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Sample records for anaplastic lymphoma kinase

  1. Timely topic: anaplastic lymphoma kinase (ALK) spreads its influence.

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    Cheuk, W; Chan, J K

    2001-02-01

    Anaplastic lymphoma kinase (ALK) is normally not expressed in human tissues except selected sites in the nervous system. Its expression and constitutive activation as a result of a chromosomal translocation involving 2p23 plays a pivotal role in the genesis of anaplastic large cell lymphoma. ALK expression has been instrumental in defining a homogeneous subset from the category of anaplastic large cell lymphoma, characterised by occurrence in young patients, primary systemic presentation, favorable prognosis, a broad morphological spectrum, nuclear and/or cytoplasmic immunostaining for ALK protein, and a number of possible fusion partner genes such as NPM, ATIC, TFG, TPM3 and CLTCL. Recently ALK has been implicated in the genesis of another tumour type, the inflammatory myofibroblastic tumours. The ALK-positive examples occur in children and young adults, involving a variety of sites, such as the abdomen, mesentery, liver, bladder, mediastinum, lung and bone. The partner genes identified in some cases are TPM3 (tropomyosin 3) and TPM4 (tropomyosin 4). These molecular findings also further support the neoplastic nature of at least a subset of inflammatory myofibroblastic tumours.

  2. Leukemic phase of anaplastic lymphoma kinase positive, anaplastic large cell lymphoma

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    Vijaya S Gadage

    2011-01-01

    Full Text Available Anaplastic large cell lymphoma (ALCL is a distinct type of CD30+ T/null-cell non-Hodgkin′s lymphoma that frequently involves nodal and extranodal sites. The presence of leukemic phase in ALCL is extremely rare and occurs exclusively with ALK1-positive ALCL. We describe two patients with ALK1-positive ALCL who developed a leukemic phase with rapid progression of the disease. Immunophenotypic pattern assessed on peripheral blood by flow cytometry revealed CD45, CD30, and CD25 positivity in both cases but NPM-ALK1 was expressed in only one case. Both patients developed leukemic phase as a terminal event of the disease and we share the immunophenotypic features of both cases.

  3. Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma

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    Zhang, Qian; Raghunath, Puthryaveett N; Xue, Liquan

    2002-01-01

    Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK), typically due to t(2;5) translocation, defines a distinct type of T/null-cell lymphoma (TCL). The resulting nucleophosmin (NPM) /ALK chimeric kinase is constitutively active and oncogenic. Downstream effector...... known STATs was consistently tyrosine phosphorylated in these cell lines. In addition, malignant cells in tissue sections from all (10 of 10) ALK+ TCL patients expressed tyrosine-phosphorylated STAT3. Transfection of BaF3 cells with NPM/ALK resulted in tyrosine phosphorylation of STAT3. Furthermore...

  4. Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma

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    Heidegger S

    2014-06-01

    Full Text Available Simon Heidegger,1 Ambros Beer,2 Eva Geissinger,3 Andreas Rosenwald,3 Christian Peschel,1 Ingo Ringshausen,1 Ulrich Keller11III Medical Department, 2Nuclear Medicine Department, Technische Universität München, Munich, Germany; 3Institute of Pathology, University of Würzburg, Würzburg, GermanyAbstract: Anaplastic large cell lymphoma (ALCL is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone. However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.Keywords: anaplastic large cell lymphoma (ALCL, refractory/relapsed lymphoma, anti-CD30 drug conjugate, DHAP

  5. Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma.

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    Heidegger, Simon; Beer, Ambros J; Geissinger, Eva; Rosenwald, Andreas; Peschel, Christian; Ringshausen, Ingo; Keller, Ulrich

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.

  6. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death.

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    Zamo, Alberto; Chiarle, Roberto; Piva, Roberto; Howes, Jennifer; Fan, Yan; Chilosi, Marco; Levy, David E; Inghirami, Giorgio

    2002-02-07

    The anaplastic lymphoma kinase (ALK) gene is characteristically translocated in Anaplastic Large Cell Lymphomas (ALCL) and the juxtaposition of the ALK gene to multiple partners results in its constitutive protein tyrosine kinase activity. We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs. Furthermore, immunohistochemical studies demonstrate that among distinct human B and T cell lymphomas, activation of Stat3 nuclear translocation is uniquely associated with ALK expression. NPM-ALK also binds and activates Jak3; however, Jak3 is not required for Stat3 activation or for cell transformation in vitro. Moreover, src family kinases are not necessary for NPM-ALK-mediated Stat3 activation or transformation, suggesting that Stat3 may be phosphorylated directly by ALK. To evaluate relevant targets of ALK-activated Stat3, we investigated the regulation of the anti-apoptotic protein Bcl-x(L) and its role in cell survival in NPM-ALK positive cells. NPM-ALK expression caused enhanced Bcl-x(L) transcription, largely mediated by Stat3. Increased expression of Bcl-x(L) provided sufficient anti-apoptotic signals to protect cells from treatment with specific inhibitors of the Jaks/Stat pathway or the Brc-Abl kinase. These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells.

  7. The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene.

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    Kelleher, Fergal C

    2012-02-01

    The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin\\'s lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered. In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system. Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3\\/4 (TMP3\\/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic. Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic

  8. Involvement of Grb2 adaptor protein in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated signaling and anaplastic large cell lymphoma growth.

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    Riera, Ludovica; Lasorsa, Elena; Ambrogio, Chiara; Surrenti, Nadia; Voena, Claudia; Chiarle, Roberto

    2010-08-20

    Most anaplastic large cell lymphomas (ALCL) express oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. Frequently ALCL carry the t(2;5) translocation, which fuses the ALK gene to the nucleophosmin (NPM1) gene. The transforming activity mediated by NPM-ALK fusion induces different pathways that control proliferation and survival of lymphoma cells. Grb2 is an adaptor protein thought to play an important role in ALK-mediated transformation, but its interaction with NPM-ALK, as well as its function in regulating ALCL signaling pathways and cell growth, has never been elucidated. Here we show that active NPM-ALK, but not a kinase-dead mutant, bound and induced Grb2 phosphorylation in tyrosine 160. An intact SH3 domain at the C terminus of Grb2 was required for Tyr(160) phosphorylation. Furthermore, Grb2 did not bind to a single region but rather to different regions of NPM-ALK, mainly Tyr(152-156), Tyr(567), and a proline-rich region, Pro(415-417). Finally, shRNA knockdown experiments showed that Grb2 regulates primarily the NPM-ALK-mediated phosphorylation of SHP2 and plays a key role in ALCL cell growth.

  9. Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep.

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    Lei Bai

    2015-11-01

    Full Text Available Though evidence is mounting that a major function of sleep is to maintain brain plasticity and consolidate memory, little is known about the molecular pathways by which learning and sleep processes intercept. Anaplastic lymphoma kinase (Alk, the gene encoding a tyrosine receptor kinase whose inadvertent activation is the cause of many cancers, is implicated in synapse formation and cognitive functions. In particular, Alk genetically interacts with Neurofibromatosis 1 (Nf1 to regulate growth and associative learning in flies. We show that Alk mutants have increased sleep. Using a targeted RNAi screen we localized the negative effects of Alk on sleep to the mushroom body, a structure important for both sleep and memory. We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk. Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes.

  10. A case of tonsillar anaplastic large cell lymphoma-anaplastic lymphoma kinase negative: An unusual site of involvement with review of literature

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    Umesh Das

    2014-01-01

    Full Text Available We present this unusual case of the clinical importance of a 50-year-old male patient who presented with foreign body sensation in the throat and halitosis of 20 days duration. On examination, there were no palpable lymph nodes and oral cavity revealed an ulcero proliferative growth over the right tonsil. Computed tomography of the paranasal sinuses and neck revealed a heterogeneously enhancing mass involving the right tonsil measuring 3.8 cm × 3 cm. Biopsy of the tonsillar mass was suggestive of anaplastic large cell lymphoma (ALCL with neoplastic large cells positive for CD30, epithelial membrane antigen and CD3 and negative for Tdt, CD56, anaplastic lymphoma kinase (ALK and cytokeratin. A diagnosis of ALK negative ALCL Stage IA was made and the patient was started on chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone every 3 weeks. He received six cycles of chemotherapy followed by 33 gray involved region radiotherapy and reassessment showed total regression of the tonsillar lesion. The patient is in complete remission and now under follow-up for the last 2 years

  11. Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers.

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    Roskoski, Robert

    2017-03-01

    Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors. Downstream signaling from the ALK fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module and the JAK/STAT cell survival pathways. Moreover, nearly two dozen ALK activating mutations are involved in the pathogenesis of childhood neuroblastomas. The occurrence of oncogenic ALK-fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ALK inhibitors. Crizotinib was the first such inhibitor approved by the US Food and Drug Administration for the treatment of ALK-positive non-small cell lung cancer in 2011. The median time for the emergence of crizotinib drug resistance is 10.5 months after the initiation of therapy. Such resistance prompted the development of second-generation drugs including ceritinib and alectinib, which are approved for the treatment of non-small cell lung cancer. Unlike the single gatekeeper mutation that occurs in drug-resistant epidermal growth factor receptor in lung cancer, nearly a dozen different mutations in the catalytic domain of ALK fusion proteins have been discovered that result in crizotinib resistance. Crizotinib, ceritinib, and alectinib form a complex within the front cleft between the small and large lobes of an inactive ALK protein-kinase domain with a compact activation segment. These drugs are classified as type I½ B

  12. Analysis of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-reactive CD8(+) T cell responses in children with NPM-ALK(+) anaplastic large cell lymphoma.

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    K Singh, V; Werner, S; Hackstein, H; Lennerz, V; Reiter, A; Wölfel, T; Damm-Welk, C; Woessmann, W

    2016-10-01

    Cellular immune responses against the oncoantigen anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large cell lymphoma (ALCL) have been detected using peptide-based approaches in individuals preselected for human leucocyte antigen (HLA)-A*02:01. In this study, we aimed to evaluate nucleophosmin (NPM)-ALK-specific CD8(+) T cell responses in ALCL patients ensuring endogenous peptide processing of ALK antigens and avoiding HLA preselection. We also examined the HLA class I restriction of ALK-specific CD8(+) T cells. Autologous dendritic cells (DCs) transfected with in-vitro-transcribed RNA (IVT-RNA) encoding NPM-ALK were used as antigen-presenting cells for T cell stimulation. Responder T lymphocytes were tested in interferon-gamma enzyme-linked immunospot (ELISPOT) assays with NPM-ALK-transfected autologous DCs as well as CV-1 in Origin with SV40 genes (COS-7) cells co-transfected with genes encoding the patients' HLA class I alleles and with NPM-ALK encoding cDNA to verify responses and define the HLA restrictions of specific T cell responses. NPM-ALK-specific CD8(+) T cell responses were detected in three of five ALK-positive ALCL patients tested between 1 and 13 years after diagnosis. The three patients had also maintained anti-ALK antibody responses. No reactivity was detected in samples from five healthy donors. The NPM-ALK-specific CD8(+) T cell responses were restricted by HLA-C-alleles (C*06:02 and C*12:02) in all three cases. This approach allowed for the detection of NPM-ALK-reactive T cells, irrespective of the individual HLA status, up to 9 years after ALCL diagnosis.

  13. Current Status of Targeted Therapy for Anaplastic Lymphoma Kinase in Non-small Cell Lung Cancer

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    Li MA

    2014-12-01

    Full Text Available The rate of the anaplastic lymphoma kinase (ALK gene rearrangements in non-small cell lung cancer (NSCLC tissues is 3%-5%. The first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. A randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients demonstrated durable responses and well tolerance in the majority of ALK-positive NSCLC patients treated with crizotinib. However, despite the initial responses, most patients develop acquired resistance to crizotinib. Several novel therapeutic approaches targeting ALK-positive NSCLC are currently under evaluation in clinical trials, including second-generation ALK inhibitors, such as LDK378, CH5424802 (RO5424802, and AP26113, and new agents shock protein 90 inhibitors. This review aims to present the current knowledge on this fusion gene, the treatment advances, and novel drug clinical trials in ALK rearranged NSCLC.

  14. Identification of anaplastic lymphoma kinase break points and oncogenic mutation profiles in acral/mucosal melanomas.

