a poorer clinical response rate than patients infected with isolates with low colistin MICs. Further clinical studies are needed to evaluate the roles of colistin MIC for predicting mortality in XDR A. baumannii pneumonia with a high colistin MIC. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

How health information is received by diabetic patients?

Directory of Open Access Journals (Sweden)

Firoozeh Zare-Farashbandi

2015-01-01

Full Text Available Background: Knowledge of correct information-seeking behavior by the patients can provide health specialists and health information specialists with valuable information in improving health care. This study aimed to investigate the passive receipt and active seeking of health information by diabetic patients. Materials and Methods: A survey method was used in this research on 6426 diabetic patients of whom 362 patients were selected by a no percentage stratified random sampling. The Longo information-seeking behavior questionnaire was used to collect data and they were analyzed by SPSS 20 software. Results: The most common information source by diabetic patients was practitioners (3.12. The minimum usage among the information sources were from charity organizations and emergency phone lines with a usage of close to zero. The amount of health information gained passively from each source has the lowest average of 4.18 and usage of this information in making health decision has the highest average score of 5.83. Analysis of the data related to active seeking of information showed that knowledge of available medical information from each source has the lowest average score of 3.95 and ability in using the acquired information for making medical decisions has the highest average score of 5.28. The paired t-test showed that differences between passive information receipt (41.68 and active information seeking (39.20 considered as statistically significant (P < 0.001. Conclusion: Because diabetic patients are more passive information receivers than active information seekers, the health information must be distributed by passive means to these patients. In addition, information-seeking behavior during different time periods should be investigated; to identify more effective distribution of health information.

Staphylococcus aureus bacteremia with iliac artery endarteritis in a patient receiving ustekinumab

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Insa Joost

2016-10-01

Full Text Available Abstract Background Ustekinumab (Stelara®, a human monoclonal antibody targeting the p40-subunit of interleukin (IL-12 and IL-23, is indicated for moderate to severe plaque psoriasis and psoriatic arthritis. In large multicenter, prospective trials assessing efficacy and safety of ustekinumab increased rates of severe infections have not been observed so far. Case presentation Here, we report the case of a 64-year old woman presenting with chills, pain and swelling of her right foot with dark maculae at the sole, and elevated inflammatory markers. She had received a third dose of ustekinumab due to psoriatic arthritis three days before admission. Blood cultures revealed growth of Staphylococcus aureus and imaging showed a thickening of the aortic wall ventral the bifurcation above the right internal iliac artery, resembling an acute bacterial endarteritis. Without the evidence of aneurysms and in absence of foreign bodies, the decision for conservative management was made. The patient received four weeks of antibiotic therapy with intravenous flucloxacillin, followed by an oral regime with levofloxacin and rifampicin for an additional four weeks. Inflammatory markers resolved promptly and the patient was discharged in good health. Conclusion To our knowledge, this is the first report of a severe S. aureus infection in a patient receiving ustekinumab. Albeit ustekinumab is generally regarded as a safe drug, severe bacterial infections should always be included in the differential diagnosis of elevated inflammatory markers in patients receiving biologicals as these might present with nonspecific symptoms and fever might be absent. Any effort to detect deep-seated or metastatic infections should be made to prevent complications and to secure appropriate treatment. Although other risk factors for an invasive staphylococcal infection like psoriasis, recent corticosteroid injection, or prior hospitalisations were present, and therefore a directive

A STUDY OF DYSLIPIDAEMIA IN HIV PATIENTS RECEIVING HAART

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Chepuri Venkata Ravikumar

2018-02-01

Full Text Available BACKGROUND Human Immunodeficiency Virus (HIV was discovered in 1986 in Chennai (India amongst female sex workers by Dr. Suniti Solomon. Since then, HIV has spread to all parts of the country from the high-risk group to the antepartum population in many states at an alarming rate. The prevalence of dyslipidaemia and other risk factors for cardiovascular disease is significant in HIV/AIDS patients receiving highly active antiretroviral therapy (HAART, ranging from 20% to 80%. In view of the high prevalence of dyslipidaemia and the increased risk for cardiovascular diseases among patients with HIV/AIDS, this is a matter of concern for public health. MATERIALS AND METHODS 143 patients who had been receiving HAART for a minimum of two years from Rajiv Gandhi Institute of Medical Sciences, Kadapa, during the period of January 2015 to September 2016 were studied. They were divided into 4 regimens groups 1 TEL (Tenofovir, Efavirenz, Lamivudine 2 TLAR (Tenofovir, Lamivudine, Atazanavir, Ritonavir 3 ZLE (Zidovudine, Lamivudine, Efavirenz 4 ZLN (Zidovudine, Lamivudine, Nevirapine. Detailed history, demographic data, anthropometric measurements, serum lipid profile obtained and analysed. RESULTS Out of 143 patients, 90 (62.9% were males and 53 (37.1% were females. 68 (47.6% were in the 30-39 years age group accounted for maximum percentage of groups. Based on BMI only 3 (2.1% were obese, 24 (16.8% were of overweight. WaistHip ratio was abnormal in 117 (81.8% and 26 (18.2% were normal. The mean values for patients on TEL regimen are TC is 195.4 mg%, LDL 122.1 mg%, HDL 34.96 mg%, TG 194.02 mg% and TC/HDL is 5.5714. In patients treated with TLAR regimen the mean values of TC are 172.15 mg%, LDL 99.15 mg %, HDL 36.35 mg%, TG 183.35 mg% and TC/HDL is 4.8. In patients treated with ZLE regimen, TC is 201.64 mg%, LDL 123.27 mg%, HDL 35.68 mg%, TG 212.27 mg% and TC/HDL is 5.6364. In patients treated with ZLN regimen, TC is 162.1 mg%, LDL 91.94 mg%, HDL 35.98 mg%, TG

Can relaxation interventions reduce anxiety in patients receiving radiotherapy? outcomes and study validity

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Elith, C.A.; Perkins, B.A.; Johnson, L.S.; Skelly, M.H.; Dempsey, S.

2001-01-01

This study piloted the use of three relaxation interventions in an attempt to reduce levels of anxiety in patients who are immobilised for radiotherapy treatment of head and neck cancers, as well as trying to validate the study methodology. In addition to receiving normal radiation therapy treatment, 14 patients were assigned to either a control group not receiving the relaxation intervention or one of three validated relaxation intervention techniques; music therapy, aromatherapy or guided imagery. Patients in the intervention groups underwent the relaxation technique daily for the first seven days of treatment. On days 1, 3, 5 and 7 of treatment patients were required to complete the State Anxiety Inventory survey. While caution should be taken in accepting the results due to the small numbers of patients involved in the study and the non-randomised assignment of patients within the study, the results of the study demonstrate a clinically significant reduction in anxiety levels in each of the three relaxation interventions compared to the control group. The study demonstrated good study validity due to the ease of implementation, the unambiguous results generated, and the use of already validated anxiety intersections and measurement tools. Copyright (2001) Australian Institute of Radiography

Impact of whole-body rehabilitation in patients receiving chronic mechanical ventilation.

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Martin, Ubaldo J; Hincapie, Luis; Nimchuk, Mark; Gaughan, John; Criner, Gerard J

2005-10-01

To evaluate the prevalence and magnitude of weakness in patients receiving chronic mechanical ventilation and the impact of providing aggressive whole-body rehabilitation on conventional weaning variables, muscle strength, and overall functional status. Retrospective analysis of 49 consecutive patients. Multidisciplinary ventilatory rehabilitation unit in an academic medical center. Forty-nine consecutive chronic ventilator-dependent patients referred to a tertiary care hospital ventilator rehabilitation unit. None. Patients were 58 +/- 7 yrs old with multiple etiologies for respiratory failure. On admission, all patients were bedridden and had severe weakness of upper and lower extremities measured by a 5-point muscle strength score and a 7-point Functional Independence Measurement. Postrehabilitation, patients had increases in upper and lower extremity strength (p respiratory muscle training with an improvement in strength, weaning outcome, and functional status. Whole-body rehabilitation should be considered a significant component of their therapy.

Effect of radiotherapy on immunity function of cancer patients receiving radiotherapy

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Li Xinli; Zhu Shentao; Xu Jiuhong

2003-01-01

Objective: In order to observe the effect of radiotherapy on immunity function of cancer patients receiving radiotherapy. Methods: Cellular immunity is determined by APAAP; Humoral immunity is determined by transmission method. Results: The items of cellular immunity is lower than the control after radiotherapy. These items decrease continually. The difference between before and after radiotherapy has statistic significance. Of all Humoral immunity items, IgA, IgM decreased after radiotherapy and the difference has statistic significance. Conclusions: Radiotherapy can damage patients' immunity function

Depression and anxiety among chronic pain patients receiving prescription opioids and medical marijuana.

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Feingold, Daniel; Brill, Silviu; Goor-Aryeh, Itay; Delayahu, Yael; Lev-Ran, Shaul

2017-08-15

High rates of depression and anxiety have been consistently reported among patients suffering from chronic pain. Prescription opioids are one of the most common modalities for pharmacological treatment of pain, however in recent years medical marijuana(MM) has been increasingly used for pain control in the US and in several countries worldwide. The aim of this study was to compare levels of depression and anxiety among pain patients receiving prescription opioids and MM. Participants were patients suffering from chronic pain treated with prescription opioids (OP,N=474), MM (N=329) or both (OPMM,N=77). Depression and anxiety were assessed using the depression module of the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder scale (GAD-7). Prevalence of depression among patients in the OP, MM and OPMM groups was 57.1%, 22.3% and 51.4%, respectively and rates of anxiety were 48.4%, 21.5% and 38.7%, respectively. After controlling for confounders, patients in the OP group were significantly more likely to screen positive for depression (Adjusted Odds Ratio(AOR)=6.18;95%CI=4.12-9.338) and anxiety(AOR=4.12;CI=3.84-5.71)) compared to those in the MM group. Individuals in the OPMM group were more prone for depression (AOR for depression=3.34;CI=1.52-7.34)) compared to those in the MM group. Cross-sectional study, restricting inference of causality. Levels of depression and anxiety are higher among chronic pain patients receiving prescription opioids compared to those receiving MM. Findings should be taken into consideration when deciding on the most appropriate treatment modality for chronic pain, particularly among those at risk for depression and anxiety. Copyright © 2017 Elsevier B.V. All rights reserved.

Nursing care of patients receiving interventional therapy for hepatic artery stenosis after liver transplantation

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Wei Lin; Liu Shiguang

2009-01-01

Objective: To discuss the perioperative nursing care of patients who is going to receive interventional therapy for hepatic artery stenosis after liver transplantation and to provide useful reference for reducing surgery-related complication and for improving the prognosis of patients. Methods: Based on the patient's condition and operative requirement,we provided effective nursing care for 20 patients who were admitted to receive the interventional therapy for hepatic artery stenosis after liver transplantation. The nursing care included preoperative preparation,postoperative nursing and medical guidance at the time of discharge. Results: Interventional therapy was successfully performed in all 20 cases, and no hemorrhagic tendency or acute thrombosis occurred. Marked symptomatic improvement was obtained in all patients. Conclusion: The interventional therapy is an effective treatment for hepatic artery stenosis after liver transplantation. Intensive perioperative nursing care can well prevent the occurrence of surgery-related complications and can surely improve the therapeutic results. (authors)

Rehospitalizations and Emergency Department Visits after Hospital Discharge in Patients Receiving Maintenance Hemodialysis.

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Harel, Ziv; Wald, Ron; McArthur, Eric; Chertow, Glenn M; Harel, Shai; Gruneir, Andrea; Fischer, Hadas D; Garg, Amit X; Perl, Jeffrey; Nash, Danielle M; Silver, Samuel; Bell, Chaim M

2015-12-01

Clinical outcomes after a hospital discharge are poorly defined for patients receiving maintenance in-center (outpatient) hemodialysis. To describe the proportion and characteristics of these patients who are rehospitalized, visit an emergency department, or die within 30 days after discharge from an acute hospitalization, we conducted a population-based study of all adult patients receiving maintenance in-center hemodialysis who were discharged between January 1, 2003, and December 31, 2011, from 157 acute care hospitals in Ontario, Canada. For patients with more than one hospitalization, we randomly selected a single hospitalization as the index hospitalization. Of the 11,177 patients included in the final cohort, 1926 (17%) were rehospitalized, 2971 (27%) were treated in the emergency department, and 840 (7.5%) died within 30 days of discharge. Complications of type 2 diabetes mellitus were the most common reason for rehospitalization, whereas heart failure was the most common reason for an emergency department visit. In multivariable analysis using a cause-specific Cox proportional hazards model, the following characteristics were associated with 30-day rehospitalization: older age, the number of hospital admissions in the preceding 6 months, the number of emergency department visits in the preceding 6 months, higher Charlson comorbidity index score, and the receipt of mechanical ventilation during the index hospitalization. Thus, a large proportion of patients receiving maintenance in-center hemodialysis will be readmitted or visit an emergency room within 30 days of an acute hospitalization. A focus on improving care transitions from the inpatient setting to the outpatient dialysis unit may improve outcomes and reduce healthcare costs. Copyright © 2015 by the American Society of Nephrology.

Experiences of Family Members of Dying Patients Receiving Palliative Sedation.

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Tursunov, Olga; Cherny, Nathan I; Ganz, Freda DeKeyser

2016-11-01

To describe the experience of family members of patients receiving palliative sedation at the initiation of treatment and after the patient has died and to compare these experiences over time.
. Descriptive comparative study.
. Oncology ward at Shaare Zedek Medical Center in Jerusalem, Israel.
. A convenience sample of 34 family members of dying patients receiving palliative sedation. 
. A modified version of a questionnaire describing experiences of family members with palliative sedation was administered during palliative sedation and one to four months after the patient died. Descriptive statistics were used to describe the results of the questionnaire, and appropriate statistical analyses were conducted for comparisons over time.
. Experiences of family members and time.
. Most relatives were satisfied with the sedation and staff support. Palliative sedation was experienced as an ethical way to relieve suffering. However, one-third felt that it shortened the patient's life. An explanation of the treatment was given less than half of the time and was usually given on the same day treatment was started. This explanation was given by physicians and nurses. Many felt that they were not ready for changes in the patient's condition and wanted increased opportunities to discuss the treatment with oncology care providers. No statistically significant differences in experiences were found over time. 
. Relatives' experiences of palliative sedation were generally positive and stable over time. Important experiences included timing of the initiation of sedation, timing and quality of explanations, and communication.
. Nurses should attempt to initiate discussions of the possible role of sedation in the event of refractory symptoms and follow through with continued discussions. The management of refractory symptoms at the end of life, the role of sedation, and communication skills associated with decision making related to palliative sedation should be a

External radiation dose from patients received diagnostic doses of 201 T1-Chloride and 99 Tc-MIBI

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Dadashzadeh, S.; Sattari, A.; Nasiroghli, G.A.

2002-01-01

Patients receiving diagnostic doses of radiopharmaceuticals become a source of contamination and exposure for those who come in contact with them, such as nuclear medicine technologists, relatives and nurses. Therefore, the measurement of external radiation dose from these patients is necessary. In this study, the dose rates at distances of 10, 50 and 100 cm from 70 patients who received diagnostic amounts of 201 T1-Chloride and 99 Tc-MIBI was measures. The results showed that the maximum external radiation dose rates for 201 T1 and 99 Tc-MIBI were 18.4 and 75.0 μ Sv.h -1 , respectively, at 5 cm distance from the patients. The average radiation dose received by nuclear medicine technologists, considering their close contact during one working day was 12.5 ± 3.4μ Sv. The highest received dose was 22.7 μSv, which was well below the acceptable dose limit

Older age impacts on survival outcome in patients receiving curative surgery for solid cancer

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Chang-Hsien Lu

2018-07-01

Full Text Available Summary: Background: Given the global increase in aging populations and cancer incidence, understanding the influence of age on postoperative outcome after cancer surgery is imperative. This study aimed to evaluate the impact of age on survival outcome in solid cancer patients receiving curative surgery. Methods: A total of 37,288 patients receiving curative surgeries for solid cancers between 2007 and 2012 at four affiliated Chang Gung Memorial Hospital were included in the study. All patients were categorized into age groups by decades for survival analysis. Results: The percentages of patient populations aged <40 years, 40–49 years, 50–59 years, 60–69 years, 70–79 years, and ≥80 years were 9.7%, 17.7%, 27.8%, 22.1%, 16.9%, and 5.7%, respectively. The median follow-up period was 38.9 months (range, 22.8–60.4 months and the overall, cancer-specific, and noncancer-specific mortality rates were 26.0%, 17.6%, and 8.5%, respectively. The overall mortality rate of patients in different age groups were 18.5%, 21.1%, 22.0%, 25.3%, 35.3%, and 49.0%, respectively. Compared to patients aged <40 years, more significant decrease in long-term survival were observed in aging patients. Multivariate analysis showed higher postoperative short-term mortality rates in patients older than 70 years, and the adjusted odds ratio of mortality risk ranged from 1.47 to 1.74 and 2.26 to 3.03 in patients aged 70–79 years and ≥80 years, respectively, compared to those aged <40 years. Conclusion: Aging was a negative prognostic factor of survival outcome in solid cancer patients receiving curative surgery. After adjustment of other clinicopathologic factors, the influence of age on survival outcome was less apparent in the elderly. Keywords: Age, Solid cancer, Surgical resection, Prognosis

Palliative medicine consultation for preparedness planning in patients receiving left ventricular assist devices as destination therapy.

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Swetz, Keith M; Freeman, Monica R; AbouEzzeddine, Omar F; Carter, Kari A; Boilson, Barry A; Ottenberg, Abigale L; Park, Soon J; Mueller, Paul S

2011-06-01

To assess the benefit of proactive palliative medicine consultation for delineation of goals of care and quality-of-life preferences before implantation of left ventricular assist devices as destination therapy (DT). We retrospectively reviewed the cases of patients who received DT between January 15, 2009, and January 1, 2010. Of 19 patients identified, 13 (68%) received proactive palliative medicine consultation. Median time of palliative medicine consultation was 1 day before DT implantation (range, 5 days before to 16 days after). Thirteen patients (68%) completed advance directives. The DT implantation team and families reported that preimplantation discussions and goals of care planning made postoperative care more clear and that adverse events were handled more effectively. Currently, palliative medicine involvement in patients receiving DT is viewed as routine by cardiac care specialists. Proactive palliative medicine consultation for patients being considered for or being treated with DT improves advance care planning and thus contributes to better overall care of these patients. Our experience highlights focused advance care planning, thorough exploration of goals of care, and expert symptom management and end-of-life care when appropriate.

Prognostic Significance of Ultraearly Hematoma Growth in Spontaneous Intracerebral Hemorrhage Patients Receiving Hematoma Evacuation.

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Yu, Zhiyuan; Zheng, Jun; Guo, Rui; Ma, Lu; Li, Mou; Wang, Xiaoze; Lin, Sen; You, Chao; Li, Hao

2018-01-01

To investigate the association between ultraearly hematoma growth (uHG) and clinical outcome in patients with spontaneous intracerebral hemorrhage (sICH) receiving hematoma evacuation. Supratentorial sICH patients receiving hematoma evacuation within 24 hours after ictus were enrolled in this study. uHG was defined as baseline hematoma volume/onset-to-computed tomography (CT) time (mL/h). The outcome was assessed by the modified Rankin Scale (mRS) score at 3 months. Unfavorable outcome was defined as mRS >2. A total of 93 patients were enrolled in this study. The mean uHG was 10.3 ± 5.5 mL/h. In 69 (74.2%) of patients, the outcome was unfavorable at 3 months. The uHG in patients with unfavorable outcome were significantly higher than in those with favorable outcome (11.0 ± 6.1 mL/h vs. 8.3 ± 2.5 mL/h, P = 0.003). The optimal cutoff of uHG for predicting unfavorable outcome was 8.7 mL/h. The sensitivity, specificity, positive predictive value, and negative predictive value of uHG >8.7 mL/h for predicting unfavorable outcome were 56.5%, 75.0%, 86.7%, and 37.5%, respectively. uHG is a helpful predictor of unfavorable outcome in sICH patients treated with hematoma evacuation. The optimal cutoff of uHG to assist in predicting unfavorable outcome in sICH patients receiving hematoma evacuation is 8.7mL/h. Copyright © 2017 Elsevier Inc. All rights reserved.

Identifying drivers of overall satisfaction in patients receiving HIV primary care: a cross-sectional study.

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Bich N Dang

Full Text Available OBJECTIVE: This study seeks to understand the drivers of overall patient satisfaction in a predominantly low-income, ethnic-minority population of HIV primary care patients. The study's primary aims were to determine 1 the component experiences which contribute to patients' evaluations of their overall satisfaction with care received, and 2 the relative contribution of each component experience in explaining patients' evaluation of overall satisfaction. METHODS: We conducted a cross-sectional study of 489 adult patients receiving HIV primary care at two clinics in Houston, Texas, from January 13-April 21, 2011. The participation rate among eligible patients was 94%. The survey included 15 questions about various components of the care experience, 4 questions about the provider experience and 3 questions about overall care. To ensure that the survey was appropriately tailored to our clinic population and the list of component experiences reflected all aspects of the care experience salient to patients, we conducted in-depth interviews with key providers and clinic staff and pre-tested the survey instrument with patients. RESULTS: Patients' evaluation of their provider correlated the strongest with their overall satisfaction (standardized β = 0.445, p<0.001 and accounted for almost half of the explained variance. Access and availability, like clinic hours and ease of calling the clinic, also correlated with overall satisfaction, but less strongly. Wait time and parking, despite receiving low patient ratings, did not correlate with overall satisfaction. CONCLUSIONS: The patient-provider relationship far exceeds other component experiences of care in its association with overall satisfaction. Our study suggests that interventions to improve overall patient satisfaction should focus on improving patients' evaluation of their provider.

Tear Film and Ocular Surface Changes in Patients Receiving Systemic Isotretinoin

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Ebru Nevin Çetin

2013-10-01

Full Text Available Purpose: Our aim in this study was to assess the ocular surface and tear film changes in acne vulgaris patients receiving systemic isotretinoin. Material and Method: Twenty-two eyes of 22 patients who received oral isotretinoin (roaccutane®, 0.7 mg/kg/day for nodular acne vulgaris were enrolled in this prospective study. Tear film break-up time (BUT, Schirmer 1 test scores with anesthesia, ocular surface disease index (OSDI scores and conjunctival impression cytology scores were recorded before treatment and at 3- and 6-month visits following the beginning of treatment. Results: BUT values decreased and OSDI scores significantly increased at 3 months after treatment (p=0.007 and p=0.018, paired samples test. Schirmer scores did not significantly change by isotretinoin treatment. Of 9 eyes with impression cytology specimens, 4 revealed normal conjunctival findings before treatment. At the 3rd month, there was an increase in the scores characterized by decrease of Goblet cells, and at 6 months of treatment, normal conjunctival findings did not exist in any of the patients (p=0.004, Friedman test. Discussion: Systemic isotretinoin treatment can cause alterations in the tear film and cause dry eye symptoms. (Turk J Ophthalmol 2013; 43: 309-12

Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

Institute of Scientific and Technical Information of China (English)

Hong; Sun; Man-Sheng; Zhu; Wen-Rui; Wu; Xiang-De; Shi; Lei-Bo; Xu

2014-01-01

As the leading cause of disease-related deaths,cancer is a major public health threat worldwide.Surgical resection is still the first-line therapy for patients with early-stage cancers.However,postoperative relapse and metastasis remain the cause of 90%of deaths of patients with solid organ malignancies,including hepatocellular carcinoma(HCC).With the rapid development of molecular biology techniques in recent years,molecularly targeted therapies using monoclonal antibodies,small molecules,and vaccines have become a milestone in cancer therapeutic by significantly improv-ing the survival of cancer patients,and have opened a window of hope for patients with advanced cancer.Hypervascularization is a major characteristic of HCC.It has been reported that anti-angiogenic treatments,which inhibit blood vessel formation,are highly effective for treating HCC.However,the efficacy and safety of anti-angiogenesis therapies remain controversial.Sorafenib is an oral multikinase inhibitor with antiproliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC.While sorafenib has shown promising therapeutic effects,substantial evidence of primary and acquired resistance to sorafenib has been reported.Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC,but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib.Therefore,understanding the mechanism(s)underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC.This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.

Quality indicators for prostate radiotherapy: are patients disadvantaged by receiving treatment in a 'generalist' centre?