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    Niu, Hai-Tao; Zhou, Qi-Ming; Wang, Fang; Shao, Qiong; Guan, Yuan-Xiang; Wen, Xi-Zhi; Chen, Li-Zhen; Feng, Qi-Sheng; Li, Wei; Zeng, Yi-Xin; Zhang, Xiao-Shi

    2013-09-01

    Acral and mucosal melanomas, the two most common subtypes of melanoma in China, exhibit different genetic alterations and biologic behavior compared with other subtypes of melanomas. The purpose of this study was to identify the genetic alterations in patients with acral or mucosal melanomas in southern China. Fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) analysis, polymerase chain reaction (PCR), and quantitative real-time reverse transcriptase PCR (qRT-PCR) were used to assess the anaplastic lymphoma kinase (ALK) break points. Furthermore, a mass spectrometry-based genotyping platform was used to analyze 30 acral melanomas and 28 mucosal melanomas to profile 238 known somatic mutations in 19 oncogenes. ALK break points were identified in four acral cases (6.9%). Eight (13.8%) cases harbored BRAF mutations, six (10.3%) had NRAS mutations, four (6.9%) had KIT mutations, two (3.5%) had EGFR mutations, two (3.5%) had KRAS mutations, two (3.5%) had MET mutations, one (1.7%) had an HRAS mutation, and one (1.7%) had a PIK3CA mutation. Two cases exhibited co-occurring mutations, and one case with a BRAF mutation had a translocation in ALK. This study represents a comprehensive and concurrent analysis of the major recurrent oncogenic mutations involved in melanoma cases from southern China. These data have implications for both clinical trial designs and therapeutic strategies.

  15. Poor response to gefitinib in lung adenocarcinoma with concomitant epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.

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    Zhou, Jianya; Zheng, Jing; Zhao, Jing; Sheng, Yihong; Ding, Wei; Zhou, Jianying

    2015-03-01

    A patient presenting with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation is rare. We report a non-small cell lung cancer (NSCLC) patient with concomitant ALK rearrangement and exon 19 (E746-A750del) EGFR mutation. The ALK rearrangement was confirmed not only in the primary tumor biopsy specimen, but also in the pleural effusion cell block by reverse transcriptase-polymerase chain reaction (RT-PCR), Ventana ALK immunohistochemistry assay, and fluorescence in situ hybridization. No clinical benefit using chemotherapy or EGFR tyrosine kinase inhibitor gefitinib was obtained in this case.

  16. {sup 18}F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

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    Lee, Dong Yun; Lee, Jong Jin; Park, Seol Hoon; Chae, Sunyoung; Kim, Shin; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung; Ryu, Jinsook [Univ. of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2013-12-15

    Primary systemic anaplastic large cell lymphoma (ALCL) is divided into two entities according to the expression of anaplastic lymphoma kinase (ALK). We investigated {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG PET) findings in primary systemic ALCL according to ALK expression. Thirty-seven patients who had baseline PET before CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based chemotherapy were enrolled. Among them, patients who underwent interim and/or post-therapy PET were further investigated for the treatment response and survival analysis. Baseline PET was analyzed visually and semi-quantitatively using peak SUV, and interim and post-therapy PETs were visually analyzed. All cases were {sup 18}F-FDG-avid on baseline PET. The peak SUV of ALK-positive ALCL (n =16, 18.7±10.5) was higher than that of ALK-negative ALCL (n =21, 10.0±4.9) (P =0.006). In ALK-negative ALCL, complete response (CR) rate in negative-interim PET was higher than positive-interim PET (100 % vs 37.5 %, P=0.02); however, there was no such difference in ALK-positive ALCL (100 % vs 75 %, P =0.19). The 3-year progression-free survival (PFS) was not significantly different between ALK-positive and ALK-negative ALCL (72.7 % vs 47.6 %, P =0.34). In ALK-negative ALCL, negative interim and post-therapy PET patients had better 3-year PFS than positive interim (83.3 % vs 25.0 %, P =0.06) and post-therapy PET patients (70.0%vs 20.0 %, P =0.04). In contrast, ALK-positive ALCL had no such differences between PFS and PET results. On baseline PET, all cases showed {sup 18}F-FDG avidity, and ALK expression was related to higher {sup 18}F-FDG uptake. ALK-positive patients tend to have better PFS than ALK-negative patients. Negative-interim PET was a good indicator of CR, and interim or post-therapy PET was helpful for predicting the prognosis only in the ALK-negative group.

  17. Expression of p63 in anaplastic large cell lymphoma but not in classical Hodgkin's lymphoma.

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    Gualco, Gabriela; Weiss, Lawrence M; Bacchi, Carlos E

    2008-10-01

    Immunohistochemical determination of p63 protein is frequently used in the pathologic diagnosis of nonhematological solid tumors. In malignant hematological disease, p63 expression has been reported in 22% of follicular lymphoma, about 35% of diffuse large B-cell lymphoma, 23% of chronic lymphocytic leukemia, and in some cases of blast crisis of chronic myelogenous leukemia. Anaplastic large cell lymphoma is a rare disease that accounts for less than 5% of all cases of non-Hodgkin's lymphoma. There is little information concerning p63 expression in this specific type of lymphoma. In some cases, the morphological and phenotypic features between anaplastic large cell lymphoma and classical Hodgkin's lymphoma are similar, making this differential diagnosis challenging. We studied p63 expression using a tissue microarray approach in 154 cases of anaplastic large cell lymphoma, including 38% anaplastic large cell kinase positive and 62% anaplastic large cell kinase negative, and 58 Hodgkin's lymphoma cases. Sixty-eight cases of anaplastic large cell lymphoma (44%) showed p63 nuclear positivity (41% of anaplastic large cell kinase positive and 47% of anaplastic large cell kinase negative). Of 130 cases of systemic-anaplastic large cell lymphoma, 42% showed p63 positivity. The neoplastic cells expressed p63 in 38% of the cases of CD45-negative/anaplastic large cell kinase-negative null cell-type anaplastic large cell lymphoma, a subgroup that offers the most difficulties in the differential diagnosis with classical Hodgkin's lymphoma. In contrast, none of the cases of classical Hodgkin's lymphoma demonstrated any p63 expression. These results demonstrate that p63 protein expression is frequently expressed in a subset of anaplastic large cell lymphoma cases and may be used as a potential tool in the differential diagnosis between anaplastic large cell lymphoma and classical Hodgkin's lymphoma.

  18. Concomitant occurrence of EGFR (epidermal growth factor receptor) and KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations in an ALK (anaplastic lymphoma kinase)-positive lung adenocarcinoma patient with acquired resistance to crizotinib

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    Rossing, Henrik H; Grauslund, Morten; Urbanska, Edyta M;

    2013-01-01

    , the events behind crizotinib-resistance currently remain largely uncharacterized. Thus, we report on an anaplastic lymphoma kinase-positive non-small cell lung carcinoma patient with concomitant occurrence of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations......Anaplastic lymphoma kinase-positive non-small cell lung carcinoma patients are generally highly responsive to the dual anaplastic lymphoma kinase and MET tyrosine kinase inhibitor crizotinib. However, they eventually acquire resistance to this drug, preventing the anaplastic lymphoma kinase...... inhibitors from having a prolonged beneficial effect. The molecular mechanisms responsible for crizotinib resistance are beginning to emerge, e.g., in some anaplastic lymphoma kinase-positive non-small cell lung carcinomas the development of secondary mutations in this gene has been described. However...

  19. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

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    Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Thomas, Mathew; Wang, Yihan; Zhou, Tianjun; Romero, Jan; Kohlmann, Anna; Li, Feng; Qi, Jiwei; Cai, Lisi; Dwight, Timothy A; Xu, Yongjin; Xu, Rongsong; Dodd, Rory; Toms, Angela; Parillon, Lois; Lu, Xiaohui; Anjum, Rana; Zhang, Sen; Wang, Frank; Keats, Jeffrey; Wardwell, Scott D; Ning, Yaoyu; Xu, Qihong; Moran, Lauren E; Mohemmad, Qurish K; Jang, Hyun Gyung; Clackson, Tim; Narasimhan, Narayana I; Rivera, Victor M; Zhu, Xiaotian; Dalgarno, David; Shakespeare, William C

    2016-05-26

    In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

  20. Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma

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    Graf N

    2014-05-01

    Full Text Available Nicolas Graf,1 Zhoulei Li,2 Ken Herrmann,2,4 Daniel Weh,2 Michaela Aichler,3 Jolanta Slawska,2 Axel Walch,3 Christian Peschel,1 Markus Schwaiger,2 Andreas K Buck,2,4 Tobias Dechow,1,* Ulrich Keller1,* 1III Medical Department, 2Department of Nuclear Medicine, Technische Universität München, Munich, Germany; 3Research Unit Analytical Pathology, Helmholtz Zentrum München, Munich, Germany; 4Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany *These authors contributed equally to this work Background: Dual phosphatidylinositol-3-kinase (PI3K/mammalian target of rapamycin (mTOR inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226, in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET imaging using the standard tracer, 2-deoxy-2-[18F]fluoro-D-glucose (FDG and the thymidine analog, 3'-deoxy-3'-[18F]fluorothymidine (FLT. Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects. Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In

  1. ALK1-Negative Anaplastic Large Cell Lymphoma of the Breast from a Nonprosthesis Cyst

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    Christopher Mulligan, MBBS

    2014-10-01

    Full Text Available Summary: Anaplastic large cell lymphoma of the breast is a rare malignancy associated with prosthetic breast implants. We present a case of a woman with no prior history of breast implants who developed anaplastic lymphoma kinase-1 negative anaplastic large cell lymphoma on a background of a previous benign cyst aspiration.

  2. Anaplastic lymphoma kinase-positive lung adenocarcinoma patient with development of sick sinus syndrome while on targeted treatment with crizotinib.

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    Jiang, Hao; Li, Mei-Mei; Jin, Shu-Xian

    2015-03-01

    The anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are younger and have never smoked, while pathologically are predominately adenocarcinomas. Crizotinib as an ALK inhibitor has been used in treating ALK positive NSCLC patients for several years and some adverse effects should be paid attention to. We now describe a case of ALK positive NSCLC patient with development of sick sinus syndrome (SSS) while on targeted treatment with crizotinib. A 46-year-old non-smoking woman with right hilar mass and underwent transesophageal endoscopic ultrasonography lymph node biopsy showed low differentiation adenocarcinoma, immunohistochemistry (IHC) of tumor samples revealed the ALK overexpression. The severe sinus bradycardia and RR interval prolongation were detected 3 months after crizotinib treatment, she underwent pacemaker implantation. Although the severe sinus bradycardia and RR interval prolongation were unusual adverse effects, physicians should be aware of these side effects when using crizotinib.

  3. Malignant transformation of mature T cells after gammaretrovirus mediated transfer of nucleophosmin-anaplastic lymphoma kinase oncogene

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    Ashok Kumar

    2015-01-01

    Full Text Available Background: Gene therapy has been in use to cure hereditary and acquired diseases by incorporating the desired gene into the cells with the help of gammaretroviral vectors. Despite the success of this therapy in X-linked severe combined immunodeficiency syndrome, few patients developed leukemia as a major adverse event due to retroviral insertional mutagenesis within stem cells. In experimental animals also, retroviral-mediated gene transfer technique resulted in the development of leukemia. On the other hand, evidence suggests that mature T cells (TC are relatively resistant to transformation even after retroviral-mediated transfer of potent oncogenes Tcl1, ΔTrkA and LMO2 with no reported side effects yet. Aims: To further address the safety issue for TC use in gene therapy, this study investigated susceptibility of mature polyclonal TC to malignant transformation by the retroviral-mediated transfer of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK oncogene. Materials and Methods: Wild-type mature TC, isolated from C57BL/6 donor mice (genetic background Ly5.1 were transduced with gamma-retroviral vectors encoding the potent TC oncogene NPM-ALK or the control vector enhanced green fluorescent protein eGFP. The cells were then transplanted into RAG-1 deficient recipient mice (genetic background Ly5.2. Results: Two out of five mice from NPM-ALK oncogene group developed leukemia/lymphoma after latency periods (153 and 250 days, respectively. None of the mice from the control group developed any malignancy throughout the observational period. Conclusion: Mature polyclonal TC are relatively susceptible to malignant transformation after gamma-retroviral mediated transfer of NPM-ALK oncogene; hence safety of TC use in gene therapy should be further investigated to avoid the possible side-effect of development of leukemia/lymphoma.