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Freeman, Amanda R; Roos, Daniel E; Kim, Laurence

2015-04-01

The purpose of this retrospective review was to evaluate concordance with evidence-based quality indicator guidelines for prostate cancer patients treated radically in a 'generalist' (as distinct from 'sub-specialist') centre. We were concerned that the quality of treatment may be lower in a generalist centre. If so, the findings could have relevance for many radiotherapy departments that treat prostate cancer. Two hundred fifteen consecutive patients received external beam radiotherapy (EBRT) and/or brachytherapy between 1.10.11 and 30.9.12. Treatment was deemed to be in line with evidence-based guidelines if the dose was: (i) 73.8-81 Gy at 1.8-2.0 Gy/fraction for EBRT alone (eviQ guidelines); (ii) 40-50 Gy (EBRT) for EBRT plus high-dose rate (HDR) brachytherapy boost (National Comprehensive Cancer Network (NCCN) guidelines); and (iii) 145 Gy for low dose rate (LDR) I-125 monotherapy (NCCN). Additionally, EBRT beam energy should be ≥6 MV using three-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT), and high-risk patients should receive neo-adjuvant androgen-deprivation therapy (ADT) (eviQ/NCCN). Treatment of pelvic nodes was also assessed. One hundred four high-risk, 84 intermediate-risk and 27 low-risk patients (NCCN criteria) were managed by eight of nine radiation oncologists. Concordance with guideline doses was confirmed in: (i) 125 of 136 patients (92%) treated with EBRT alone; (ii) 32 of 34 patients (94%) treated with EBRT + HDR BRT boost; and (iii) 45 of 45 patients (100%) treated with LDR BRT alone. All EBRT patients were treated with ≥6 MV beams using 3D-CRT (78%) or IMRT (22%). 84%, 21% and 0% of high-risk, intermediate-risk and low-risk patients received ADT, respectively. Overall treatment modality choice (including ADT use and duration where assessable) was concordant with guidelines for 176/207 (85%) of patients. The vast majority of patients were treated concordant with evidence-based guidelines suggesting that

Clinical Outcomes of Patients Receiving Integrated PET/CT-Guided Radiotherapy for Head and Neck Carcinoma

International Nuclear Information System (INIS)

Vernon, Matthew R.; Maheshwari, Mohit; Schultz, Christopher J.; Michel, Michelle A.; Wong, Stuart J.; Campbell, Bruce H.; Massey, Becky L.; Wilson, J. Frank; Wang Dian

2008-01-01

Purpose: We previously reported the advantages of 18 F-fluorodeoxyglucose-positron emission tomography (PET) fused with CT for radiotherapy planning over CT alone in head and neck carcinoma (HNC). The purpose of this study was to evaluate clinical outcomes and the predictive value of PET for patients receiving PET/CT-guided definitive radiotherapy with or without chemotherapy. Methods and Materials: From December 2002 to August 2006, 42 patients received PET/CT imaging as part of staging and radiotherapy planning. Clinical outcomes including locoregional recurrence, distant metastasis, death, and treatment-related toxicities were collected retrospectively and analyzed for disease-free and overall survival and cumulative incidence of recurrence. Results: Median follow-up from initiation of treatment was 32 months. Overall survival and disease-free survival were 82.8% and 71.0%, respectively, at 2 years, and 74.1% and 66.9% at 3 years. Of the 42 patients, seven recurrences were identified (three LR, one DM, three both LR and DM). Mean time to recurrence was 9.4 months. Cumulative risk of recurrence was 18.7%. The maximum standard uptake volume (SUV) of primary tumor, adenopathy, or both on PET did not correlate with recurrence, with mean values of 12.0 for treatment failures vs. 11.7 for all patients. Toxicities identified in those patients receiving intensity modulated radiation therapy were also evaluated. Conclusions: A high level of disease control combined with favorable toxicity profiles was achieved in a cohort of HNC patients receiving PET/CT fusion guided radiotherapy plus/minus chemotherapy. Maximum SUV of primary tumor and/or adenopathy was not predictive of risk of disease recurrence

Factors associated with residual gastroesophageal reflux disease symptoms in patients receiving proton pump inhibitor maintenance therapy.

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Kawara, Fumiaki; Fujita, Tsuyoshi; Morita, Yoshinori; Uda, Atsushi; Masuda, Atsuhiro; Saito, Masaya; Ooi, Makoto; Ishida, Tsukasa; Kondo, Yasuyuki; Yoshida, Shiei; Okuno, Tatsuya; Yano, Yoshihiko; Yoshida, Masaru; Kutsumi, Hiromu; Hayakumo, Takanobu; Yamashita, Kazuhiko; Hirano, Takeshi; Hirai, Midori; Azuma, Takeshi

2017-03-21

To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice. The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed. The FSSG scores ranged from 1 to 28 points (median score: 7.5 points), and 19 patients (48.7%) had a score of 8 points or more. The patients' GSRS scores were significantly correlated with their FSSG scores (correlation coefficient = 0.47, P reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P reflux disease patients were significantly lower than those of the other patients (total scores: 5.5 ± 1.0 vs 11.8 ± 6.3, P < 0.05; dysmotility symptom-related scores: 1.0 ± 0.4 vs 6.0 ± 0.8, P < 0.01). Approximately half of the GERD patients receiving maintenance PPI therapy had residual symptoms associated with a lower quality of life, and the CYP2C19 genotype appeared to be associated with these residual symptoms.

Bevacizumab Demonstrates Prolonged Disease Stabilization in Patients with Heavily Pretreated Metastatic Renal Cell Carcinoma: A Case Series and Review of the Literature

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Nicole M. Agostino

2010-01-01

Full Text Available There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC. These include the immunotherapeutics, alfa-interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR, such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study.

Elderly patients with suspected chronic digoxin toxicity: A comparison of clinical characteristics of patients receiving and not receiving digoxin-Fab.

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Arbabian, Hooman; Lee, Hwee Min; Graudins, Andis

2018-04-01

The aim of the present study was to compare clinical features of patients with elevated serum digoxin concentrations who were treated with digoxin-Fab with those where the immunotherapy was not given by a tertiary hospital toxicology service. This was a retrospective series of patients with supratherapeutic serum digoxin concentrations referred to the toxicology service from August 2013 to October 2015. Data collected included demographics, presenting complaint, digoxin dose, other medications taken, serum digoxin, potassium and creatinine concentration on presentation and initial and post-digoxin-Fab heart rate. There were 47 referrals. Digoxin-Fab was administered in 21 cases. It was given more commonly when the heart rate was 5.0 mmol/L. Patients receiving digoxin-Fab were more likely to be on maintenance therapy with beta-blockers or calcium channel blockers (95% vs 61%; OR 13.1; 95% CI 1.5-113) and/or potassium-sparing medications (95% vs 54%; OR 17.1; 95% CI 2.0-147). They had elevated serum creatinine (76% vs 42%; OR 8.2; 95% CI 1.9-34), higher serum potassium (median: 5.1 mmol/L vs 4.2 mmol/L, P = 0.02), higher serum digoxin concentration (median: 3.5 nmol/L vs 2.3 nmol/L, P = 0.02) and pretreatment heart rate Fab. However, individual heart rate response to digoxin-Fab was variable. Digoxin-Fab was more commonly administered when heart rate was Fab was variable as patients were using other negative chronotropic medications. In symptomatic bradycardic patients on multiple heart failure medications, positive chronotropic and potassium-lowering therapies should be considered in concert with digoxin-Fab. © 2018 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Effects of Natural Sounds on Pain: A Randomized Controlled Trial with Patients Receiving Mechanical Ventilation Support.

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Saadatmand, Vahid; Rejeh, Nahid; Heravi-Karimooi, Majideh; Tadrisi, Sayed Davood; Vaismoradi, Mojtaba; Jordan, Sue

2015-08-01

Nonpharmacologic pain management in patients receiving mechanical ventilation support in critical care units is under investigated. Natural sounds may help reduce the potentially harmful effects of anxiety and pain in hospitalized patients. The aim of this study was to examine the effect of pleasant, natural sounds on self-reported pain in patients receiving mechanical ventilation support, using a pragmatic parallel-arm, randomized controlled trial. The study was conducted in a general adult intensive care unit of a high-turnover teaching hospital, in Tehran, Iran. Between October 2011 and June 2012, we recruited 60 patients receiving mechanical ventilation support to the intervention (n = 30) and control arms (n = 30) of a pragmatic parallel-group, randomized controlled trial. Participants in both arms wore headphones for 90 minutes. Those in the intervention arm heard pleasant, natural sounds, whereas those in the control arm heard nothing. Outcome measures included the self-reported visual analog scale for pain at baseline; 30, 60, and 90 minutes into the intervention; and 30 minutes post-intervention. All patients approached agreed to participate. The trial arms were similar at baseline. Pain scores in the intervention arm fell and were significantly lower than in the control arm at each time point (p natural sounds via headphones is a simple, safe, nonpharmacologic nursing intervention that may be used to allay pain for up to 120 minutes in patients receiving mechanical ventilation support. Copyright © 2015 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Malfunctions of Implantable Cardiac Devices in Patients Receiving Proton Beam Therapy: Incidence and Predictors

International Nuclear Information System (INIS)

Gomez, Daniel R.; Poenisch, Falk; Pinnix, Chelsea C.; Sheu, Tommy; Chang, Joe Y.; Memon, Nada; Mohan, Radhe; Rozner, Marc A.; Dougherty, Anne H.

2013-01-01

Purpose: Photon therapy has been reported to induce resets of implanted cardiac devices, but the clinical sequelae of treating patients with such devices with proton beam therapy (PBT) are not well known. We reviewed the incidence of device malfunctions among patients undergoing PBT. Methods and Materials: From March 2009 through July 2012, 42 patients with implanted cardiac implantable electronic devices (CIED; 28 pacemakers and 14 cardioverter-defibrillators) underwent 42 courses of PBT for thoracic (23, 55%), prostate (15, 36%), liver (3, 7%), or base of skull (1, 2%) tumors at a single institution. The median prescribed dose was 74 Gy (relative biological effectiveness; range 46.8-87.5 Gy), and the median distance from the treatment field to the CIED was 10 cm (range 0.8-40 cm). Maximum proton and neutron doses were estimated for each treatment course. All CIEDs were checked before radiation delivery and monitored throughout treatment. Results: Median estimated peak proton and neutron doses to the CIED in all patients were 0.8 Gy (range 0.13-21 Gy) and 346 Sv (range 11-1100 mSv). Six CIED malfunctions occurred in 5 patients (2 pacemakers and 3 defibrillators). Five of these malfunctions were CIED resets, and 1 patient with a defibrillator (in a patient with a liver tumor) had an elective replacement indicator after therapy that was not influenced by radiation. The mean distance from the proton beam to the CIED among devices that reset was 7.0 cm (range 0.9-8 cm), and the mean maximum neutron dose was 655 mSv (range 330-1100 mSv). All resets occurred in patients receiving thoracic PBT and were corrected without clinical incident. The generator for the defibrillator with the elective replacement indicator message was replaced uneventfully after treatment. Conclusions: The incidence of CIED resets was about 20% among patients receiving PBT to the thorax. We recommend that PBT be avoided in pacing-dependent patients and that patients with any type of CIED receiving

Fluorescence imaging of bombesin and transferrin receptor expression is comparable to 18F-FDG PET in early detection of sorafenib-induced changes in tumor metabolism.