  4. IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells.

    Science.gov (United States)

    Shi, Ping; Lai, Raymond; Lin, Quan; Iqbal, Abid S; Young, Leah C; Kwak, Larry W; Ford, Richard J; Amin, Hesham M

    2009-07-01

    Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase plays important roles in the pathogenesis of several malignancies. Although it promotes the growth of stimulated hematopoietic cells, a direct role of IGF-IR in malignant lymphoma has not been identified. Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK(+) ALCL) is a unique type of T-cell lymphoma. Approximately 85% of ALK(+) ALCL cases harbor the translocation t(2;5)(p23;q35), which generates the chimeric oncogene NPM-ALK. In the present study, we explored a possible role of IGF-IR in ALK(+) ALCL. Our results demonstrate that IGF-IR and IGF-I are widely expressed in ALK(+) ALCL cell lines and primary tumors. Importantly, we identified novel reciprocal functional interactions between IGF-IR and NPM-ALK. Antagonism of IGF-IR decreased the viability, induced apoptosis and cell-cycle arrest, and decreased proliferation and colony formation of ALK(+) ALCL cell lines. These effects could be explained by alterations of cell survival regulatory proteins downstream of IGF-IR signaling. Our findings improve current understanding of the biology of IGF-IR and NPM-ALK and have significant therapeutic implications as they identify IGF-IR signaling as a potential therapeutic target in ALK(+) ALCL and possibly other types of malignant lymphoma.

  5. ALK kinase domain mutations in primary anaplastic large cell lymphoma: consequences on NPM-ALK activity and sensitivity to tyrosine kinase inhibitors.

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    Federica Lovisa

    Full Text Available ALK inhibitor crizotinib has shown potent antitumor activity in children with refractory Anaplastic Large Cell Lymphoma (ALCL and the opportunity to include ALK inhibitors in first-line therapies is oncoming. However, recent studies suggest that crizotinib-resistance mutations may emerge in ALCL patients. In the present study, we analyzed ALK kinase domain mutational status of 36 paediatric ALCL patients at diagnosis to identify point mutations and gene aberrations that could impact on NPM-ALK gene expression, activity and sensitivity to small-molecule inhibitors. Amplicon ultra-deep sequencing of ALK kinase domain detected 2 single point mutations, R335Q and R291Q, in 2 cases, 2 common deletions of exon 23 and 25 in all the patients, and 7 splicing-related INDELs in a variable number of them. The functional impact of missense mutations and INDELs was evaluated. Point mutations were shown to affect protein kinase activity, signalling output and drug sensitivity. INDELs, instead, generated kinase-dead variants with dominant negative effect on NPM-ALK kinase, in virtue of their capacity of forming non-functional heterocomplexes. Consistently, when co-expressed, INDELs increased crizotinib inhibitory activity on NPM-ALK signal processing, as demonstrated by the significant reduction of STAT3 phosphorylation. Functional changes in ALK kinase activity induced by both point mutations and structural rearrangements were resolved by molecular modelling and dynamic simulation analysis, providing novel insights into ALK kinase domain folding and regulation. Therefore, these data suggest that NPM-ALK pre-therapeutic mutations may be found at low frequency in ALCL patients. These mutations occur randomly within the ALK kinase domain and affect protein activity, while preserving responsiveness to crizotinib.

  6. ALK kinase domain mutations in primary anaplastic large cell lymphoma: consequences on NPM-ALK activity and sensitivity to tyrosine kinase inhibitors.

    Science.gov (United States)

    Lovisa, Federica; Cozza, Giorgio; Cristiani, Andrea; Cuzzolin, Alberto; Albiero, Alessandro; Mussolin, Lara; Pillon, Marta; Moro, Stefano; Basso, Giuseppe; Rosolen, Angelo; Bonvini, Paolo

    2015-01-01

    ALK inhibitor crizotinib has shown potent antitumor activity in children with refractory Anaplastic Large Cell Lymphoma (ALCL) and the opportunity to include ALK inhibitors in first-line therapies is oncoming. However, recent studies suggest that crizotinib-resistance mutations may emerge in ALCL patients. In the present study, we analyzed ALK kinase domain mutational status of 36 paediatric ALCL patients at diagnosis to identify point mutations and gene aberrations that could impact on NPM-ALK gene expression, activity and sensitivity to small-molecule inhibitors. Amplicon ultra-deep sequencing of ALK kinase domain detected 2 single point mutations, R335Q and R291Q, in 2 cases, 2 common deletions of exon 23 and 25 in all the patients, and 7 splicing-related INDELs in a variable number of them. The functional impact of missense mutations and INDELs was evaluated. Point mutations were shown to affect protein kinase activity, signalling output and drug sensitivity. INDELs, instead, generated kinase-dead variants with dominant negative effect on NPM-ALK kinase, in virtue of their capacity of forming non-functional heterocomplexes. Consistently, when co-expressed, INDELs increased crizotinib inhibitory activity on NPM-ALK signal processing, as demonstrated by the significant reduction of STAT3 phosphorylation. Functional changes in ALK kinase activity induced by both point mutations and structural rearrangements were resolved by molecular modelling and dynamic simulation analysis, providing novel insights into ALK kinase domain folding and regulation. Therefore, these data suggest that NPM-ALK pre-therapeutic mutations may be found at low frequency in ALCL patients. These mutations occur randomly within the ALK kinase domain and affect protein activity, while preserving responsiveness to crizotinib.

  7. Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Gregory N., E-mail: gregory.gan@ucdenver.edu [Department of Radiation Oncology, University of Colorado, Aurora, Colorado (United States); Weickhardt, Andrew J.; Scheier, Benjamin; Doebele, Robert C. [Department of Medical Oncology, University of Colorado, Aurora, Colorado (United States); Gaspar, Laurie E.; Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado, Aurora, Colorado (United States); Camidge, D. Ross [Department of Medical Oncology, University of Colorado, Aurora, Colorado (United States)

    2014-03-15

    Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients. Methods and Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results: Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001). Conclusions: Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose–response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival.

  8. MicroRNA Expression Profiling Identifies Molecular Diagnostic Signatures for Anaplastic Large Cell Lymphoma

    DEFF Research Database (Denmark)

    Liu, Cuiling; Iqbal, Javeed; Teruya-Feldstein, Julie

    2013-01-01

    Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[-]) ALCLs, 9 angioimm...

  9. Aberrant anaplastic lymphoma kinase activity induces a p53 and Rb-dependent senescence-like arrest in the absence of detectable p53 stabilization.

    Directory of Open Access Journals (Sweden)

    Fiona Kate Elizabeth McDuff

    Full Text Available Anaplastic Lymphoma Kinase (ALK is a receptor tyrosine kinase aberrantly expressed in a variety of tumor types, most notably in Anaplastic Large Cell Lymphoma (ALCL where a chromosomal translocation generates the oncogenic fusion protein, Nucleophosmin-ALK (NPM-ALK. Whilst much is known regarding the mechanism of transformation by NPM-ALK, the existence of cellular defence pathways to prevent this pathological process has not been investigated. Employing the highly tractable primary murine embryonic fibroblast (MEF system we show that cellular transformation is not an inevitable consequence of NPM-ALK activity but is combated by p53 and Rb. Activation of p53 and/or Rb by NPM-ALK triggers a potent proliferative block with features reminiscent of senescence. While loss of p53 alone is sufficient to circumvent NPM-ALK-induced senescence and permit cellular transformation, sole loss of Rb permits continued proliferation but not transformation due to p53-imposed restraints. Furthermore, NPM-ALK attenuates p53 activity in an Rb and MDM2 dependent manner but this activity is not sufficient to bypass senescence. These data indicate that senescence may constitute an effective barrier to ALK-induced malignancies that ultimately must be overcome for tumor development.

  10. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.

    Science.gov (United States)

    Crescenzo, Ramona; Abate, Francesco; Lasorsa, Elena; Tabbo', Fabrizio; Gaudiano, Marcello; Chiesa, Nicoletta; Di Giacomo, Filomena; Spaccarotella, Elisa; Barbarossa, Luigi; Ercole, Elisabetta; Todaro, Maria; Boi, Michela; Acquaviva, Andrea; Ficarra, Elisa; Novero, Domenico; Rinaldi, Andrea; Tousseyn, Thomas; Rosenwald, Andreas; Kenner, Lukas; Cerroni, Lorenzo; Tzankov, Alexander; Ponzoni, Maurilio; Paulli, Marco; Weisenburger, Dennis; Chan, Wing C; Iqbal, Javeed; Piris, Miguel A; Zamo', Alberto; Ciardullo, Carmela; Rossi, Davide; Gaidano, Gianluca; Pileri, Stefano; Tiacci, Enrico; Falini, Brunangelo; Shultz, Leonard D; Mevellec, Laurence; Vialard, Jorge E; Piva, Roberto; Bertoni, Francesco; Rabadan, Raul; Inghirami, Giorgio

    2015-04-13

    A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.

  11. MOLECULAR BIOLOGICAL CHARACTERISTICS OF ALK-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA

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    E. V. Chernyshova

    2016-01-01

    Full Text Available ALK-positive anaplastic large cell lymphoma is a heterogeneous group of mature T-cell non-Hodgkin lymphoma, and is characterized by CD30/Ki-1 expression. Recently, value of various prognostic factors is investigated. These include clinical, histological and molecular genetic changes associated with different signaling pathways activation. Some features of the mechanism of action of anaplastic lymphoma kinases and targeted therapies possibilities addressed in this review.

  12. NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma.

    Science.gov (United States)

    Leventaki, Vasiliki; Drakos, Elias; Medeiros, L Jeffrey; Lim, Megan S; Elenitoba-Johnson, Kojo S; Claret, Francois X; Rassidakis, George Z

    2007-09-01

    Anaplastic large-cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35), resulting in aberrant expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). We show that in 293T and Jurkat cells, forced expression of active NPM-ALK, but not kinase-dead mutant NPM-ALK (210K>R), induced JNK and cJun phosphorylation, and this was linked to a dramatic increase in AP-1 transcriptional activity. Conversely, inhibition of ALK activity in NPM-ALK(+) ALCL cells resulted in a concentration-dependent dephosphorylation of JNK and cJun and decreased AP-1 DNA-binding. In addition, JNK physically binds NPM-ALK and is highly activated in cultured and primary NPM-ALK(+) ALCL cells. cJun phosphorylation in NPM-ALK(+) ALCL cells is mediated by JNKs, as shown by selective knocking down of JNK1 and JNK2 genes using siRNA. Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP-1 transcriptional activity and this was associated with decreased cell proliferation and G2/M cell-cycle arrest in a dose-dependent manner. Silencing of the cJun gene by siRNA led to a decreased S-phase cell-cycle fraction associated with upregulation of p21 and downregulation of cyclin D3 and cyclin A. Taken together, these findings reveal a novel function of NPM-ALK, phosphorylation and activation of JNK and cJun, which may contribute to uncontrolled cell-cycle progression and oncogenesis.

  13. Identification of a novel crosstalk between casein kinase 2α and NPM-ALK in ALK-positive anaplastic large cell lymphoma.

    Science.gov (United States)

    Armanious, Hanan; Gelebart, Pascal; Anand, Mona; Lai, Raymond

    2013-02-01

    It was previously reported that β-catenin contributes to the tumorigenesis of ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL), and the oncogenic effects of β-catenin in these tumors are promoted by NPM-ALK, an abnormal fusion protein characteristic of ALK(+)ALCL. In this study, we hypothesized that NPM-ALK promotes the oncogenic activity of β-catenin via its functional interactions with the Wnt canonical pathway (WCP). To test this hypothesis, we examined if NPM-ALK modulates the gene expression of various members in the WCP. Using a Wnt pathway-specific oligonucleotide array and Western blots, we found that the expression of casein kinase 2α (CK2α) was substantially downregulated in ALK(+)ALCL cells in response to siRNA knockdown of NPM-ALK. CK2α is biologically important in ALK(+)ALCL, as its inhibition using 4,5,6,7-tetrabromobenzotriazole or siRNA resulted in a significant decrease in cell growth and a substantial decrease in the β-catenin protein level. Furthermore, CK2α co-immunoprecipitated with NPM-ALK and regulated its level of serine phosphorylation, a feature previously shown to correlate with the oncogenic potential of this fusion protein. To conclude, this study has revealed a novel crosstalk between NPM-ALK and CK2α, and our data supports the model that these two molecules work synergistically to promote the tumorigenicity of these lymphomas.

  14. Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement-positive non-small cell lung cancer treated with alectinib.

    Science.gov (United States)

    Yamamoto, Yuzo; Okamoto, Isamu; Otsubo, Kohei; Iwama, Eiji; Hamada, Naoki; Harada, Taishi; Takayama, Koichi; Nakanishi, Yoichi

    2015-10-01

    Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug.

  15. STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma.

    Science.gov (United States)

    Wu, Chengsheng; Molavi, Ommoleila; Zhang, Haifeng; Gupta, Nidhi; Alshareef, Abdulraheem; Bone, Kathleen M; Gopal, Keshav; Wu, Fang; Lewis, Jamie T; Douglas, Donna N; Kneteman, Norman M; Lai, Raymond

    2015-07-16

    The tumorigenicity of most cases of ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL) is driven by the oncogenic fusion protein NPM-ALK in a STAT3-dependent manner. Because it has been shown that STAT3 can be inhibited by STAT1 in some experimental models, we hypothesized that the STAT1 signaling pathway is defective in ALK+ ALCL, thereby leaving the STAT3 signaling unchecked. Compared with normal T cells, ALK+ ALCL tumors consistently expressed a low level of STAT1. Inhibition of the ubiquitin-proteasome pathway appreciably increased STAT1 expression in ALK+ ALCL cells. Furthermore, we found evidence that NPM-ALK binds to and phosphorylates STAT1, thereby promoting its proteasomal degradation in a STAT3-dependent manner. If restored, STAT1 is functionally intact in ALK+ ALCL cells, because it effectively upregulated interferon-γ, induced apoptosis/cell-cycle arrest, potentiated the inhibitory effects of doxorubicin, and suppressed tumor growth in vivo. STAT1 interfered with the STAT3 signaling by decreasing STAT3 transcriptional activity/DNA binding and its homodimerization. The importance of the STAT1/STAT3 functional interaction was further highlighted by the observation that short interfering RNA knockdown of STAT1 significantly decreased apoptosis induced by STAT3 inhibition. Thus, STAT1 is a tumor suppressor in ALK+ ALCL. Phosphorylation and downregulation of STAT1 by NPM-ALK represent other mechanisms by which this oncogenic tyrosine kinase promotes tumorigenesis.

  16. The tyrosine 343 residue of nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) is important for its interaction with SHP1, a cytoplasmic tyrosine phosphatase with tumor suppressor functions.

    Science.gov (United States)

    Hegazy, Samar A; Wang, Peng; Anand, Mona; Ingham, Robert J; Gelebart, Pascal; Lai, Raymond

    2010-06-25

    The cytoplasmic tyrosine phosphatase SHP1 has been shown to inhibit the oncogenic fusion protein nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK), and loss of SHP1 contributes to NPM-ALK-mediated tumorigenesis. In this study, we aimed to further understand how SHP1 interacts and regulates NPM-ALK. We employed an in vitro model in which GP293 cells were transfected with various combinations of NPM-ALK (or mutants) and SHP1 (or mutants) expression vectors. We found that SHP1 co-immunoprecipitated with NPM-ALK, but not the enzymatically inactive NPM-ALK(K210R) mutant, or the mutant in which all three functionally important tyrosine residues (namely, Tyr(338), Tyr(342), and Tyr(343)) in the kinase activation loop (KAL) of ALK were mutated. Interestingly, whereas mutation of Tyr(338) or Tyr(342) did not result in any substantial change in the NPM-ALK/SHP1 binding (assessed by co-immunoprecipitation), mutation of Tyr(343) abrogated this interaction. Furthermore, the NPM-ALK/SHP1 binding was readily detectable when each of the remaining 8 tyrosine residues known to be phosphorylated were mutated. Although the expression of SHP1 effectively reduced the level of tyrosine phosphorylation of NPM-ALK, it did not affect that of the NPM-ALK(Y343F) mutant. In soft agar clonogenic assay, SHP1 expression significantly reduced the tumorigenicity of NPM-ALK but not that of NPM-ALK(Y343F). In conclusion, we identified Tyr(343) of NPM-ALK as the crucial site for mediating the NPM-ALK/SHP1 interaction. Our results also support the notion that the tumor suppressor effects of SHP1 on NPM-ALK are dependent on its ability to bind to this oncogenic protein.

  17. Novel covalent modification of human anaplastic lymphoma kinase (ALK and potentiation of crizotinib-mediated inhibition of ALK activity by BNP7787

    Directory of Open Access Journals (Sweden)

    Parker AR

    2015-02-01

    Full Text Available Aulma R Parker,1 Pavankumar N Petluru,1 Vicki L Nienaber,2 Min Zhao,1 Philippe Y Ayala,1 John Badger,2 Barbara Chie-Leon,2 Vandana Sridhar,2 Cheyenne Logan,2 Harry Kochat,1 Frederick H Hausheer1 1BioNumerik Pharmaceuticals, Inc., San Antonio, TX, USA; 2Zenobia Therapeutics, Inc., La Jolla, CA, USA Abstract: BNP7787 (Tavocept, disodium 2,2’-dithio-bis-ethanesulfonate is a novel, investigational, water-soluble disulfide that is well-tolerated and nontoxic. In separate randomized multicenter Phase II and Phase III clinical trials in non-small-cell lung cancer (NSCLC patients, treatment with BNP7787 in combination with standard chemotherapy resulted in substantial increases in the overall survival of patients with advanced adenocarcinoma of the lung in the first-line treatment setting. We hypothesized that BNP7787 might interact with and modify human anaplastic lymphoma kinase (ALK. At least seven different variants of ALK fusions with the gene encoding the echinoderm microtubule-associated protein-like 4 (EML4 are known to occur in NSCLC. EML4–ALK fusions are thought to account for approximately 3% of NSCLC cases. Herein, we report the covalent modification of the kinase domain of human ALK by a BNP7787-derived mesna moiety and the functional consequences of this modification in ALK assays evaluating kinase activity. The kinase domain of the ALK protein crystallizes as a monomer, and BNP7787-derived mesna-cysteine adducts were observed at Cys 1235 and Cys 1156. The BNP7787-derived mesna adduct at Cys 1156 is located in close proximity to the active site and results in substantial disorder of the P-loop and activation loop (A-loop. Comparison with the P-loop of apo-ALK suggests that the BNP7787-derived mesna adduct at Cys 1156 interferes with the positioning of Phe 1127 into a small pocket now occupied by mesna, resulting in a destabilization of the loop's binding orientation. Additionally, in vitro kinase activity assays indicate that BNP7787

  18. Destaining of Diff-Quik stained cytologic smears is not necessary for the detection of anaplastic lymphoma kinase gene rearrangement in lung adenocarcinoma by fluorescence in situ hybridization

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    Weisheng Xu

    2016-01-01

    Full Text Available Background: Anaplastic lymphoma kinase (ALK gene rearrangement analysis by fluorescence in situ hybridization (FISH is one of the standard molecular tests for targeted therapy of lung adenocarcinoma. However, insufficient cell block cellularity may impede molecular testing. A recent study showed that Diff-Quik (DQ stained cytology smear is suitable for ALK by FISH. Aims: The aim of our study was to observe the impact of destaining intervals on the quality of FISH signals and determine if DQ smears without destaining would allow FISH analysis. Materials and Methods: Thirty-five DQ smears from 27 cases of lung adenocarcinoma were analyzed for ALK gene rearrangement by FISH. Twenty three DQ smears were destained for different intervals, including 30 s (13 cases, 1 min (6 cases, or 2 min (4 cases. Twelve DQ smears were not subjected to destaining. For further validation, FISH signals in 8 smears and 6 cell blocks were compared with the paired destained DQ smears. The signal quality was semi-quantified and analyzed with Chi-squared test. Results: Of the total 27 selected cases, three (11% were positive for ALK gene rearrangement, whereas 24 (89% were negative. FISH signal was satisfactory in all DQ smears. There was no significant difference in the quality of signal among smears with different destaining intervals (P = 0.55 or between smears with and without destaining (P = 0.41. DQ smears without destaining showed identical FISH results and similar or better signals as compared with paired destained smears and cell blocks in all cases. Conclusions: Duration of destaining intervals does not impact the quality of FISH signal on DQ smears. Destaining of DQ smears is not necessary for ALK by FISH.

  19. Clinicopathologic characteristics andtherapeutic responses ofChinese patients withnon-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement

    Institute of Scientific and Technical Information of China (English)

    ShaFu; HaiYunWang; FangWang; MaYanHuang; LingDeng; XiaoZhang; ZuLuYe; JianYong Shao

    2015-01-01

    Introduction:The rearrangement of the anaplastic lymphoma kinase (ALK) gene accounts for approximately 1%–6%of lung adenocarcinoma cases and deifnes a molecular subgroup of tumors characterized by clinical sensitivity toALK inhibitors such as crizotinib. This study aimed to identify the relationship betweenALK rearrangement and the clinico‑pathologic characteristics of non‑small cell lung cancer (NSCLC) and to analyze the therapeutic responses of crizotinib and conventional chemotherapy toALK rearrangement in NSCLC patients. Methods:A total of 487 lung cancer patients who underwent testing forALK rearrangement in our department were included in this study.ALK rearrangement was examined by using lfuorescence insitu hybridization (FISH) assay. Results:Among the 487 patients, 44 (9.0%) were diagnosed withALK rearrangement by using FISH assay. In 123 patients with adenocarcinoma who were non‑smokers and of a young age (≤58years old), the frequency ofALK rearrangement was 20.3% (25/123). Short overall survival (OS) was associated with non‑adenocarcinoma tumor type (P=0.006), poorly differentiated tumors (P=0.001), advanced‑stage tumors (P<0.001), smoking history (P=0.008), and wild‑type epidermal growth factor receptor (EGFR) (P=0.008). Moreover, patients with poorly differentiated and advanced‑stage tumors had a shorter time to cancer progression compared with those with well differentiated (P=0.023) and early‑stage tumors (P=0.001), respectively. Conclusions:ALK‑rearranged NSCLC tends to occur in younger individuals who are either non‑smokers or light smokers with adenocarcinoma. Patients withALK rearrangement might beneift fromALK inhibitor therapy.

  20. Diagnostic and therapeutic issues for patients with advanced non‑small cell lung cancer harboring anaplastic lymphoma kinase rearrangement: European vs. US perspective (review).

    Science.gov (United States)

    Di Maio, Massimo; De Marinis, Filippo; Hirsch, Fred R; Gridelli, Cesare

    2014-08-01

    The recent availability of crizotinib in clinical practice, for the treatment of patients with advanced non-small cell lung cancer (NSCLC) selected by the presence of anaplastic lymphoma kinase (ALK) rearrangement, has relevant implications for both the diagnostic phase and the treatment choices. In the United States, crizotinib was approved by the Food and Drug Administration (FDA) in 2011 for patients with ALK positivity detected by FDA-approved companion diagnostic test. As of January, 2014, the only FDA-approved diagnostic test is Vysis ALK Break-Apart FISH Probe Kit. In Europe, European Medicines Agency (EMA) approved crizotinib for ALK-positive patients in 2012, without specifying the type of test used for determining the positivity. FISH remains the reference technique for ALK determination, but, if fully validated, immunohistochemistry could challenge the current ALK screening practice. Given the robust evidence of activity of crizotinib in ALK-positive patients both pretreated and chemotherapy-naïve, and the favourable tolerability profile of the drug, many oncologists would prefer to administer the drug as early as possible. This is technically feasible in the United States, where crizotinib was approved well before the availability of the results of the randomized phase III trial comparing the drug with standard second-line chemotherapy, and the use of crizotinib in ALK-positive patients is not restricted to a specific line of treatment. On the contrary, in Europe, differently from the FDA decision, crizotinib cannot be used in chemotherapy-naïve patients. In both realities, a deeper knowledge of mechanisms of resistance, the role of repeated biopsies, the treatment strategy for patients experiencing disease progression with crizotinib, the choice of the best chemotherapy regimen are challenging topics for the management of ALK-positive patients in clinical practice.