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Jen-Chieh Tseng

Full Text Available Physical measurement of tumor volume reduction is the most commonly used approach to assess tumor progression and treatment efficacy in mouse tumor models. However, it is relatively insensitive, and often requires long treatment courses to achieve gross physical tumor destruction. As alternatives, several non-invasive imaging methods such as bioluminescence imaging (BLI, fluorescence imaging (FLI and positron emission tomography (PET have been developed for more accurate measurement. As tumors have elevated glucose metabolism, 18F-fludeoxyglucose (18F-FDG has become a sensitive PET imaging tracer for cancer detection, diagnosis, and efficacy assessment by measuring alterations in glucose metabolism. In particular, the ability of 18F-FDG imaging to detect drug-induced effects on tumor metabolism at a very early phase has dramatically improved the speed of decision-making regarding treatment efficacy. Here we demonstrated an approach with FLI that offers not only comparable performance to PET imaging, but also provides additional benefits, including ease of use, imaging throughput, probe stability, and the potential for multiplex imaging. In this report, we used sorafenib, a tyrosine kinase inhibitor clinically approved for cancer therapy, for treatment of a mouse tumor xenograft model. The drug is known to block several key signaling pathways involved in tumor metabolism. We first identified an appropriate sorafenib dose, 40 mg/kg (daily on days 0-4 and 7-10, that retained ultimate therapeutic efficacy yet provided a 2-3 day window post-treatment for imaging early, subtle metabolic changes prior to gross tumor regression. We then used 18F-FDG PET as the gold standard for assessing the effects of sorafenib treatment on tumor metabolism and compared this to results obtained by measurement of tumor size, tumor BLI, and tumor FLI changes. PET imaging showed ~55-60% inhibition of tumor uptake of 18F-FDG as early as days 2 and 3 post-treatment, without

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

Quality of life assessment in asthmatic patients receiving fluticasone compared with equipotent doses of beclomethasone or budesonide

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Thomas Sabin

2005-01-01

Full Text Available Aims: To assess the quality of life in patients with asthma receiving either fluticasone or other inhaled steroids like beclomethasone or budesonide. To assess the effect of equipotent dosage of inhaled steroids at 3 months duration. Methods: Patients were randomised to receive either fluticasone or beclomethasone/budesonide. After spirometry, St. George′s Respiratory Questionnaire (SGRQ was administered at baseline and at 15 th , 30 th , 45 th , 60 th and 90 th day, to assess improvement in lung function and HRQoL. Results: Out of 96 patients who were enrolled, eighty patients completed three months duration of the study, while sixteen patients dropped out. Forty patients received fluticasone and forty received either beclomethasone or budesonide. No significant difference (p>0.05 was found in the baseline values of St. George′s Respiratory Questionnaire (SGRQ scores and Forced Expiratory Volume at first second (FEV 1 between the two groups. However, significant difference (p< 0.05 was noted between the above two groups, in Quality of Life (QoL but not in pulmonary functions, on 15th day favoring fluticasone. No significant difference (p>0.05 was noted either in QoL or in pulmonary function tests on subsequent follow-ups. Conclusion: Early response in terms of improved QoL was observed in fluticasone treated group in patients with moderate to severe asthma.

Effectiveness of pharmacist dosing adjustment for critically ill patients receiving continuous renal replacement therapy: a comparative study

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Jiang SP

2014-06-01

Full Text Available Sai-Ping Jiang,1 Zheng-Yi Zhu,2 Xiao-Liang Wu,3 Xiao-Yang Lu,1 Xing-Guo Zhang,1 Bao-Hua Wu1 1Department of Pharmacy, the First Affiliated Hospital, 2Department of Pharmacy, Children’s Hospital, College of Medicine, Zhejiang University, Hangzhou, 3Intensive Care Unit, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China Background: The impact of continuous renal replacement therapy (CRRT on drug removal is complicated; pharmacist dosing adjustment for these patients may be advantageous. This study aims to describe the development and implementation of pharmacist dosing adjustment for critically ill patients receiving CRRT and to examine the effectiveness of pharmacist interventions. Methods: A comparative study was conducted in an intensive care unit (ICU of a university-affiliated hospital. Patients receiving CRRT in the intervention group received specialized pharmacy dosing service from pharmacists, whereas patients in the no-intervention group received routine medical care without pharmacist involvement. The two phases were compared to evaluate the outcome of pharmacist dosing adjustment. Results: The pharmacist carried out 233 dosing adjustment recommendations for patients receiving CRRT, and 212 (90.98% of the recommendations were well accepted by the physicians. Changes in CRRT-related variables (n=144, 61.81% were the most common risk factors for dosing errors, whereas antibiotics (n=168, 72.10% were the medications most commonly associated with dosing errors. Pharmacist dosing adjustment resulted in a US$2,345.98 ICU cost savings per critically ill patient receiving CRRT. Suspected adverse drug events in the intervention group were significantly lower than those in the preintervention group (35 in 27 patients versus [vs] 18 in eleven patients, P<0.001. However, there was no significant difference between length of ICU stay and mortality after pharmacist dosing adjustment, which

Do Inflammatory Bowel Disease patients with anxiety and depressive symptoms receive the care they need?

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Bennebroek Evertsz', F; Thijssens, N A M; Stokkers, P C F; Grootenhuis, M A; Bockting, C L H; Nieuwkerk, P T; Sprangers, M A G

2012-02-01

Inflammatory Bowel Disease (IBD) patients with anxiety and/or depressive symptoms may not receive the care they need. Provision of care requires insight into the factors affecting these psychiatric symptoms. The study was designed to examine the extent to which: (1) IBD patients with anxiety and/or depressive symptoms receive mental treatment and (2) clinical and socio-demographic variables are associated with these symptoms. 231 adult IBD patients (79% response rate), attending a tertiary care center, completed standardized measures on anxiety and depressive symptoms (HADS), quality of life (SF-12) and mental health care use (TIC-P). Diagnosis and disease activity were determined by the gastroenterologist. 43% had high levels of anxiety and/or depressive symptoms, indicative of a psychiatric disorder (HADS ≥ 8), of whom 18% received psychological treatment and 21% used psychotropic medication. In multivariate analysis, high disease activity was associated with anxiety (OR=2.72 | psymptoms and poor quality of life, psychiatric complaints in IBD patients were undertreated. Screening for and treatment of psychiatric symptoms should become an integral part of IBD medical care. Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Health status, food insecurity, and time allocation patterns of patients with AIDS receiving antiretroviral treatment in South Africa.

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Bhargava, Alok; Booysen, Frederik Le Roux; Walsh, Corinna M

2018-03-01

For patients with AIDS receiving antiretroviral treatment (ART) in South Africa via public clinics, improvements in nutritional status and economic productivity are likely to depend on adherence to drug regimen and quality of diet reflected in protein and micronutrient intakes. This study randomized 643 patients receiving ART from public clinics in the Free State Province into a Control group, a treatment group receiving adherence support, and a treatment group receiving adherence support and a nutritious food supplement. The data on food insecurity levels and time spent on various activities were analyzed for assessing the impact of the intervention programs. The main results were, first, changes between survey rounds 1 and 3 were significant at the 5% level for outcomes such as food insecurity levels and CD4 cell counts. Moreover, there was a significant reduction in food insecurity levels of patients with BMI less than 25 who received the nutritious food supplement. Second, the estimated parameters from models for patients' food insecurity levels showed that household incomes were significantly associated with lower food insecurity levels. Third, patients' BMI was a significant predictor of time spent on sedentary, moderate and overall activity levels, and it was important to separately evaluate the effects of BMI for under-weight and over-weight patients. Overall, the results indicated the need for reducing food insecurity levels, and for designing different interventions for under-weight and over-weight patients with AIDS for enhancing their labor productivity.

Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Ranitidine or Sucralfate as Stress Ulcer Prophylaxis

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Smita Prakash

2008-01-01

We concluded that stress ulcer prophylaxis with ranitidine increases the risk for late- onset pneumonia in mechanically ventilated critically ill patients by favoring gastric colonization by gram- negative bacilli compared with sucralfate. In patients receiving mechanical ventilation, the use of sucralfate may be preferable to H 2 blockers.

Different rectal toxicity tolerance with and without simultaneous conventionally-fractionated pelvic lymph node treatment in patients receiving hypofractionated prostate radiotherapy

International Nuclear Information System (INIS)

McDonald, Andrew M; Baker, Christopher B; Popple, Richard A; Shekar, Kiran; Yang, Eddy S; Jacob, Rojymon; Cardan, Rex; Kim, Robert Y; Fiveash, John B

2014-01-01

To investigate added morbidity associated with the addition of pelvic elective nodal irradiation (ENI) to hypofractionated radiotherapy to the prostate. Two-hundred twelve patients, treated with hypofractionated radiotherapy to the prostate between 2004 and 2011, met the inclusion criteria for the analysis. All patients received 70 Gy to the prostate delivered over 28 fractions and 103 (49%) received ENI consisting of 50.4 Gy to the pelvic lymphatics delivered simultaneously in 1.8 Gy fractions. The mean dose-volume histograms were compared between the two subgroups defined by use of ENI, and various dose-volume parameters were analyzed for effect on late lower gastrointestinal (GI) and genitourinary (GU) toxicity. Acute grade 2 lower GI toxicity occurred in 38 (37%) patients receiving ENI versus 19 (17%) in those who did not (p = 0.001). The Kaplan-Meier estimate of grade ≥ 2 lower GI toxicity at 3 years was 15.3% for patients receiving ENI versus 5.3% for those who did not (p = 0.026). Each rectal isodose volume was increased for patients receiving ENI up to 50 Gy (p ≤ 0.021 for each 5 Gy increment). Across all patients, the absolute V 70 of the rectum was the only predictor of late GI toxicity. When subgroups, defined by the use of ENI, were analyzed separately, rectal V 70 was only predictive of late GI toxicity for patients who received ENI. For patients receiving ENI, V 70 > 3 cc was associated with an increased risk of late GI events. Elective nodal irradiation increases the rates of acute and late GI toxicity when delivered simultaneously with hypofractioanted prostate radiotherapy. The use of ENI appears to sensitize the rectum to hot spots, therefore we recommend added caution to minimize the volume of rectum receiving 100% of the prescription dose in these patients

Different rectal toxicity tolerance with and without simultaneous conventionally-fractionated pelvic lymph node treatment in patients receiving hypofractionated prostate radiotherapy.

Science.gov (United States)

McDonald, Andrew M; Baker, Christopher B; Popple, Richard A; Shekar, Kiran; Yang, Eddy S; Jacob, Rojymon; Cardan, Rex; Kim, Robert Y; Fiveash, John B

2014-06-03

To investigate added morbidity associated with the addition of pelvic elective nodal irradiation (ENI) to hypofractionated radiotherapy to the prostate. Two-hundred twelve patients, treated with hypofractionated radiotherapy to the prostate between 2004 and 2011, met the inclusion criteria for the analysis. All patients received 70 Gy to the prostate delivered over 28 fractions and 103 (49%) received ENI consisting of 50.4 Gy to the pelvic lymphatics delivered simultaneously in 1.8 Gy fractions. The mean dose-volume histograms were compared between the two subgroups defined by use of ENI, and various dose-volume parameters were analyzed for effect on late lower gastrointestinal (GI) and genitourinary (GU) toxicity. Acute grade 2 lower GI toxicity occurred in 38 (37%) patients receiving ENI versus 19 (17%) in those who did not (p = 0.001). The Kaplan-Meier estimate of grade ≥ 2 lower GI toxicity at 3 years was 15.3% for patients receiving ENI versus 5.3% for those who did not (p = 0.026). Each rectal isodose volume was increased for patients receiving ENI up to 50 Gy (p ≤ 0.021 for each 5 Gy increment). Across all patients, the absolute V70 of the rectum was the only predictor of late GI toxicity. When subgroups, defined by the use of ENI, were analyzed separately, rectal V70 was only predictive of late GI toxicity for patients who received ENI. For patients receiving ENI, V70 > 3 cc was associated with an increased risk of late GI events. Elective nodal irradiation increases the rates of acute and late GI toxicity when delivered simultaneously with hypofractioanted prostate radiotherapy. The use of ENI appears to sensitize the rectum to hot spots, therefore we recommend added caution to minimize the volume of rectum receiving 100% of the prescription dose in these patients.

A systematic review of oral fungal infections in patients receiving cancer therapy

NARCIS (Netherlands)

Lalla, Rajesh V.; Latortue, Marie C.; Hong, Catherine H.; Ariyawardana, Anura; D'Amato-Palumbo, Sandra; Fischer, Dena J.; Martof, Andrew; Nicolatou-Galitis, Ourania; Patton, Lauren L.; Elting, Linda S.; Spijkervet, Fred K. L.; Brennan, Michael T.

The aims of this systematic review were to determine, in patients receiving cancer therapy, the prevalence of clinical oral fungal infection and fungal colonization, to determine the impact on quality of life and cost of care, and to review current management strategies for oral fungal infections.

Radioembolization with Yttrium-90 microspheres for patients with unresectable hepatocellular carcinoma.