  1. Rearranged anaplastic lymphoma kinase (ALK) gene found for the first time in adult-onset papillary thyroid cancer cases among atomic bomb survivors

    Energy Technology Data Exchange (ETDEWEB)

    Hamatani, K.; Mukai, M.; Takahashi, K.; Nakachi, K.; Kusunoki, Y. [Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima (Japan); Hayashi, Y. [Geriatric Health Service Facility Hidamari, Hiroshima (Japan)

    2012-07-01

    Full text of the publication follows: Thyroid cancer is one of the malignancies most strongly associated with ionizing radiation in humans. Epidemiology studies of atomic bomb (A-bomb) survivors have indicated that excess relative risk of papillary thyroid cancer per Gy was remarkably high in the survivors. We therefore aim to clarify mechanisms linking A-bomb radiation exposure and development of papillary thyroid cancer. Toward this end, we intend to clarify characteristics of gene alterations occurring in radiation-associated adult-onset papillary thyroid cancer from the Life Span Study cohort of A-bomb survivors. We have thus far found that with increased radiation dose, papillary thyroid cancer cases with chromosomal rearrangements (mainly RET/PTC rearrangements) significantly increased and papillary thyroid cancer cases with point mutations (mainly BRAF-V600E) significantly decreased. Papillary thyroid cancer cases with non-detected gene alterations that carried no mutations in RET, NTRK1, BRAF or RAS genes tended to increase with increased radiation dose. In addition, we found that relative frequency of these papillary thyroid cancer cases significantly decreased with time elapsed since exposure. Through analysis of papillary thyroid cancer cases with non-detected gene alterations, we recently discovered a new type of rearrangement for the first time in papillary thyroid cancer, i.e., rearranged anaplastic lymphoma kinase (ALK) gene, although identification of any partner gene(s) is needed. Specifically, rearrangement of ALK was found in 10 of 19 exposed papillary thyroid cancer cases with non-detected gene alterations but not in any of the six non-exposed papillary thyroid cancer cases. Furthermore, papillary thyroid cancer with ALK rearrangement was frequently found in the cases with high radiation dose or with short time elapsed since A-bomb exposure. These results suggest that chromosomal rearrangement, typically of RET and ALK, may play an important

  2. [KI-1-positive, anaplastic, large-cell lymphoma related to Hodgkin's disease].

    Science.gov (United States)

    Veiga, M; Fresno, M F; Pérez del Río, M J; García, I; Madrigal, B; Herrero, A

    1997-02-01

    We report a case of lymphoma associated with lung carcinoma that shows morphological and immunohistochemical features of anaplastic large cell Ki-1 positive lymphoma and Hodgkin's disease, with positivity for Ki-1 (CD-30) (characteristic of both lymphomas) and Leu-M1 (CD-15) (normally dosent absent in anaplastic lymphoma). This subtype of lymphoma is designated anaplastic large-cell Hodgkin's related lymphoma (ALCL related to HD) and is considered by some authors as a secondary anaplastic large-cell lymphoma.

  3. Pathobiology of Anaplastic Large Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Pier Paolo Piccaluga

    2010-01-01

    Full Text Available The authors revise the concept of anaplastic large cell lymphoma (ALCL in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated with special reference to the cytological spectrum that is indeed characteristic of the tumor. The phenotype is reported in detail: the expression of the ALK protein as well as the chromosomal abnormalities is discussed with their potential pathogenetic implications. The clinical features of ALCL are presented by underlining the difference in terms of response to therapy and survival between the ALK-positive and ALK-negative forms. Finally, the biological rationale for potential innovative targeted therapies is presented.

  4. Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy

    OpenAIRE

    2016-01-01

    A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The...

  5. Cytokeratin positive anaplastic large cell lymphoma: Difficulty in differentiation from metastatic carcinoma

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    Nishat Afroz

    2015-01-01

    Full Text Available Cytokeratin and epithelial membrane antigen (EMA are usually included in the first panel of immunomarkers used to differentiate metastatic carcinoma from lymphoma in cases presenting with enlarged lymph nodes. While carcinomas are cytokeratin and EMA positive, most lymphomas are negative for the above. However, recently few cases of cytokeratin positive lymphomas have also been reported. Here, we describe a very rare case of cytokeratin positive anaplastic large cell lymphoma (ALCL masquerading as a poorly differentiated carcinoma. Simultaneously, we also discuss the differential diagnosis and difficulty in differentiation from metastatic carcinoma in such a scenario. Review of literature shows that this is probably the first case report of anaplastic lymphoma kinase negative-ALCL seen in a young adult.

  6. A citrus flavonoid, 6-demethoxytangeretin, suppresses production and gene expression of interleukin-6 in human mast cell-1 via anaplastic lymphoma kinase and mitogen-activated protein kinase pathways.

    Science.gov (United States)

    Kim, Young-Mi; Chae, Hee-Sung; Lee, Eun Joo; Yang, Min Hye; Park, Jin Hee; Yoon, Kee Dong; Kim, Jinwoong; Ahn, Hee Chul; Choi, Young Hee; Chin, Young-Won

    2014-01-01

    Citrus species has been traditionally used in Korea for the treatment of coughing, sputum and dyspepsia. Of the known citrus flavonoids, 6-demethoxytangeretin was reported to exert anti-inflammatory activity. In order to determine the anti-allergic activity of 6-demethoxytangeretin, we examined whether or not 6-demethoxytangeretin was able to suppress activation of the human mast cell line, HMC-1, induced by phorbol 12-myristate 13-acetate (PMA) plus A23187. Interleukin-6 production and relevant gene expression in activated HMC-1 cells were determined by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. Also, the involvement of the anaplastic lymphoma kinase (ALK) and mitogen-activated protein kinases (MAPKs) in activated HMC-1 cells were studied. 6-Demethoxytangeretin suppresses interleukin-6 production, tumor necrosis factor-alpha gene expression, ALK and MAPKs in HMC-1 cells stimulated by PMA plus A23187. Therefore, it was evident that 6-demethoxytangeretin suppressed activation of HMC-1 cells by PMA plus A23187 by inhibiting the activity of ALK and MAPKs and subsequently suppressing gene expression, which suggest that 6-demethoxytangeretin may be involved in the regulation of mast cell-mediated inflammatory responses.

  7. Anaplastic lymphoma kinase (ALK inhibitors for second-line therapy of non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Berghmans T

    2012-12-01

    Full Text Available Thierry Berghmans,1 Myriam Remmelink,2 Ahmad Awada31Clinic of Thoracic Oncology and Department of Intensive Care, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; 2Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; 3Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, BelgiumAbstract: Targeted therapies are nowadays a treatment option in metastatic non-small cell lung cancer, for which oncogenic drivers have been identified. The epidermal growth factor-receptor tyrosine kinase inhibitors gefitinib and erlotinib, are the standard of care for patients in whom tumors are presenting with an activating epidermal growth factor-receptor mutation, with new active agents like afatinib reaching clinics in the near future. Other genetic abnormalities have been documented in squamous and non-squamous lung cancer. The EML4–ALK gene fusion is a rare event, occurring in around 5% of lung cancer, quite exclusively in adenocarcinoma with a predominance of young non/light smokers. Detection of ALK-positive tumors is challenging, as there is no gold-standard technique. Fluorescence in situ hybridization is the method used in prospective trials assessing the activity of crizotinib and is recommended by the American FDA. Crizotinib is the first orally active inhibitor of receptor tyrosine kinases, including ALK and ROS1, in clinical practice. Impressive results came from a phase I study and are now confirmed in a large phase II study with response rate of 60%, whatever the number of previous lines of chemotherapy. Other ALK inhibitors are currently in the preclinical phase, and some are showing promising results in early phase I/II studies. This review aims to present the current knowledge on the EML4–ALK gene fusion, the pitfalls for the pathologist and the clinician in searching this abnormality, and to review the existing literature on ALK inhibitors under

  8. IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK.

    Science.gov (United States)

    Zhang, Qian; Wang, Hong Yi; Liu, Xiaobin; Bhutani, Gauri; Kantekure, Kanchan; Wasik, Mariusz

    2011-07-19

    Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4(+) T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4(+) T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

  9. Composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma involving the right inguinal lymph node.

    Science.gov (United States)

    Persad, Paul; Pang, Changlee S

    2014-02-01

    Anaplastic large cell lymphoma and small lymphocytic lymphoma are two lymphoid malignancies with completely distinct morphologies and natural histories. We present a rare case of composite anaplastic large cell lymphoma and small lymphocytic lymphoma in an inguinal lymph node of an otherwise healthy 47-year-old male patient. Immunohistochemical and molecular studies identified the two populations clearly. Their separation is imperative as anaplastic large cell lymphoma can be an aggressive neoplasm and easily overlooked in cases of small lymphocytic lymphoma with a small population of anaplastic large cell lymphoma cells.

  10. Research progresses in the pathogenesis of anaplastic large cell lymphoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-Lan Shi; Xiao-Wen Tang; De-Pei Wu

    2011-01-01

    Anaplastic large cell lymphoma (ALCL) is a distinct subset of T-cell non-Hodgkin's lymphoma. As a consequence of its low incidence, general pathogenic consideration of ALCL is lacking. In this review, we summarize the pathogenesis, epidemiology, clinical manifestations, and treatment of ALCL, so as to better understand key stages of the development of this disease and provide valuable information for future treatment.

  11. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib

    Science.gov (United States)

    Mahuad, Carolina Valeria; Repáraz, María de los Ángeles Vicente; Zerga, Marta E.; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-01-01

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy. PMID:27441079

  12. Primary anaplastic large T cell lymphoma of central nervous system

    Directory of Open Access Journals (Sweden)

    ZHANG Yan

    2013-01-01

    Full Text Available Background Primary anaplastic large T cell lymphoma (ALCL of central nervous system (CNS can occur in people of all ages, and is usually unrelated with immunodeficiency. It is often misdiagnosed as meningitis, especially tuberculous meningitis, on clinical practice and imaging examination. In pathological diagnosis, the morphological changes of primary ALCL of CNS are similar to the systemic ALCL and the anaplastic lymphoma kinase-1 (ALK-1 can be positive or negative. Being misdiagnosed as meningitis, hormone therapy with glucocorticoid before biopsy is always used, and massive necrosis and a lot of histocyte proliferation and phagocytosis can be found under histological findings. Therefore, when the material is not enough, primary ALCL of CNS is often misdiagnosed as cerebral infarction or malignant histocytosis and so on. This paper reports a case of primary ALCL of CNS and makes a review of relevant literature, so as to summarize the clinical manifestations and elevate the recognition of clinicians and pathologists on this disease. Methods and Results A 12-year-old boy was admitted because of fever, worsening headache, numbness and weakness of right limbs. MRI showed local gyri swelling and abnormal enhancement of pia mater in the right parietal lobe, expanding to the right temporal lobe, and pia mater enhancement in the left parietal lobe. The right temporo-parietal lobe lesion biopsy revealed irregularly shaped tumor cells of large size, rich and eosinophilic cytoplasm and horseshoe-shaped or kidney-shaped nuclei. Immunohistochemical examination showed tumor cells positive for CD3, CD45RO, CD30, ALK-1 and epithelial membrane antigen (EMA, and negative for CD20 and CD79a. Conclusion Primary ALCL of CNS is an extremely rare tumor which is usually misdiagnosed as meningitis according to clinical and imaging examinations. Therefore, for those patients who are considered as meningitis but with poor treatment effect and replase of illness, brain

  13. ALK-positive anaplastic large cell lymphoma with soft tissue involvement in a young woman

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    Gao KH

    2016-07-01

    Full Text Available Kehai Gao, Hongtao Li, Caihong Huang, Huazhuang Li, Jun Fang, Chen Tian Department of Orthopaedics, Yidu Central Hospital, Shandong, People’s Republic of China Introduction: Anaplastic large cell lymphoma (ALCL is a type of non-Hodgkin lymphoma that has strong expression of CD30. ALCL can sometimes involve the bone marrow, and in advanced stages, it can produce destructive extranodal lesions. But anaplastic large cell lymphoma kinase (ALK+ ALCL with soft tissue involvement is very rare.Case report: A 35-year-old woman presented with waist pain for over 1 month. The biopsy of soft tissue lesions showed that these cells were positive for ALK-1, CD30, TIA-1, GranzymeB, CD4, CD8, and Ki67 (90%+ and negative for CD3, CD5, CD20, CD10, cytokeratin (CK, TdT, HMB-45, epithelial membrane antigen (EMA, and pan-CK, which identified ALCL. After six cycles of Hyper-CVAD/MA regimen, she achieved partial remission. Three months later, she died due to disease progression.Conclusion: This case illustrates the unusual presentation of ALCL in soft tissue with a bad response to chemotherapy. Because of the tendency for rapid progression, ALCL in young adults with extranodal lesions are often treated with high-grade chemotherapy, such as Hyper-CVAD/MA. Keywords: anaplastic large cell lymphoma, ALK+, soft tissue involvement, Hyper-CVAD/MA

  14. Functional characterization of the kinase activation loop in nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) using tandem affinity purification and liquid chromatography-mass spectrometry.