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Bhangoo, Munveer Singh; Karnani, Diraj R; Hein, Paul N; Giap, Huan; Knowles, Harry; Issa, Chris; Steuterman, Steve; Pockros, Paul; Frenette, Catherine

2015-10-01

Hepatocellular carcinoma (HCC) is aggressive primary malignancy of the liver that most commonly presents late in the disease course. As a result, the majority of patients are not candidates for curative therapies. Locoregional therapies including Yttrium-90 (Y-90) radioembolization play an important role in management of the vast majority of patients with HCC. Patients with unnresectable HCC (n=17) treated with Y-90 radioembolization from 2005 to 2014 were evaluated retrospectively. Data was abstracted from medical records including patient charts, laboratory data, and imaging. Toxicities were recorded using Common Terminology Criteria 3.0. Response was recorded according to modified RECIST (mRECIST) criteria. Seventeen patients received 33 treatments with Y-90 radioembolization. A majority (65%) received TheraSphere with a minority (35%) receiving SIR-Spheres. The median treatment activity delivered was 1.725 gBq (range, 1.4-2.5 gBq). The median treatment dose delivered was 100 Gy (range, 90-120 Gy). The median lung shunt fraction was 2.02% (range, 1.5-4.1%). The most common clinical toxicity among all patients was nausea and vomiting (59%), primarily grade 1 and 2. Other post-treatment findings included abdominal pain (29%), fatigue (53%), and weight loss (18%). One patient developed a grade 5 gastric ulcer after the treatment. A clinical benefit, defined as patients achieving complete response (CR), partial response (PR) or stable disease (SD), was seen in 48% of patients. PR was seen in 24% of cases; progressive disease (PD) was noted in 35%. Patients survived for a median of 8.4 months (range, 1.3 to 21.1 months) after the first radioembolization treatment. Median survival after Y-90 treatment was 8.4 months among patients treated TheraSphere as compared with 7.8 months in patients treated with SIR-Spheres. The mean overall survival from the time of diagnosis was 11.7 months (range, 3.4 to 43.2 months). For patients with unresectable HCC, Y-90

Every second cancer patient receives radiotherapy

International Nuclear Information System (INIS)

Ojala, A.

1996-01-01

Radiotherapy to treat cancer was given for the first time exactly one hundred years ago. Today, radiotherapy and surgery are the two main modes of treating cancer. One in two cancer patients receives radiotherapy at some point during the course of treatment for the disease. Radiotherapy is applied most commonly in cases where surgery is not possible. Moreover, these two modes of treatment are often used together to supplement each other. About half of new cancer cases detected today can be ordered. The estimate given by the EU for cancers cured is 45 per cent, which is divided between the various treatment modes as follows: surgery 22 %, radiotherapy 12 %, surgery plus radiotherapy 6 %, and drug therapy 6 %. In addition to curative treatment, radiotherapy plays a crucial role in palliative treatment, i.e. treatment that alleviates symptoms. The sensitivity of malignant tumours to radiotherapy varies over a wide range; the same is true for healthy tissues. Radiotherapy can only be used to cure a tumour that is more sensitive to radiation than the surrounding healthy tissue. The tumour must also be sufficiently small in size and limited to a relatively small area. (orig.)

Which diabetic patients should receive podiatry care? An objective analysis.

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McGill, M; Molyneaux, L; Yue, D K

2005-08-01

Diabetes is the leading cause of lower limb amputation in Australia. However, due to limited resources, it is not feasible for everyone with diabetes to access podiatry care, and some objective guidelines of who should receive podiatry is required. A total of 250 patients with neuropathy (Biothesiometer; Biomedical Instruments, Newbury, Ohio, USA) ( > 30, age podiatry care (mean of estimates from 10 reports), the NNT to prevent one foot ulcer per year was: no neuropathy (vibration perception threshold (VPT) 30) alone, NNT = 45; +cannot feel monofilament, NNT = 18; +previous ulcer/amputation, NNT = 7. Provision of podiatry care to diabetic patients should not be only economically based, but should also be directed to those with reduced sensation, especially where there is a previous history of ulceration or amputation.

Inner conflict in patients receiving oral anticancer agents: a qualitative study.

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Yagasaki, Kaori; Komatsu, Hiroko; Takahashi, Tsunehiro

2015-04-14

To explore the experiences of patients receiving oral anticancer agents. A qualitative study using semistructured interviews with a grounded theory approach. A university hospital in Japan. 14 patients with gastric cancer who managed their cancer with oral anticancer agents. Patients with cancer experienced inner conflict between rational belief and emotional resistance to taking medication due to confrontation with cancer, doubt regarding efficacy and concerns over potential harm attached to use of the agent. Although they perceived themselves as being adherent to medication, they reported partial non-adherent behaviours. The patients reassessed their lives through the experience of inner conflict and, ultimately, they recognised their role in medication therapy. Patients with cancer experienced inner conflict, in which considerable emotional resistance to taking their medication affected their occasional non-adherent behaviours. In patient-centred care, it is imperative that healthcare providers understand patients' inner conflict and inconsistency between their subjective view and behaviour to support patient adherence. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Performance on a probabilistic inference task in healthy subjects receiving ketamine compared with patients with schizophrenia

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Almahdi, Basil; Sultan, Pervez; Sohanpal, Imrat; Brandner, Brigitta; Collier, Tracey; Shergill, Sukhi S; Cregg, Roman; Averbeck, Bruno B

2012-01-01

Evidence suggests that some aspects of schizophrenia can be induced in healthy volunteers through acute administration of the non-competitive NMDA-receptor antagonist, ketamine. In probabilistic inference tasks, patients with schizophrenia have been shown to ‘jump to conclusions’ (JTC) when asked to make a decision. We aimed to test whether healthy participants receiving ketamine would adopt a JTC response pattern resembling that of patients. The paradigmatic task used to investigate JTC has been the ‘urn’ task, where participants are shown a sequence of beads drawn from one of two ‘urns’, each containing coloured beads in different proportions. Participants make a decision when they think they know the urn from which beads are being drawn. We compared performance on the urn task between controls receiving acute ketamine or placebo with that of patients with schizophrenia and another group of controls matched to the patient group. Patients were shown to exhibit a JTC response pattern relative to their matched controls, whereas JTC was not evident in controls receiving ketamine relative to placebo. Ketamine does not appear to promote JTC in healthy controls, suggesting that ketamine does not affect probabilistic inferences. PMID:22389244

Predictors of Radiation Pneumonitis in Patients Receiving Intensity Modulated Radiation Therapy for Hodgkin and Non-Hodgkin Lymphoma

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Pinnix, Chelsea C., E-mail: ccpinnix@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Smith, Grace L.; Milgrom, Sarah; Osborne, Eleanor M.; Reddy, Jay P.; Akhtari, Mani; Reed, Valerie; Arzu, Isidora; Allen, Pamela K.; Wogan, Christine F. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Fanale, Michele A.; Oki, Yasuhiro; Turturro, Francesco; Romaguera, Jorge; Fayad, Luis; Fowler, Nathan; Westin, Jason; Nastoupil, Loretta; Hagemeister, Fredrick B.; Rodriguez, M. Alma [Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); and others

2015-05-01

Purpose: Few studies to date have evaluated factors associated with the development of radiation pneumonitis (RP) in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), especially in patients treated with contemporary radiation techniques. These patients represent a unique group owing to the often large radiation target volumes within the mediastinum and to the potential to receive several lines of chemotherapy that add to pulmonary toxicity for relapsed or refractory disease. Our objective was to determine the incidence and clinical and dosimetric risk factors associated with RP in lymphoma patients treated with intensity modulated radiation therapy (IMRT) at a single institution. Methods and Materials: We retrospectively reviewed clinical charts and radiation records of 150 consecutive patients who received mediastinal IMRT for HL and NHL from 2009 through 2013. Clinical and dosimetric predictors associated with RP according to Radiation Therapy Oncology Group (RTOG) acute toxicity criteria were identified in univariate analysis using the Pearson χ{sup 2} test and logistic multivariate regression. Results: Mediastinal radiation was administered as consolidation therapy in 110 patients with newly diagnosed HL or NHL and in 40 patients with relapsed or refractory disease. The overall incidence of RP (RTOG grades 1-3) was 14% in the entire cohort. Risk of RP was increased for patients who received radiation for relapsed or refractory disease (25%) versus those who received consolidation therapy (10%, P=.019). Several dosimetric parameters predicted RP, including mean lung dose of >13.5 Gy, V{sub 20} of >30%, V{sub 15} of >35%, V{sub 10} of >40%, and V{sub 5} of >55%. The likelihood ratio χ{sup 2} value was highest for V{sub 5} >55% (χ{sup 2} = 19.37). Conclusions: In using IMRT to treat mediastinal lymphoma, all dosimetric parameters predicted RP, although small doses to large volumes of lung had the greatest influence. Patients with relapsed

Comparing Effects of Melatonin versus Trazodone on Sleep Quality in Major Depressed Patients Receiving Sertraline

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Zahra Mirsepassi

2018-02-01

Full Text Available Background_ Sleep disturbance is a common complaint in major depressive disorder (MDD including impairment of both subjective and objective parameters, Also SSRIs as antidepressant drugs can affect sleep architecture (SA.Aim _This randomized trial was designed to compare the effects of trazodone with melatonin on sleep quality (SQ of patients with MDD based on Diagnostic and Statistical Manual for Mental Disorders –5th edition (DSM-5 criteria.Method_ Sixty patients who have the study criteria were entered in this study and were divided into two groups receiving either trazodone or melatonin. They were evaluated for sleep quality and depression severity by using Pittsburgh Sleep Quality Index (PSQI and Hamilton Depression Rating Scale (HAM-D at baseline and after 4 and 8 weeks.Result_ Thirty two patients complete the study. Fourteen patients received 3mg of melatonin and eighteen patients received 50mg of trazodone before sleep time. After 4 and 8 weeks treatment with melatonin or Trazodone, significant improvements in SQ were showed in both groups. Additionally, a significant reduction in sleep latency (SL was showed after 4 weeks of treatment with melatonin but not with trazodone.Conclusion_ This study demonstrated that both Melatonin and Trazodone improved SQ in outpatients with MDD after 8 weeks of treatment but melatonin created greater reduction in SL than trazodone after 4 weeks.

Doripenem pharmacokinetics in critically ill patients receiving continuous hemodiafiltration (CHDF).

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Hidaka, Seigo; Goto, Koji; Hagiwara, Satoshi; Iwasaka, Hideo; Noguchi, Takayuki

2010-01-01

Objectives of the prospective, open-label study were to investigate pharmacokinetics of doripenem and determine appropriate doripenem regimens during continuous hemodiafiltration (CHDF) in critically ill patients with renal failure (creatinine clearance times during one dosing interval were measured in order to calculate pharmacokinetic parameters and clearance via hemodiafiltration. Mean half-life (+/-standard deviation) of doripenem was 7.9+/-3.7 hours. Total body clearance of doripenem was 58.0+/-12.7 ml/min, including clearance of 13.5+/-1.6 ml/min via CHDF. An IV dose of 250 mg of doripenem every 12 hours during CHDF provided adequate plasma concentrations for critically ill patients with renal failure, without resulting in accumulation upon steady-state. Thus, under the conditions tested, CHDF appeared to have little effect on doripenem clearance. Therefore, the blood level of doripenem can be satisfactorily controlled by adjustment of doripenem dose and dosing interval, in accordance with residual renal function in patients receiving CHDF.

Effect of Supportive Nursing Care on Self Esteem of Patients Receiving Electroconvulsive Therapy: A Randomized Controlled Clinical Trial

Science.gov (United States)

Ebrahimi, Hossein; Navidian, Ali; Keykha, Roghaieh

2014-01-01

Introduction: Self-esteem is an important potential indicator in etiology, diagnosis and treatment of patients with severe mental illness. ECT is a popular treatment for these patients that can effect on their self-esteem and reinforce their problems. The purpose of this study is to determine the effect of supportive nursing care in increasing self esteem of patients receiving ECT. Methods: This clinical trial was conducted in the Baharan psychiatric hospital of Zahedan. A total of 70 cases of patients who received ECT were randomly allocated to control (n=35) and intervention (n=35) groups. The data were collected by demographic characteristics questionnaire and Rosenberg Self Esteem Scale (RSES). Intervention group received the supportive nursing care. The control group received only routine treatment. Self esteem level was measured and compared before and after intervention for two groups. The data was analyzed by SPSS using the χ2, t-test and ANCOVA. Results: Results showed that both groups were homogeneous on the socio- demographic characteristics. The mean self esteem in the intervention group compared with the control group was significantly increased. While controlling the effects of individual and social variables, the result shows significant differences between two groups in the mean scores of self esteem after the intervention. Conclusion: The results suggest that supportive nursing care can have positive effect on self esteem of patients receiving ECT. It is recommended to use this method for increasing self esteem of these patients. PMID:25276758

Effect of supportive nursing care on self esteem of patients receiving electroconvulsive therapy: a randomized controlled clinical trial.