    Science.gov (United States)

    Wang, Peng; Wu, Fang; Ma, Yupo; Li, Liang; Lai, Raymond; Young, Leah C

    2010-01-01

    Previous studies have shown that the kinase activation loop (KAL) of the oncogenic fusion protein NPM-ALK regulates its overall tyrosine phosphorylation status and tumorigenicity. Using tandem affinity purification-mass spectrometry, we assessed how the KAL of NPM-ALK regulates the phosphorylation status of its individual tyrosines. Using the lysates of GP293 cells transfected with NPM-ALK, our highly reproducible results showed evidence of phosphorylation in all 3 tyrosines in KAL and 8 tyrosines outside KAL. We created 7 KAL mutants, each of which carried a Tyr-to-Phe mutation of >or=1 of the 3 tyrosines in KAL. A complete loss of the 8 phosphotyrosines outside KAL was found in 3 KAL mutants, and their oncogenicity (assessed by cell viability, colony formation, and the ability to phosphorylate effector proteins) was abrogated. A partial loss of the 8 phosphotyrosines was found in 4 KAL mutants, but their oncogenicity did not show simple correlation with the number of residual phosphotyrosines. Tyr-to-Phe mutations of each of the 8 phosphotyrosines outside KAL did not result in a significant decrease in the oncogenicity. In conclusion, we have provided details of how the KAL in NPM-ALK regulates its tyrosine phosphorylation pattern. Our results challenge some of the current concepts regarding the relationship between the tyrosine phosphorylation and oncogenicity of NPM-ALK.

  15. Dual anaplastic large cell lymphoma mimicking meningioma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Keun Ho; Kim, Ki Hwan; Lee, Ghi Jai; Lee, Hye Kyung; Shim, Jae Chan; Lee, Kyoung Eun; Suh, Jung Ho [Seoul Paik Hospital, Inje University College of Medicine, Seoul (Korea, Republic of); Lee, Chae Heuck [Dept. of Neurosurgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang (Korea, Republic of)

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is a rare T cell lymphoma composed of CD30-positive lymphoid cells. Most ALCLs present as nodal disease, with skin, bone, soft tissue, lung, and liver as common extranodal sites. ALCL rarely occurs in the central nervous system and is even more infrequent in the dura of the brain. We report a case of dural-based ALCL secondary to systemic disease in a 17-year-old male that mimicked meningioma on magnetic resonance imaging and angiography.

  16. 原发系统型间变性大细胞淋巴瘤间变性淋巴瘤激酶基因异常与其融合蛋白表达及预后分析%Anaplastic lymphoma kinase gene abnormality and the expression of its fusion protein in primary systemic anaplastic large cell lymphoma

    Institute of Scientific and Technical Information of China (English)

    时云飞; 刘翠苓; 周春菊; 宫丽平; 董丽娜; 李敏; 黄欣; 高子芬

    2008-01-01

    目的:回顾性研究原发系统型间变性大细胞淋巴瘤(primary systemic anaplastic large cell lymphoma,S-ALCL)间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合蛋白表达及ALK基因异常情况,探讨两者关系及预后意义.方法:收集北京大学基础医学院病理学系淋巴瘤研究室及北京儿童医院28例确诊S-ALCL的病例,重新进行常规形态观察,复习及补充必要免疫组化标记以核实诊断.采用EnVision法进行免疫组织化学染色(immu-nohistochemical stainining,IHC).应用ALK-1单克隆抗体检测ALK融合蛋白表达,应用位点特异性间期荧光原位杂交(locus specific interphase fluorescence in situ hybridization,LSI-FISH)方法检测石蜡包埋组织中肿瘤细胞ALk基因断裂及其他异常情况.收集临床资料,随访.结果:8例S-ALCL病例IHC检测ALK-1蛋白阳性19例,阴性9例.用LSI-FISH法检测到ALK基因断裂14例,其余14例无ALK基因断裂的病例中,5例呈2个拷贝,9例呈多个拷贝.全部病例中有完整随访的共22例,随访截止时16例生存,6例死亡,生存期0.5~36.0个月,平均生存期12.8个月;1年累计生存率73.9%.ALk基因多个完整拷贝者1年累计生存率仅47.6%,预后相对较差.结论:-ALcL病例肿瘤细胞有ALK-1融合蛋白表达,在S-ALCL诊断中高度特异.S-ALCL病例ALK基因的异常改变很复杂,ALK-l融合蛋白表达与ALK基因断裂不完全吻合.S-ALCL中ALK基因异常的不同类型间预后可能有差异.ALK基因呈多个完整拷贝病例的预后可能更差.

  17. PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma.

    Science.gov (United States)

    Boi, Michela; Rinaldi, Andrea; Kwee, Ivo; Bonetti, Paola; Todaro, Maria; Tabbò, Fabrizio; Piva, Roberto; Rancoita, Paola M V; Matolcsy, András; Timar, Botond; Tousseyn, Thomas; Rodríguez-Pinilla, Socorro Maria; Piris, Miguel A; Beà, Sílvia; Campo, Elias; Bhagat, Govind; Swerdlow, Steven H; Rosenwald, Andreas; Ponzoni, Maurilio; Young, Ken H; Piccaluga, Pier Paolo; Dummer, Reinhard; Pileri, Stefano; Zucca, Emanuele; Inghirami, Giorgio; Bertoni, Francesco

    2013-10-10

    Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-) ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication.

  18. A case of Primary Bone Anaplastic Large Cell Lymphoma

    Science.gov (United States)

    Kim, Kyung Hyun; Jung, Yun Hwa; Han, Chi Wha; Woo, In Sook; Son, Jong ho

    2016-01-01

    Patient: Female, 52 Final Diagnosis: Primary bone anaplastic large cell lymphoma Symptoms: Bone pain Medication: — Clinical Procedure: — Specialty: Oncology Objective: Unusual clinical course Background: Anaplastic large cell lymphoma (ALCL) is a relatively rare subtype of non-Hodgkin’s lymphoma (NHL). Like other types of NHL, ALCL primarily involves the nodal area, and sometimes it can involve several extra-nodal sites such as skin, soft tissue, and lungs. However, extensive bone involvement in cases of ALCL is very rare whether it is primary or secondary. Without nodular involvement, ALCL can be misdiagnosed as bone tumor or metastatic carcinoma such as lung, breast, or prostate cancer, which frequently spread to bone. Case Report: A 52-year-old woman with generalized pain and 2 months of fever of unknown origin presented to our institution. After extensive evaluation, only multiple osteolytic bone lesions with periosteal soft tissue reaction were identified. Repeated core needle biopsy revealed only inflammatory cells with histiocytic reactions. After pathologic and chromosomal analysis of sufficient tissue, which was acquired from incisional biopsy, primary bone ALCL was confirmed. Conclusions: Clinicians should keep in mind that ALCL can present with extensive bone involvement without nodal involvement. PMID:27729639

  19. 间变性淋巴瘤激酶阴性的间变性大细胞淋巴瘤泛发性皮肤侵犯一例%Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma with generalized cutaneous involvement:a case report

    Institute of Scientific and Technical Information of China (English)

    孙春秋; 唐旭; 王松; 沈宏

    2012-01-01

    A rare case of anaplastic lymphoma kinase(ALK)-negative anaplastic large cell lymphoma (ALCL)with generalized cutaneous involvement is reported in a 37-year-old man.Seven months prior to the presentation,he developed a goose egg-sized mass in his right thigh without obvious triggers,which gradually grew and no significant discomfort was felt.Diffuse and nonpitting edema gradually appeared in his right thigh and hip.Two months prior to the presentation,multiple dark red papules,nodules,and plaques emerged over the body surface with erosions and ulcers of varying size arising on some of the plaques.Laboratory examination revealed reduced albumin and significantly elevated lactate dehydrogenase in serum.B-mode sonography showed swelling and mutual fusion of superficial lymph nodes,and color Doppler flow imaging revealed markedly increased branch blood flow signals in lymph nodes.Computed tomography(CT)displayed generalized swelling of lymph nodes associated with soft-tissue edema in the right thigh and perineal region,as well as extensive enlargement of epigastric and mediastinal lymph nodes.Pathological examination of the skin lesion revealed a dense dermal infiltrate with mononuclear cells,some of which presented with cellular atypia and atypical nuclear division.Immunohistochemistry of the skin lesion showed that the mononuclear cells stained positive for CD3,CD8,CD30(80% positive),CD4,CD45RO and granzyme B,but negative for CD56,ALK and T cell intracellular antigen-1(TIA-1).Pathology of lymph nodes indicated that the lymph node structure was completely destroyed with a diffuse growth of tumor cells,which were larger than common large cell lymphoma cells,and contained basophilic or bi-color abundant cytoplasm,deviating,horseshoe-,kidney-shaped,or lobulated cell nuclei,sparse nuclear chromatin and single or multiple small basophilic nucleoli.Angiogenesis,stromal fibrosis and infiltration of varying number of plasma cells and lymphocytes were seen in pathological

  20. Anaplastic large cell lymphoma ALK-negative clinically mimicking alcoholic hepatitis – a review

    Directory of Open Access Journals (Sweden)

    Fernando Peixoto Ferraz de Campos

    2013-10-01

    Full Text Available Anaplastic large cell lymphoma (ALCL, described less than 30 years ago by Karl Lennert and Herald Stein in Kiel, West Germany, is a T-cell or null non-Hodgkin lymphoma, with distinctive morphology (hallmark cells, prominent sinus and/or perivascular growth pattern, characteristic immunophenotype (CD30+, cytotoxic granules protein+, CD3–/+ and specific genetic features as translocations involving the receptor tyrosine kinase called anaplastic lymphoma kinase (ALK on 2p23 and variable partners genes, which results in the expression of ALK fusion protein. The absence of ALK expression is also observed and is associated with poorer prognosis that seen with ALK expression. ALK-negative ALCL is more frequent in adults, with both nodal and extra nodal clinical presentation and includes several differential diagnoses with other CD30+ lymphomas. Liver involvement by ALCL is rare and is generally seen as mass formation; the diffuse pattern of infiltration is even more unusual. The authors present a case of a 72-year-old man who presented clinical symptoms of acute hepatic failure. The patient had a long history of alcohol abuse and the diagnosis of alcoholic hepatitis was highly considered, although the serum lactic dehydrogenase (LDH value was highly elevated. The clinical course was fulminant leading to death on the fourth day of hospitalization. Autopsy demonstrated diffuse neoplastic hepatic infiltration as well as splenic, pulmonary, bone marrow, and minor abdominal lymph nodes involvement by the tumor. Based on morphological, immunophenotypical, and immunohistochemical features, a diagnosis of ALK- negative ALCL was concluded. When there is marked elevation of LDH the possibility of lymphoma, ALCL and other types, should be the principal diagnosis to be considered.

  1. Detection of Echinoderm Microtubule Associated Protein Like 4-Anaplastic Lymphoma Kinase Fusion Genes in Non-small Cell Lung Cancer Clinical Samples by a Real-time Quantitative Reverse Transcription Polymerase Chain Reaction Method.

    Science.gov (United States)

    Zhao, Jing; Zhao, Jin-Yin; Chen, Zhi-Xia; Zhong, Wei; Li, Long-Yun; Liu, Li-Cheng; Hu, Xiao-Xu; Chen, Wei-Jun; Wang, Meng-Zhao

    2016-12-20

    Objective To establish a real-time quantitative reverse transcription polymerase chain reaction assay (qRT-PCR) for the rapid, sensitive, and specific detection of echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion genes in non-small cell lung cancer. Methods The specific primers for the four variants of EML4-ALK fusion genes (V1, V2, V3a, and V3b) and Taqman fluorescence probes for the detection of the target sequences were carefully designed by the Primer Premier 5.0 software. Then, using pseudovirus containing EML4-ALK fusion genes variants (V1, V2, V3a, and V3b) as the study objects, we further analyzed the lower limit, sensitivity, and specificity of this method. Finally, 50 clinical samples, including 3 ALK-fluorescence in situ hybridization (FISH) positive specimens, were collected and used to detect EML4-ALK fusion genes using this method. Results The lower limit of this method for the detection of EML4-ALK fusion genes was 10 copies/μl if no interference of background RNA existed. Regarding the method's sensitivity, the detection resolution was as high as 1% and 0.5% in the background of 500 and 5000 copies/μl wild-type ALK gene, respectively. Regarding the method's specificity, no non-specific amplification was found when it was used to detect EML4-ALK fusion genes in leukocyte and plasma RNA samples from healthy volunteers. Among the 50 clinical samples, 47 ALK-FISH negative samples were also negative. Among 3 ALK-FISH positive samples, 2 cases were detected positive using this method, but another was not detected because of the failure of RNA extraction. Conclusion The proposed qRT-PCR assay for the detection of EML4-ALK fusion genes is rapid, simple, sensitive, and specific, which is deserved to be validated and widely used in clinical settings.