Science.gov (United States)

Ebrahimi, Hossein; Navidian, Ali; Keykha, Roghaieh

2014-06-01

Self-esteem is an important potential indicator in etiology, diagnosis and treatment of patients with severe mental illness. ECT is a popular treatment for these patients that can effect on their self-esteem and reinforce their problems. The purpose of this study is to determine the effect of supportive nursing care in increasing self esteem of patients receiving ECT. This clinical trial was conducted in the Baharan psychiatric hospital of Zahedan. A total of 70 cases of patients who received ECT were randomly allocated to control (n=35) and intervention (n=35) groups. The data were collected by demographic characteristics questionnaire and Rosenberg Self Esteem Scale (RSES). Intervention group received the supportive nursing care. The control group received only routine treatment. Self esteem level was measured and compared before and after intervention for two groups. The data was analyzed by SPSS using the χ(2), t-test and ANCOVA. RESULTS showed that both groups were homogeneous on the socio- demographic characteristics. The mean self esteem in the intervention group compared with the control group was significantly increased. While controlling the effects of individual and social variables, the result shows significant differences between two groups in the mean scores of self esteem after the intervention. The results suggest that supportive nursing care can have positive effect on self esteem of patients receiving ECT. It is recommended to use this method for increasing self esteem of these patients.

Effect of Supportive Nursing Care on Self Esteem of Patients Receiving Electroconvulsive Therapy: A Randomized Controlled Clinical Trial

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Hossein Ebrahimi

2014-06-01

Full Text Available Introduction: Self-esteem is an important potential indicator in etiology, diagnosis and treatment of patients with severe mental illness. ECT is a popular treatment for these patients that can effect on their self-esteem and reinforce their problems. The purpose of this study is to determine the effect of supportive nursing care in increasing self esteem of patients receiving ECT. Methods: This clinical trial was conducted in the Baharan psychiatric hospital of Zahedan. A total of 70 cases of patients who received ECT were randomly allocated to control (n=35 and intervention (n=35 groups. The data were collected by demographic characteristics questionnaire and Rosenberg Self Esteem Scale (RSES. Intervention group received the supportive nursing care. The control group received only routine treatment. Self esteem level was measured and compared before and after intervention for two groups. The data was analyzed by SPSS using the χ2, t-test and ANCOVA. Results: Results showed that both groups were homogeneous on the socio- demographic characteristics. The mean self esteem in the intervention group compared with the control group was significantly increased. While controlling the effects of individual and social variables, the result shows significant differences between two groups in the mean scores of self esteem after the intervention.Conclusion: The results suggest that supportive nursing care can have positive effect on self esteem of patients receiving ECT. It is recommended to use this method for increasing self esteem of these patients.

What Do Patients Prefer? Understanding Patient Perspectives on Receiving a New Breast Cancer Diagnosis.

Science.gov (United States)

Attai, Deanna J; Hampton, Regina; Staley, Alicia C; Borgert, Andrew; Landercasper, Jeffrey

2016-10-01

There is variability in physician practice regarding delivery method and timeliness of test results to cancer patients. Our aim was to survey patients to determine if there was a difference between actual and preferred care for disclosure of test results. A de-identified survey was distributed to online cancer support groups to query patients about their experience regarding communication of cancer testing and timeliness. Analyses of the differences between actual and preferred communication and wait times were performed. Overall, 1000 patients completed the survey. The analysis herein was restricted to 784 breast cancer survivors. Survey responders were predominately White (non-Hispanic; 89 %), college educated (78 %), and media 'savvy' (online medical media usage; 97 %). Differences between actual and preferred care were identified for the domains of mode of communication and wait times for initial breast cancer diagnostic biopsies and other tests. A total of 309 (39 %) of 784 patients received face-to-face communication for a new cancer diagnosis, with 394 (50 %) patients preferring this option (p cancer biopsy result within 2 days, with 646 (82 %) patients preferring this option (p < 0.0001). Differences were also identified between actual and preferred care for multiple other test types. Actual care for timeliness and modes of communication did not reflect patient-desired care. National and local initiatives to improve performance are needed. As a first step, we recommend that each patient be queried about their preference for mode of communication and timeliness, and efforts made to comply.

Characteristics of Symptomatic Intracranial Hemorrhage in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulant Therapy.

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Hisanao Akiyama

Full Text Available The first non-vitamin K antagonist oral anticoagulant (NOAC introduced to the market in Japan was dabigatran in March 2011, and three more NOACs, rivaroxaban, apixaban, and edoxaban, have since become available. Randomized controlled trials of NOACs have revealed that intracranial hemorrhage (ICH occurs less frequently with NOACs compared with warfarin. However, the absolute incidence of ICH associated with NOACs has increased with greater use of these anticoagulants, and we wanted to explore the incidence, clinical characteristics, and treatment course of patients with NOACs-associated ICH.We retrospectively analyzed the characteristics of symptomatic ICH patients receiving NOACs between March 2011 and September 2014.ICH occurred in 6 patients (5 men, 1 woman; mean ± SD age, 72.8 ± 3.2 years. Mean time to onset was 146.2 ± 111.5 days after starting NOACs. Five patients received rivaroxaban and 1 patient received apixaban. None received dabigatran or edoxaban. Notably, no hematoma expansion was observed within 24 h of onset in the absence of infusion of fresh frozen plasma, activated prothrombin complex concentrate, recombinant activated factor VIIa or hemodialysis. When NOAC therapy was initiated, mean HAS-BLED and PANWARDS scores were 1.5 ± 0.5 and 39.5 ± 7.7, respectively. Mean systolic blood pressure was 137.8 ± 15.9 mmHg within 1 month before spontaneous ICH onset.Six symptomatic ICHs occurred early in NOAC therapy but hematoma volume was small and did not expand in the absence of infusion of reversal agents or hemodialysis. The occurrence of ICH during NOAC therapy is possible even when there is acceptable mean systolic blood pressure control (137.8 ± 15.9 mmHg and HAS-BLED score ≤ 2. Even stricter blood pressure lowering and control within the acceptable range may be advisable to prevent ICH during NOAC therapy.

Cerebral tuberculoma in a patient receiving anti-TNF alpha (adalimumab) treatment.

LENUS (Irish Health Repository)

Lynch, Karen

2010-10-01

We report a case of a cerebral tuberculoma in a 60-year-old woman with rheumatoid arthritis while receiving the anti-tumor necrosis factor alpha monoclonal antibody, adalimumab (Humira), for active disease. MR brain imaging for dyspraxia revealed a left parietal ring-enhancing lesion, which on resection was shown to be a necrotizing granuloma. There were no associated pulmonary lesions, and the patient was systemically well. Sputum and urine cultures were negative for tuberculosis. The patient was treated with anti-tuberculous medications and made an excellent recovery. We consider this to be the first documented case of tuberculosis involving the central nervous system occurring in the setting of adalimumab treatment.

Anterior cruciate ligament reconstruction in a patient who has received systemic steroids for autoimmune disease

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Tetsuro Ushio

2018-01-01

Conclusion: The patient who had received systemic steroids for a long time recovered satisfactorily after the operation, with achievement of knee stability and possibility to prevent degenerative change in the knee joint. ACL reconstruction should be considered even in patients with such medication.

Stent patency in patients with distal malignant biliary obstruction receiving chemo(radio)therapy

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Haal, Sylke; van Hooft, Jeanin E.; Rauws, Erik A. J.; Fockens, Paul; Voermans, Rogier P.

2017-01-01

Background and study aims  Recent literature suggests that chemo(radio)therapy might reduce the patency of plastic stents in patients with malignant biliary obstruction. Whether this might also be valid for other types of stents is unknown. The aim of this study was to determine the influence of chemo(radio)therapy on the patency of fully-covered self-expandable metal stents (FCSEMSs) and plastic stents. Patients and methods  We retrospectively reviewed the electronic medical records of patients with distal malignant biliary obstruction who underwent biliary stent placement between April 2001 and July 2015. Primary outcome was duration of stent patency. Secondary outcome was stent patency at 3 and 6 months. We used Kaplan–Meier survival analyses to compare stent patency rates between patients who received chemo(radio)therapy and patients who did not. Results  A total of 291 biliary stents (151 metal and 140 plastic) were identified. The median cumulative stent patency of FCSEMSs did not differ between patients receiving chemo(radio)therapy (n = 51) and those (n = 100) who did not ( P  = 0.70, log-rank test). The estimated cumulative stent patency of plastic stents was also comparable in 99 patients without and 41 patients with chemo(radio)therapy ( P  = 0.73, log-rank test). At 3 and 6 months, FCSEMS patency rates were 87 % and 83 % in patients without chemo(radio)therapy and 96 % and 83 % in patients with therapy, respectively. Plastic patency rates were 69 % and 55 % in patients without and 85 % and 39 % in patients with therapy, respectively. After 1 year, 78 % of the FCSEMSs were still patent in patients without chemo(radio)therapy and 69 % of the FCSEMSs were still patent in patients with therapy. Conclusion  Our data indicate that chemo(radio)therapy does not reduce the patency of biliary fully-covered metal and plastic stents. PMID:29090242

Evaluating changes in stable chromosomal translocation frequency in patients receiving radioimmunotherapy

International Nuclear Information System (INIS)

Wong, Jeffrey Y.C.; Wang Jianyi; Liu An; Odom-Maryon, Tamara; Shively, John E.; Raubitschek, Andrew A.; Williams, Lawrence E.

2000-01-01

Purpose: The lack of any consistent correlation between radioimmunotherapy (RIT) dose and observed hematologic toxicity has made it difficult to validate RIT radiation dose estimates to marrow. Stable chromosomal translocations (SCT) which result after radiation exposure may be a biologic parameter that more closely correlates with RIT radiation dose. Increases in the frequency of SCT are observed after radiation exposure and are highly correlated with absorbed radiation dose. SCT are cumulative after multiple radiation doses and conserved through an extended number of cell divisions. The purpose of this study was to evaluate whether increases in SCT frequency were detectable in peripheral lymphocytes after RIT and whether the magnitude of these increases correlated with estimated radiation dose to marrow and whole body. Methods and Materials: Patients entered in a Phase I dose escalation therapy trial each received 1-3 intravenous cycles of the radiolabeled anti-carcinoembryonic antigen (CEA) monoclonal antibody, 90 Y-chimeric T84.66. Five mCi of 111 In-chimeric T84.66 was co-administered for imaging and biodistribution purposes. Blood samples were collected immediately prior to the start of therapy and 5-6 weeks after each therapy cycle. Peripheral lymphocytes were harvested after 72 hours of phytohemagglutinin stimulation and metaphase spreads prepared. Spreads were then stained by fluorescence in situ hybridization (FISH) using commercially available chromosome paint probes to chromosomes 3 and 4. Approximately 1000 spreads were evaluated for each chromosome sample. Red marrow radiation doses were estimated using the AAPM algorithm and blood clearance curves. Results: Eighteen patients were studied, each receiving at least one cycle of therapy ranging from 5-22 mCi/m 2 . Three patients received 2 cycles and two patients received 3 cycles of therapy. Cumulative estimated marrow doses ranged from 9.2 to 310 cGy. Increases in SCT frequencies were observed after

Perceptions of Received Information, Social Support, and Coping in Patients with Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension

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Bodil Ivarsson

2014-01-01

Full Text Available Patients with a life-limiting diagnosis of pulmonary arterial hypertension (PAH or chronic thromboembolic pulmonary hypertension (CTEPH need disease-specific information, ability to cope, and functioning social networks. This cohort study investigated the experiences of PAH and CTEPH patients who received information about their diagnosis, treatment, and management, in addition to coping and social support. Sixty-eight adult patients (mean ∓ SD, age 67 ∓ 14; 66% women were included. A total of 54% of the patients wanted more information. Patients received information mostly in areas concerning medical test procedures, the diagnosis, disease severity, possible disease causes, and how to manage their disease. Coping ability was significantly better in patients who were satisfied with the received information (P= 0.0045. The information given to PAH or CTEPH patients and their communication with healthcare professionals can be greatly improved. Gaps in information and misunderstandings can be avoided by working in cooperation with the patients, their relatives, and within the PAH team.

The customization of APACHE II for patients receiving orthotopic liver transplants

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Moreno, Rui

2002-01-01

General outcome prediction models developed for use with large, multicenter databases of critically ill patients may not correctly estimate mortality if applied to a particular group of patients that was under-represented in the original database. The development of new diagnostic weights has been proposed as a method of adapting the general model – the Acute Physiology and Chronic Health Evaluation (APACHE) II in this case – to a new group of patients. Such customization must be empirically tested, because the original model cannot contain an appropriate set of predictive variables for the particular group. In this issue of Critical Care, Arabi and co-workers present the results of the validation of a modified model of the APACHE II system for patients receiving orthotopic liver transplants. The use of a highly heterogeneous database for which not all important variables were taken into account and of a sample too small to use the Hosmer–Lemeshow goodness-of-fit test appropriately makes their conclusions uncertain. PMID:12133174

Patients' perceptions of their general practitioner's health and weight influences their perceptions of nutrition and exercise advice received.

Science.gov (United States)

Fraser, Sally E; Leveritt, Michael D; Ball, Lauren E

2013-12-01

General practitioners (GPs) play an important role in the management of patients who are overweight or obese. Previous research suggests that GPs' physical characteristics may influence patients' perceptions of health care received during consultations, mediating the likelihood of patients following health advice provided by GPs. This study aimed to explore patients' perceptions of their GP's health status and its influence on patients' perceptions of healthy eating and exercise advice. An interpretive approach to phenomenology underpinned the qualitative inquiry and study design. Twenty-one participants (aged 55.9 ± 6.5 years; 14 females, 7 males) who had previously received healthy eating and/or exercise advice from a GP participated in an individual semi-structured interview. A constant comparison approach to thematic analysis was conducted. Participants identified three key indicators of perceived health of their GP. These included the GP's physical appearance, particularly weight status; perceived absence of ill health; and disclosure of a GP's health behaviours. Participants expressed favourable perceptions of the weight status of their GP. Participants expected their GP to be a healthy role model and often, but not always, felt more confident receiving advice from a GP that they perceived as healthy. The findings highlight that a GP's perceived health status influences patients' perceptions of the health advice received during consultations. These findings provide a foundation for future research that may allow GPs to modify patients' perceptions of their health status in order to facilitate behaviour change in overweight or obese patients.

Predictive factors for moderate or severe exacerbations in asthma patients receiving outpatient care

OpenAIRE

Guti?rrez, Francisco Javier ?lvarez; Galv?n, Marta Ferrer; Gallardo, Juan Francisco Medina; Mancera, Marta Barrera; Romero, Beatriz Romero; Falc?n, Auxiliadora Romero

2017-01-01

Background Asthma exacerbations are important events that affect disease control, but predictive factors for severe or moderate exacerbations are not known. The objective was to study the predictive factors for moderate (ME) and severe (SE) exacerbations in asthma patients receiving outpatient care. Methods Patients aged?>?12?years with asthma were included in the study and followed-up at 4-monthly intervals over a 12-month period. Clinical (severity, level of control, asthma control test [AC...

The effectiveness of RECIST on survival in patients with NSCLC receiving chemotherapy with or without target agents as first-line treatment.

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Zhou, Ting; Zheng, Lie; Hu, Zhihuang; Zhang, Yang; Fang, Wenfeng; Zhao, Yuanyuan; Ge, Jieying; Zhao, Hongyun; Zhang, Li

2015-01-08

We analyzed the correlation between survival and antitumor effect evaluated by RECIST in advanced NSCLC patients with chemotherapy plus target therapy or not as first-line treatment, to examine the applicability of RECIST in this population. The patients were screened from 4 clinical trials (12621, 12006, FASTACT-I, and FASTACT-II), and those who received chemotherapy plus target therapy or chemotherapy alone were eligible. Among the 59 enrolled patients, 29 received combination therapy, while the other 30 received chemotherapy only. In the combination therapy group, patients with PR or SD had longer overall survival (OS) than those with PD (P chemotherapy alone group, compared with PD patients, either PR or SD group had no significant overall survival benefit (P = 0.690 and P = 0.528, respectively). In summary, for advanced NSCLC patients receiving chemotherapy plus target therapy as first-line treatment and evaluated by RECIST criteria, SD has the same overall survival benefit as PR, suggesting that antitumor effective evaluation by RECIST criteria cannot be translated to overall survival benefit especially for this kind of patients. Therefore, developing a more comprehensive evaluation method to perfect RECIST criteria is thus warranted for patients received target therapy in NSCLC.

Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone.

Science.gov (United States)

Bendadi, Fatiha; de Koning, Tom J; Visser, Gepke; Prinsen, Hubertus C M T; de Sain, Monique G M; Verhoeven-Duif, Nanda; Sinnema, Gerben; van Spronsen, Francjan J; van Hasselt, Peter M

2014-02-01

To examine cognitive functioning in patients with tyrosinemia type I treated with nitisinone and a protein-restricted diet. We performed a cross-sectional study to establish cognitive functioning in children with tyrosinemia type I compared with their unaffected siblings. Intelligence was measured using age-appropriate Wechsler Scales. To assess cognitive development over time, we retrieved sequential IQ scores in a single-center subset of patients. We also evaluated whether plasma phenylalanine and tyrosine levels during treatment was correlated with cognitive development. Average total IQ score in 10 patients with tyrosinemia type I receiving nitisinone was significantly lower compared with their unaffected siblings (71 ± 13 vs 91 ± 13; P = .008). Both verbal and performance IQ subscores differed (77 ± 14 vs 95 ± 11; P cognitive function despite a protein-restricted diet. Copyright © 2014 Mosby, Inc. All rights reserved.

Efficacy of olanzapine in symptom relief and quality of life in gastric cancer patients receiving chemotherapy

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Novin Nikbakhsh

2016-01-01

Full Text Available Background: Considering the incidence and prevalence rates of gastric cancer in Mazandaran Province of Iran, this research was performed to evaluate the efficacy and safety of olanzapine in symptom relief and quality of life (QOL improvement of gastric patients receiving chemotherapy. Materials and Methods: This clinical trial was conducted on thirty new cases of gastric cancer patients whose treatment protocol was planned on chemotherapy and were allocated into two groups by simple random sampling. Intervention group (15 patients received olanzapine tablets (2.5–10 mg/day a day before the beginning of chemotherapy; in the 1st day of chemotherapy to 8 weeks after chemotherapy, besides the routine treatment regimens. The control group received only the routine treatment regimens. The patients were followed for 8 weeks after intervention. All of the patients were assessed with Hospital Anxiety and Depression Scale (HADS and WHO-QOL-BREF questionnaires; further, Rhodes index was used to evaluate nausea and vomiting (N/V status. Results: All the recruited patients continued the allocated interventions (no lost to follow-up. N/V decreased in the case group, but the difference was not statistically significant (P = 0.438. The patients' appetite and body mass index increased (P = 0.006. Anxiety and depression subscales of HADS had significant differences between the two groups (P 0.05. No significant increase was observed in fasting and 2-h postprandial blood glucose and lipid profile (P > 0.05. Conclusion: Olanzapine can be considered as an effective drug to increase appetite and decrease anxiety and depression in patients with gastric cancer.

Trend and outcome of Korean patients receiving overseas solid organ transplantation between 1999 and 2005.

Science.gov (United States)

Kwon, Choon Hyuck David; Lee, Suk-Koo; Ha, Jongwon

2011-01-01

The disparity between patients awaiting transplantation and available organs forced many patients to go overseas to receive a transplant. Few data concerning overseas transplantation in Korea are available and the Korea Society for Transplantation conducted a survey to evaluate the trend and outcome of overseas transplantation. The survey, conducted on June 2006, included 25 hospitals nationwide that followed up patients after receiving kidney transplant (KT) or liver transplant (LT) overseas. The number of KT increased from 6 in 2001 to 206 in 2005 and for LT from 1 to 261. The information about overseas transplant came mostly from other patients (57%). The mean cost for KT was $21,000 and for LT $47,000. Patients were admitted for 18.5 days for KT and 43.4 days for LT. Graft and patient survival was 96.8% and 96.5% for KT (median follow up 23.1 months). Complication occurred in 42.5% including surgical complication (5.3%), acute rejection (9.7%) and infection (21.5%). Patient survival for LT was 91.8% (median follow up 21.2 months). Complication occurred in 44.7% including 19.4% biliary complication. Overseas KT and LT increased rapidly from 2001 to 2005. Survival of patients and grafts was comparable to domestic organ transplantation, but had a high complication rate.

A Randomized Controlled Trial of Lorazepam to Reduce Liver Motion in Patients Receiving Upper Abdominal Radiation Therapy

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Tsang, Derek S.; Voncken, Francine E.M.; Tse, Regina V. [Princess Margaret Cancer Centre, University Health Network, Department of Radiation Oncology, University of Toronto, Toronto (Canada); Sykes, Jenna [Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto (Canada); Wong, Rebecca K.S.; Dinniwell, Rob E.; Kim, John; Ringash, Jolie; Brierley, James D.; Cummings, Bernard J.; Brade, Anthony [Princess Margaret Cancer Centre, University Health Network, Department of Radiation Oncology, University of Toronto, Toronto (Canada); Dawson, Laura A., E-mail: laura.dawson@rmp.uhn.on.ca [Princess Margaret Cancer Centre, University Health Network, Department of Radiation Oncology, University of Toronto, Toronto (Canada)

2013-12-01

Purpose: Reduction of respiratory motion is desirable to reduce the volume of normal tissues irradiated, to improve concordance of planned and delivered doses, and to improve image guided radiation therapy (IGRT). We hypothesized that pretreatment lorazepam would lead to a measurable reduction of liver motion. Methods and Materials: Thirty-three patients receiving upper abdominal IGRT were recruited to a double-blinded randomized controlled crossover trial. Patients were randomized to 1 of 2 study arms: arm 1 received lorazepam 2 mg by mouth on day 1, followed by placebo 4 to 8 days later; arm 2 received placebo on day 1, followed by lorazepam 4 to 8 days later. After tablet ingestion and daily radiation therapy, amplitude of liver motion was measured on both study days. The primary outcomes were reduction in craniocaudal (CC) liver motion using 4-dimensional kV cone beam computed tomography (CBCT) and the proportion of patients with liver motion ≤5 mm. Secondary endpoints included motion measured with cine magnetic resonance imaging and kV fluoroscopy. Results: Mean relative and absolute reduction in CC amplitude with lorazepam was 21% and 2.5 mm respectively (95% confidence interval [CI] 1.1-3.9, P=.001), as assessed with CBCT. Reduction in CC amplitude to ≤5 mm residual liver motion was seen in 13% (95% CI 1%-25%) of patients receiving lorazepam (vs 10% receiving placebo, P=NS); 65% (95% CI 48%-81%) had reduction in residual CC liver motion to ≤10 mm (vs 52% with placebo, P=NS). Patients with large respiratory movement and patients who took lorazepam ≥60 minutes before imaging had greater reductions in liver CC motion. Mean reductions in liver CC amplitude on magnetic resonance imaging and fluoroscopy were nonsignificant. Conclusions: Lorazepam reduces liver motion in the CC direction; however, average magnitude of reduction is small, and most patients have residual motion >5 mm.

Primary Tumour Resection Could Improve the Survival of Unresectable Metastatic Colorectal Cancer Patients Receiving Bevacizumab-Containing Chemotherapy

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Zhiming Wang

2016-09-01

Full Text Available Background: The effect of primary tumour resection (PTR among metastatic colorectal cancer (mCRC patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. Methods: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS time and overall survival (OS time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation between the two groups. Results: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p Conclusions: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.

Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma

Science.gov (United States)

Hurabielle, Charlotte; Pillebout, Evangéline; Stehlé, Thomas; Pagès, Cécile; Roux, Jennifer; Schneider, Pierre; Chevret, Sylvie; Chaffaut, Cendrine; Boutten, Anne; Mourah, Samia; Basset-Seguin, Nicole; Vidal-Petiot, Emmanuelle; Lebbé, Céleste; Flamant, Martin

2016-01-01

Context Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known. Objective We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma. Methods We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients. Results 70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion. Conclusion Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective. PMID:26930506

Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine

NARCIS (Netherlands)

Conway, B.; Wainberg, M. A.; Hall, D.; Harris, M.; Reiss, P.; Cooper, D.; Vella, S.; Curry, R.; Robinson, P.; Lange, J. M.; Montaner, J. S.