  2. ALK signaling and target therapy in anaplastic large cell lymphoma

    Directory of Open Access Journals (Sweden)

    Fabrizio eTabbo

    2012-05-01

    Full Text Available The discovery by Morris SW et al. in 1994 of the genes contributing to the t(2;5(p23;q35 translocation has put the foundation for a molecular based recognition of Anaplastic Large Cell Lymphoma (ALCL and pointed out the need for a further stratification of T-cell neoplasia. Likewise the detection of ALK genetic lesions among many human cancers has defined unique subsets of cancer patients, providing new opportunities for innovative therapeutic interventions. The objective of this review is to appraise the molecular mechanisms driving ALK-mediated transformation, and to maintain the neoplastic phenotype. The understanding of these events will allow the design and implementation of novel tailored strategies for a well-defined subset of cancer patients.

  3. Anaplastic lymphoma kinase gene alteration in gastric signet ring cell carcinoma%间变性淋巴瘤激酶融合基因在胃印戒细胞癌中的表达

    Institute of Scientific and Technical Information of China (English)

    赵瑞华; 姜文静; 张伟杰; 周亚楠; 宗红

    2016-01-01

    目的 观察间变性淋巴瘤激酶(ALK)融合基因在胃印戒细胞癌患者中的表达,探讨ALK融合基因与胃癌临床病理的关系.方法 搜集177例我院病理检查确诊的胃印戒细胞癌患者的组织标本,采用免疫组织化学染色(IHC)法观察ALK蛋白的表达.随后,针对ALK蛋白阳性的病理标本,采用荧光原位杂交技术(FISH)验证其ALK基因重排.结果 IHC显示177例胃印戒细胞癌中4例(2.3%)ALK蛋白表达阳性.4例ALK蛋白表达阳性的患者FISH检测均为阳性.结论 IHC及FISH为检测胃印戒细胞癌ALK表达的可靠方法,ALK阳性的胃印戒细胞癌患者的肿瘤浸润性可能更强,确诊时淋巴结阳性率高,人类表皮生长因子受体-2 (HER-2)多为阴性.%Objective To investigate the frequency of anaplastic lymphoma kinase (ALK) alterations in patients with gastric signet ring cell carcinoma (SRC) and the correlations between ALK alterations and the clinicopathological features.Methods The expression of ALK protein was determined in paraffin-embedded tissue specimens (FFPE) from 177 pathologically confirmed SRC patients by Ventana immunohistochemistry (IHC).The patients with positive ALK detected by IHC were assayed in ALK rearrangement by fluorescence in situ hybridization (FISH).Results We assessed 4 of 177 cases (2.3%) as positive by IHC.Three of the 4 patients had T4 tumors and positive nodal status,and rest one had metastasis.All of them were human epidermalgrowth factor receptor-2 (HER-2) negative.All of the 4 patients were positive for ALK rearrangement using the standard criteria of FISH.Conclusion Ventana IHC and FISH were both of the reliable approaches in SRC patients.Patients with positive ALK seemed to have deep infiltration and positive lymph nodes and negative HER-2.

  4. Prognostic significance of NPM-ALK fusion transcript overexpression in ALK-positive anaplastic large-cell lymphoma.

    Science.gov (United States)

    Li, Chunmei; Takino, Hisashi; Eimoto, Tadaaki; Ishida, Takashi; Inagaki, Atsushi; Ueda, Ryuzo; Suzuki, Ritsuro; Yoshino, Tadashi; Nakagawa, Atsuko; Nakamura, Shigeo; Inagaki, Hiroshi

    2007-06-01

    In anaplastic large-cell lymphomas positive for anaplastic lymphoma kinase (ALK) protein, the ALK gene is most commonly fused to the NPM gene, and less commonly to TPM3, TFG, ATIC, and other rare genes. Although this lymphoma is generally associated with a favorable clinical outcome, 25% of the patients die of the disease within 5 years. In this study, we developed three assays, all of which can be used with archival formalin-fixed, paraffin-embedded tissues: (1) a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay for various X-ALK fusion genes, (2) a 5' rapid amplification of cDNA ends (RACE) assay to identify unknown fusion partners, and (3) a real-time RT-PCR assay to quantify the amount of the NPM-ALK fusion transcript. In 26 cases of ALK(+) anaplastic large-cell lymphoma, the RT-PCR assay showed that the ALK was fused to NPM in 21 cases, to TPM3 in three, and to TFG in one. The 5' RACE assay detected ATIC-ALK fusion in the remaining case. The real-time quantitative RT-PCR assay showed that the NPM-ALK transcript was over expressed in four of 20 quantifiable cases. Patients with NPM-ALK overexpression showed a significantly unfavorable overall survival compared with those with a low expression of this transcript. The RT-PCR and 5' RACE assays developed here may be useful for identification of known and unknown gene partners fused to the ALK gene. Overexpression of the NPM-ALK fusion transcript may be associated with a poor prognosis of the patients with ALK(+) anaplastic large-cell lymphomas.

  5. Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin

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    Chen X

    2013-12-01

    Full Text Available Xueyan Chen, Lorinda A Soma, Jonathan R FrommDepartment of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USAAbstract: Despite the relative success of chemotherapy for Hodgkin lymphoma (HL and systemic anaplastic large cell lymphoma (ALCL, novel therapeutic agents are needed for refractory or relapsed patients. Targeted immunotherapy has emerged as a novel treatment option for these patients. Although unconjugated anti-cluster of differentiation (CD30 antibodies showed minimal antitumor activity in early clinical trials, development of antibody–drug conjugates (ADCs appears promising. Brentuximab vedotin is an ADC composed of an anti-CD30 antibody linked to a potent microtubule-disrupting agent monomethyl auristatin E (MMAE. It has the ability to target CD30-positive tumor cells and, once bound to CD30, brentuximab vedotin is internalized and MMAE is released to induce cell cycle arrest and apoptosis. In two phase II trials, objective response was reported in 75% and 86% of patients with refractory or relapsed HL and systemic ALCL, respectively, with an acceptable toxicity profile. Based on these studies, the US Food and Drug Administration (FDA granted accelerated approval of brentuximab vedotin in August 2011 for the treatment of refractory and relapsed HL and ALCL. We review the key characteristics of brentuximab vedotin, clinical data supporting its therapeutic efficacy, and current ongoing trials to explore its utility in other CD30-positive malignancies.Keywords: classical Hodgkin lymphoma, systemic anaplastic large cell lymphoma, CD30, brentuximab vedotin, SGN-35

  6. Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas.

    Science.gov (United States)

    Thornber, K; Colomba, A; Ceccato, L; Delsol, G; Payrastre, B; Gaits-Iacovoni, F

    2009-07-23

    The chimera nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the tyrosine kinase activity of which is constitutively upregulated, is the causative agent of 75% of the anaplastic large-cell lymphomas (ALCLs). We have demonstrated that NPM-ALK induces the production of reactive oxygen species (ROS) by a pathway involving the arachidonic acid-metabolizing enzymes of the lipoxygenase (LOX) family. The use of the LOX inhibitor nordihydroguaiaretic acid (NDGA) and of the anti-oxidant N-acetylcysteine (NAC) demonstrated that ROS are important in maintaining the ALK kinase active. Consistent with this, NDGA treatment resulted in the inhibition of key pathways, such as Akt, signal transducer and activator of transcription factor 3 (STAT3) and extracellular signal-regulated kinase (ERK), which are involved in NPM-ALK antiapoptotic and pro-mitogenic functions. Conversely, the stress-activated kinase p38, described in some instances as a mediator of apoptosis, was activated. Interestingly, 5-LOX, an isoform involved in many cancers, was found to be activated in NPM-ALK(+) cells. Functional studies have shown that transforming properties, namely proliferation and resistance to apoptosis, were abrogated by treatment with either NDGA or the 5-LOX inhibitor (N-(3-phenoxycinnamyl)-acetohydroxamic acid) (BW A4C). Together, these data point to the ROS/LOX pathway as a potential new target for therapy in NPM-ALK-positive tumors.

  7. Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy

    Science.gov (United States)

    Buetti-Dinh, Antoine; O’Hare, Thomas

    2016-01-01

    A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance. PMID:27669408

  8. Analysis of human T-cell lymphotropic virus in CD25+ anaplastic large cell lymphoma in children.

    Science.gov (United States)

    Gualco, Gabriela; Chioato, Lucimara; Weiss, Lawrence M; Harrington, William J; Bacchi, Carlos E

    2009-07-01

    Anaplastic large cell lymphoma (ALCL) is recognized as 2 distinct diseases: anaplastic lymphoma kinase (ALK)+ ALCL and ALK- ALCL. ALK+ ALCL occurs in younger patients and has a better prognosis. Human T-cell lymphotropic virus (HTLV-1) is linked to the development of adult T-cell leukemia/lymphoma (ATLL), which frequently expresses CD25. CD25 is significantly expressed in childhood ALCL. In Brazil, HTLV-1 infection is endemic, and vertical transmission is responsible for spread to children. Of HTLV-1 carriers, 90% or more remain asymptomatic. Some cases of adult HTLV-1-related lymphomas have characteristics of ALCL but are considered CD30+ ATLL subtypes. No similar cases have been described in children. We analyzed 33 cases of pediatric ALCL, CD25+ and CD25-, for proviral HTLV-1 DNA. All cases corresponded to the common histologic ALCL type and were CD30+ in virtually all neoplastic cells. ALK expression was observed in 31 (94%) of 33 cases; CD25 was positive in 27 (82%), including 1 ALK- ALCL case. There was a strong positive correlation between ALK and CD25 expression. None of the cases showed proviral HTLV-1 DNA. ALCL in children has no relationship with HTLV-1; the frequent CD25 expression must be explained by a mechanism different from that in ATLL.

  9. A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.

    Science.gov (United States)

    Abate, F; Todaro, M; van der Krogt, J-A; Boi, M; Landra, I; Machiorlatti, R; Tabbò, F; Messana, K; Abele, C; Barreca, A; Novero, D; Gaudiano, M; Aliberti, S; Di Giacomo, F; Tousseyn, T; Lasorsa, E; Crescenzo, R; Bessone, L; Ficarra, E; Acquaviva, A; Rinaldi, A; Ponzoni, M; Longo, D L; Aime, S; Cheng, M; Ruggeri, B; Piccaluga, P P; Pileri, S; Tiacci, E; Falini, B; Pera-Gresely, B; Cerchietti, L; Iqbal, J; Chan, W C; Shultz, L D; Kwee, I; Piva, R; Wlodarska, I; Rabadan, R; Bertoni, F; Inghirami, G

    2015-06-01

    Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.

  10. Advances in understanding the pathogenesis of systemic anaplastic large cell lymphomas.

    Science.gov (United States)

    Boi, Michela; Zucca, Emanuele; Inghirami, Giorgio; Bertoni, Francesco

    2015-03-01

    The currently used 2008 World Health Organization classification recognizes two types of systemic anaplastic large T cell lymphoma according to ALK protein expression in tumour cells. First, the 'anaplastic large cell lymphoma, ALK positive' (ALK(+) ALCL) that is characterized by the presence of ALK gene rearrangements and consequent ALK protein expression, and, second, the 'anaplastic large cell lymphoma, ALK negative' (ALK(-) ALCL) that is a provisional entity lacking ALK protein expression but cannot be distinguished morphologically from ALK(+) ALCL. In this review we summarize the current knowledge on the genetic lesions and biological features that underlie the pathogenesis of ALK(+) and the ALK(-) ALCL and that can lead to the use of targeted anti-cancer agents.