2001-01-01

OBJECTIVE: To evaluate the development of phenotypic and genotypic resistance to zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents. DESIGN: All patients were enrolled in a

Recall of UVB-induced erythema in breast cancer patient receiving multiple drug chemotherapy

DEFF Research Database (Denmark)

Andersen, Klaus Ejner; Lindskov, R

1984-01-01

One day after sunbathing, a breast cancer patient received intravenous methotrexate, cyclophosphamide and 5-fluorouracil and had a recall of her UV erythema over the following week. Phototesting with UVA and UVB prior to and after a subsequent chemotherapy treatment showed a UVB-induced recall...

Patients' perceptions of their general practitioner's health and weight influences their perceptions of nutrition and exercise advice received

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Fraser SE

2013-12-01

Full Text Available INTRODUCTION: General practitioners (GPs play an important role in the management of patients who are overweight or obese. Previous research suggests that GPs' physical characteristics may influence patients' perceptions of health care received during consultations, mediating the likelihood of patients following health advice provided by GPs. This study aimed to explore patients' perceptions of their GP's health status and its influence on patients' perceptions of healthy eating and exercise advice. METHODS: An interpretive approach to phenomenology underpinned the qualitative inquiry and study design. Twenty-one participants (aged 55.9 ± 6.5 years; 14 females, 7 males who had previously received healthy eating and/or exercise advice from a GP participated in an individual semi-structured interview. A constant comparison approach to thematic analysis was conducted. FINDINGS: Participants identified three key indicators of perceived health of their GP. These included the GP's physical appearance, particularly weight status; perceived absence of ill health; and disclosure of a GP's health behaviours. Participants expressed favourable perceptions of the weight status of their GP. Participants expected their GP to be a healthy role model and often, but not always, felt more confident receiving advice from a GP that they perceived as healthy. CONCLUSION: The findings highlight that a GP's perceived health status influences patients' perceptions of the health advice received during consultations. These findings provide a foundation for future research that may allow GPs to modify patients' perceptions of their health status in order to facilitate behaviour change in overweight or obese patients.

TH-AB-207A-03: Skin Dose to Patients Receiving Multiple CTA and CT Exams of the Head

International Nuclear Information System (INIS)

Nawfel, RD; Young, G

2016-01-01

Purpose: To measure patient skin dose from CT angiography (CTA) and CT exams of the head, and determine if patients having multiple exams could receive cumulative doses that approach or exceed deterministic thresholds. Methods: This study was HIPAA compliant and conducted with IRB approval. Patient skin doses were measured over a 4 month period using nanoDot OSL dosimeters placed on the head of 52 patients for two CT scanners. On each scanner, 26 patients received CT exams (scanner 1: 10 females, 16 males, mean age 64.2 years; scanner 2: 18 females, 8 males, mean age 61.2 years). CT exam dose metrics, CTDIvol and dose-length product (DLP) were recorded for each exam. Additionally, skin dose was measured on an acrylic skull phantom in each scanner and on a neuro-interventional imaging system using clinical protocols. Measured dose data was used to estimate peak skin dose (PSD) for 4 patients receiving multiple exams including CTA, head CT, and cerebral angiography. Results: For scanner 1, the mean PSD for CTA exams (98.9 ± 5.3 mGy) and for routine head CT exams (39.2 ± 3.7 mGy) agreed reasonably well with the PSD measured on the phantom, 105.4 mGy and 40.0 mGy, respectively. Similarly for scanner 2, the mean PSD for CTA exams (98.8 ± 7.4 mGy) and for routine head CT exams (42.9 ± 9.4 mGy) compared well with phantom measurements, 95.2 mGy and 37.6 mGy, respectively. In addition, the mean PSD was comparable between scanners for corresponding patient exams, CTA and routine head CT respectively. PSD estimates ranged from 1.9 – 4.5 Gy among 4 patients receiving multiple exams. Conclusion: Patients having several exams including both CTA and routine head CT may receive cumulative doses approaching or exceeding the threshold for single dose deterministic effects.

TH-AB-207A-03: Skin Dose to Patients Receiving Multiple CTA and CT Exams of the Head

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Nawfel, RD; Young, G [Brigham & Women’s Hospital, Boston, MA (United States)

2016-06-15

Purpose: To measure patient skin dose from CT angiography (CTA) and CT exams of the head, and determine if patients having multiple exams could receive cumulative doses that approach or exceed deterministic thresholds. Methods: This study was HIPAA compliant and conducted with IRB approval. Patient skin doses were measured over a 4 month period using nanoDot OSL dosimeters placed on the head of 52 patients for two CT scanners. On each scanner, 26 patients received CT exams (scanner 1: 10 females, 16 males, mean age 64.2 years; scanner 2: 18 females, 8 males, mean age 61.2 years). CT exam dose metrics, CTDIvol and dose-length product (DLP) were recorded for each exam. Additionally, skin dose was measured on an acrylic skull phantom in each scanner and on a neuro-interventional imaging system using clinical protocols. Measured dose data was used to estimate peak skin dose (PSD) for 4 patients receiving multiple exams including CTA, head CT, and cerebral angiography. Results: For scanner 1, the mean PSD for CTA exams (98.9 ± 5.3 mGy) and for routine head CT exams (39.2 ± 3.7 mGy) agreed reasonably well with the PSD measured on the phantom, 105.4 mGy and 40.0 mGy, respectively. Similarly for scanner 2, the mean PSD for CTA exams (98.8 ± 7.4 mGy) and for routine head CT exams (42.9 ± 9.4 mGy) compared well with phantom measurements, 95.2 mGy and 37.6 mGy, respectively. In addition, the mean PSD was comparable between scanners for corresponding patient exams, CTA and routine head CT respectively. PSD estimates ranged from 1.9 – 4.5 Gy among 4 patients receiving multiple exams. Conclusion: Patients having several exams including both CTA and routine head CT may receive cumulative doses approaching or exceeding the threshold for single dose deterministic effects.

Depressive features among adult patients receiving antiretroviral therapy for HIV in Rustenburg district, SA

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T Bongongo

2013-06-01

Full Text Available Background. Globally, it is estimated that depressive features occur in 15 - 36% of people suffering from chronic diseases and 60% of people with HIV/AIDS. A high prevalence of mental disorders among HIV-infected individuals has been shown in South Africa and other parts of sub-Saharan Africa. Untreated depression leads to poor adherence to treatment and poor quality of life for patients with chronic diseases. Methods. Using the Zung self-rating scale, we screened for depressive features among adult patients receiving highly active antiretroviral therapy (HAART who attended primary healthcare facilities in the Rustenburg district of North West Province in South Africa during December 2009. Results. Among 117 participants, 81 (69.2 % had mild depressive features, 2 (1.7% had moderate depressive features, 1 (0.9 % had severe depressive features and 33 (28.2% did not have depressive features. Depressive features were more common in males (77.1% than in females (69.5%, and were most common in patients taking the combination of efavirenz, lamivudine and stavudine. Conclusion. Depressive features seem to be common among adult patients receiving HAART and attending primary healthcare facilities in the Rustenburg district.

Incidence and severity of phlebitis in patients receiving peripherally infused amiodarone.

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Boyce, Brenda A Brady; Yee, Barbara Homer

2012-08-01

Nurses noted that the rate of phlebitis was high when intravenous amiodarone was infused via a peripheral site. Hospital policy recommends a central vascular catheter, but this method is often not feasible because the drug is administered in emergent situations for short periods. To determine the rate and severity of phlebitis in patients given peripherally infused amiodarone. The literature, policy, and procedures for administration of amiodarone were reviewed; the pharmacy was consulted; and a data collection tool was developed. The tool was pilot tested and revised, and face validation was established. Data were collected during a 6-month period. A convenience sample was used. The study included a total of 12 patients. Each new infusion of intravenous amiodarone was considered a separate occurrence, for a total of 24 infusions. Various grades of phlebitis developed in 8 patients (67%). Phlebitis developed at 12 of the 24 infusion sites (50%). Patients receiving peripherally infused amiodarone are at high risk for phlebitis. This complication may lead to infection, additional medical intervention, delay in treatment, and prolonged hospitalization.

"Do not resuscitate" orders among deceased patients who received acute neurological care: an observation analysis.

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Chao, Tzu-Hao; Hsieh, Tien-Jen; Wang, Vinchi

2014-12-01

There were many reports about the "do not resuscitate" (DNR) order while practicing in the critical care units and conducting hospice affairs but limited in the neurological issues. This study investigated the possible flaws in the execution of the DNR order among patients who received acute neurological care in Taiwan. Over a 3-year period, we retrospectively reviewed the medical records of 77 deceased patients with neurological conditions for DNR orders. Registry and analysis works included demography, hospital courses, DNR data, and clinical usefulness of the lab and image examinations. Sixty-seven DNR orders were requested by the patients' families, and more than half were signed by the patients' children or grandchildren. The main DNR items were chest compression, cardiac defibrillation, and pacemaker use, although several DNR patients received resuscitation. The mean duration from the coding date to death was 7.6 days. Two-thirds of the patients with DNR requests remained in the intensive care unit, with a mean stay of 6.9 days. Several patients underwent regular roentgenography and blood tests on the day of their death, despite their DNR orders. Hospital courses and DNR items may be valuable information on dealing with the patients with DNR orders. The results of this study also suggest the public education about the DNR orders implemented for neurological illnesses.

Patients with schizophrenia or schizoaffective disorder who receive multiple electroconvulsive therapy sessions: characteristics, indications, and results.

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Iancu, Iulian; Pick, Nimrod; Seener-Lorsh, Orit; Dannon, Pinhas

2015-01-01

While electroconvulsive therapy (ECT) has been used for many years, there is insufficient research regarding the indications for continuation/maintenance (C/M)-ECT, its safety and efficacy, and the characteristics of patients with schizophrenia or schizoaffective disorder who receive multiple ECT sessions. The aims of this study were to characterize a series of patients who received 30 ECT sessions or more, to describe treatment regimens in actual practice, and to examine the results of C/M-ECT in terms of safety and efficacy, especially the effect on aggression and functioning. We performed a retrospective chart review of 20 consecutive patients (mean age 64.6 years) with schizophrenia (n=16) or schizoaffective disorder (n=4) who received at least 30 ECT sessions at our ECT unit, and also interviewed the treating physician and filled out the Clinical Global Impression-Severity, Global Assessment of Functioning, and the Staff Observation Aggression Scale-Revised. Patients received a mean of 91.3 ECT sessions at a mean interval of 2.6 weeks. All had been hospitalized for most or all of the previous 3 years. There were no major adverse effects, and cognitive side effects were relatively minimal (cognitive deficit present for several hours after treatment). We found that ECT significantly reduced scores on the Staff Observation Aggression Scale-Revised subscales for verbal aggression and self-harm, and improved Global Assessment of Functioning scores. There were reductions in total aggression scores, subscale scores for harm to objects and to others, and Clinical Global Impression-Severity scores, these were not statistically significant. C/M-ECT is safe and effective for chronically hospitalized patients. It improves general functioning and reduces verbal aggression and self-harm. More research using other aggression tools is needed to determine its effects and to reproduce our findings in prospective and controlled studies.

Correlation of Serum Cystatin C with Glomerular Filtration Rate in Patients Receiving Platinum-Based Chemotherapy

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Ernesta Cavalcanti

2016-01-01

Full Text Available Objectives. Serum cystatin C seems to be an accurate marker of glomerular filtration rate (GFR compared to serum creatinine. The aim of this work was to explore the possibility of using serum cystatin C instead of serum creatinine to early predict renal failure in cancer patients who received platinum based chemotherapy. Design and Methods. Serum creatinine, serum cystatin C concentrations, and GFR were determined simultaneously in 52 cancer patients received carboplatin-based or cisplatin-based chemotherapy. Serum creatinine was assayed on Cobas C6000-Roche, serum cystatin C assay was performed on AIA 360-Tosoh, and GFR was determined in all patients, before the first cycle of chemotherapy and before the subsequent administrations. Results. In the overall series, for the prediction of a fall of GFR < 80 mL/min/1.73 m2, the AUC of the ROC curve for cystatin C was 0,667 and the best threshold was 1.135 mg/L (sensitivity 90.5%, specificity 61.1%. For a GFR fall < 60 mL/min/1.73 m2, the AUC of ROC curve for cystatin C was 74.3% and the best threshold was 1.415 mg/L (sensitivity 66.7%, specificity 73.2%. Conclusions. Baseline cystatin C values were not able to predict renal failure during subsequent treatment. In conclusion, serum cystatin C is not a reliable early marker to efficiently predict renal failure in patients receiving chemotherapy.