  11. The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration.

    Science.gov (United States)

    Voena, Claudia; Conte, Chiara; Ambrogio, Chiara; Boeri Erba, Elisabetta; Boccalatte, Francesco; Mohammed, Shabaz; Jensen, Ole N; Palestro, Giorgio; Inghirami, Giorgio; Chiarle, Roberto

    2007-05-01

    Anaplastic large cell lymphomas (ALCL) are mainly characterized by the reciprocal translocation t(2;5)(p23;q35) that involves the anaplastic lymphoma kinase (ALK) gene and generates the fusion protein NPM-ALK with intrinsic tyrosine kinase activity. NPM-ALK triggers several signaling cascades, leading to increased cell growth, resistance to apoptosis, and changes in morphology and migration of transformed cells. To search for new NPM-ALK interacting molecules, we developed a mass spectrometry-based proteomic approach in HEK293 cells expressing an inducible NPM-ALK and identified the tyrosine phosphatase Shp2 as a candidate substrate. We found that NPM-ALK was able to bind Shp2 in coprecipitation experiments and to induce its phosphorylation in the tyrosine residues Y542 and Y580 both in HEK293 cells and ALCL cell lines. In primary lymphomas, antibodies against the phosphorylated tyrosine Y542 of Shp2 mainly stained ALK-positive cells. In ALCL cell lines, Shp2-constitutive phosphorylation was dependent on NPM-ALK, as it significantly decreased after short hairpin RNA (shRNA)-mediated NPM-ALK knock down. In addition, only the constitutively active NPM-ALK, but not the kinase dead NPM-ALK(K210R), formed a complex with Shp2, Gab2, and growth factor receptor binding protein 2 (Grb2), where Grb2 bound to the phosphorylated Shp2 through its SH2 domain. Shp2 knock down by specific shRNA decreased the phosphorylation of extracellular signal-regulated kinase 1/2 and of the tyrosine residue Y416 in the activation loop of Src, resulting in impaired ALCL cell proliferation and growth disadvantage. Finally, migration of ALCL cells was reduced by Shp2 shRNA. These findings show a direct involvement of Shp2 in NPM-ALK lymphomagenesis, highlighting its critical role in lymphoma cell proliferation and migration.

  12. Clinical and laboratory characteristics of systemic anaplastic large cell lymphoma in Chinese patients

    Directory of Open Access Journals (Sweden)

    Wang Yan-Fang

    2012-07-01

    Full Text Available Abstract Background Systemic anaplastic large cell lymphoma (S-ALCL is a rare disease with a highly variable prognosis and no standard chemotherapy regimen. Anaplastic lymphoma kinase (ALK has been reported as an important prognostic factor correlated with S-ALCL in many but not all studies. In our study, we retrospectively analyzed 92 patients with S-ALCL from the Peking University Lymphoma Center for clinical and molecular prognostic factors to make clear the role of ALK and other prognostic factors in Han Chinese S-ALCL. Results The majority of Chinese S-ALCL patients were young male patients (median age 26, male/female ratio 1.7 and the median age was younger than previous reports regardless of ALK expression status. The only statistically significant different clinical characteristic in S-ALCL between ALK positive (ALK+ and ALK negative (ALK- was age, with a younger median age of 22 for ALK+ compared with 30 for ALK-. However, when pediatric patients (≤18 were excluded, there was no age difference between ALK+ and ALK-. The groups did not differ in the proportion of males, those with clinical stage III/IV (49 vs 51% or those with extranodal disease (53 vs 59%. Of 73 evaluable patients, the 3-year and 5-year survival rates were 60% and 47%, respectively. Univariate analysis showed that three factors: advanced stage III/IV, lack of expression of ALK, and high Ki-67 expression, were associated with treatment failure in patients with S-ALCL. However, ALK expression correlated with improved survival only in patients younger than 14 years, while not in adult patients. In multivariate analysis, only clinical stage was an independent prognostic factor for survival. Expressions of Wilms tumor 1 (WT1 and B-cell lymphoma 2 protein (BCL-2 correlated with the expression of ALK, but they did not have prognostic significance. High Ki-67 expression was also a poor prognostic factor. Conclusions Our results show that ALK expression alone is not

  13. Analysis of gene expression profile of TPM3-ALK positive anaplastic large cell lymphoma reveals overlapping and unique patterns with that of NPM-ALK positive anaplastic large cell lymphoma.

    Science.gov (United States)

    Bohling, Sandra D; Jenson, Stephen D; Crockett, David K; Schumacher, Jonathan A; Elenitoba-Johnson, Kojo S J; Lim, Megan S

    2008-03-01

    Anaplastic large cell lymphoma (ALCL) comprises a group of non-Hodgkin lymphomas characterized by the expression of the CD30/Ki-1 antigen. A subset of ALCL is characterized by chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2. While the most common translocation is the t(2;5)(p23;q35) involving the nucleophosmin (NPM) gene on chromosome 5, up to 12 other translocations partners of the ALK gene have been identified. One of these is the t(1;2)(q25;p23) which results in the formation of the chimeric protein TPM3-ALK. While several of the signaling pathways induced by NPM-ALK have been elucidated, those involved in ALCLs harboring TPM3-ALK are largely unknown. In order to investigate the expression profiles of ALCLs carrying the NPM-ALK and TPM3-ALK fusions, we carried out cDNA microarray analysis of two ALCL tissue samples, one expressing the NPM-ALK fusion protein and the other the TPM3-ALK fusion protein. RNA was extracted from snap-frozen tissues, labeled with fluorescent dyes and analyzed using cDNAs microarray containing approximately 9,200 genes and expressed sequence tags (ESTs). Quantitative fluorescence RT-PCR was performed to validate the cDNA microarray data on nine selected gene targets. Our results show a significant overlap of genes deregulated in the NPM-ALK and TPM-ALK positive lymphomas. These deregulated genes are involved in diverse cellular functions, such as cell cycle regulation, apoptosis, proliferation, and adhesion. Interestingly, a subset of the genes was distinct in their expression pattern in the two types of lymphomas. More importantly, many genes that were not previously associated with ALK positive lymphomas were identified. Our results demonstrate the overlapping and unique transcriptional patterns associated with the NPM-ALK and TPM3-ALK fusions in ALCL.

  14. CD13-positive anaplastic large cell lymphoma of T-cell origin--a diagnostic and histogenetic problem.

    Science.gov (United States)

    Popnikolov, N K; Payne, D A; Hudnall, S D; Hawkins, H K; Kumar, M; Norris, B A; Elghetany, M T

    2000-12-01

    The expression of myelomonocytic-associated antigens in anaplastic large cell lymphomas (ALCLs), particularly those presenting in extranodal sites, can make their distinction from extramedullary myeloid cell tumors (EMCTs) or histiocytic tumors problematic. Yet, this distinction is clinically significant because of its therapeutic and prognostic implications. Herein, we describe a case of extranodal anaplastic lymphoma kinase-positive CD30-positive ALCL of T-cell origin in a 12-year-old boy, which was initially called an EMCT because of the expression of CD13 and HLA-DR detected by flow cytometry and the absence of other T-cell-related surface markers. However, the detection of cytoplasmic CD3 by flow cytometry prompted further studies. The tumor was composed of large cells with abundant slightly eosinophilic vacuolated cytoplasm and ovoid or reniform nuclei with a few small nucleoli. Using immunohistochemistry, the tumor was positive for CD45, CD30, CD45RO, and CD43 with a strong cytoplasmic and nuclear anaplastic lymphoma kinase stain. The tumor cells showed a T-cell clonal genotype. Electron microscopy revealed no ultrastructural features of myelomonocytic or histiocytic origin. The patient responded well to the chemotherapy and was in complete remission for 10 months at the time of submission of this manuscript. Review of the literature showed inconsistencies regarding the diagnosis, nomenclature, and, therefore, treatment and prognosis of these tumors. In addition, the CD13 expression in ALCL raises some histogenetic questions and may indicate origin from a pluripotent stem cell, misprogramming during malignant transformation, or a microenvironmental effect on lymphoid cell expression of surface antigens. Therefore, ALCL should be considered in the differential diagnosis of EMCTs or histiocytic tumors, particularly when surface marker lineage assignment is ambiguous.

  15. Brain metastasis of ALK positive anaplastic large cell lymphoma after a long-term disease free survival in an old adult

    Science.gov (United States)

    Wang, Cai-Xia; Wang, Hai; Li, Jie; Ma, Heng-Hui; Yu, Bo; Shi, Shan-Shan; Zhou, Xiao-Jun; Shi, Qun-Li

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma composed of CD30-positive cells and now recognized as three different entities: primary cutaneous ALCL, primary systemic anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL and primary ALK-negative (ALK-) ALCL. ALK+ ALCL is supposed to have a better prognosis than ALK- ALCL. It is rarely metastasized to other sites, especially to the central nervous system (CNS). Herein, we present a rare case of systemic ALK+ ALCL which metastasized to the brain after a long-term disease free survival in an adult. Neuroimaging revealed a well-enhanced mass in the left frontal lobe. And it was completely resected. The results of the pathological and immunohistochemical studies were consistent with the metastasized ALK+ ALCL. The clinical findings, pathologic characteristics and treatment are described. PMID:24696735

  16. Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma.

    Science.gov (United States)

    McDonnell, Scott R P; Hwang, Steven R; Rolland, Delphine; Murga-Zamalloa, Carlos; Basrur, Venkatesha; Conlon, Kevin P; Fermin, Damian; Wolfe, Thomas; Raskind, Alexander; Ruan, Chunhai; Jiang, Jian-Kang; Thomas, Craig J; Hogaboam, Cory M; Burant, Charles F; Elenitoba-Johnson, Kojo S J; Lim, Megan S

    2013-08-01

    The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis.

  17. Silibinin suppresses NPM-ALK, potently induces apoptosis and enhances chemosensitivity in ALK-positive anaplastic large cell lymphoma.

    Science.gov (United States)

    Molavi, Ommoleila; Samadi, Nasser; Wu, Chengsheng; Lavasanifar, Afsaneh; Lai, Raymond

    2016-05-01

    Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), an oncogenic fusion protein carrying constitutively active tyrosine kinase, is known to be central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK+ALCL). Here, it is reported that silibinin, a non-toxic naturally-occurring compound, potently suppressed NPM-ALK and effectively inhibited the growth and soft agar colony formation of ALK+ALCL cells. By western blots, it was found that silibinin efficiently suppressed the phosphorylation/activation of NPM-ALK and its key substrates/downstream mediators (including STAT3, MEK/ERK and Akt) in a time- and dose-dependent manner. Correlating with these observations, silibinin suppressed the expression of Bcl-2, survivin and JunB, all of which are found to be upregulated by NPM-ALK and pathogenetically important in ALK+ALCL. Lastly, silibinin augmented the chemosensitivity of ALK+ALCL cells to doxorubicin, particularly the small cell sub-set expressing the transcriptional activity of Sox2, an embryonic stem cell marker. To conclude, the findings suggest that silibinin might be useful in treating ALK+ALCL.

  18. Anaplastic lymphoma kinase-positive adenocarcinoma of lung:a cytopathologic analysis%间变性淋巴瘤激酶阳性肺腺癌细胞病理学特点初探

    Institute of Scientific and Technical Information of China (English)

    陈颖; 杨文韬; 宋以菊; 曾欢; 张静; 柏乾明; 周晓燕; 平波; 高丽丽; 王彦丽; 桂贤; 张皓; 王龙富; 顾良宏; 冯丽青; 吴佳文

    2015-01-01

    Objective To study the cytomorphologic features of anaplastic lymphoma kinase ( ALK )-rearranged pulmonary adenocarcinoma.Methods The morphologic features in 153 pulmonary adenocarcinoma cytology specimens encountered during the period from September, 2011 to April, 2015 in Shanghai Cancer Hospital were retrospectively reviewed.Fluorescence in-situ hybridization ( FISH) and/or immunohistochemistry ( Ventana D5F3) for ALK gene rearrangement were carried out.The samples studied included 34 pleural effusion specimens, 40 endobronchial ultrasound-guided transbronchial needle aspirates ( EBUS-TBNA) and 79 fine needle aspirates of palpable masses on body surface.Results Thirty-nine cases (25.5%) of ALK-rearranged samples were identified by FISH and/or immunohistochemistry, including 3 cases diagnosed by FISH and 36 cases by both technologies.The median age of the ALK-positive group was 50 years, significantly younger than that of the ALK-negative group (60 years old,P=0.002) .Only 4 of the ALK-positive patients were smokers, which was significantly less than that of the ALK-negative group (P<0.01).In ALK-positive group, 3 cases showed cribriform pattern with prominent nucleoli, 3 cases showed cribriform pattern with mucin-rich cells and 8 cases showed extracellular mucus with mucin-rich cells.The above cytomorphologic patterns were significantly less common in ALK-negative tumors ( P <0.01 ) . Conclusions ALK-rearranged lung adenocarcinoma is associated with certain distinctive morphologic patterns, including cribriform architecture, presence of prominent nucleoli, mucin-rich cells and extracellular mucus, which can be observed in cytology specimens ( including conventional smears and cell block sections) .These findings, when combined with clinical features, may give clues to detection of ALK-positive cases.%目的探讨间变性淋巴瘤激酶( ALK)基因重排阳性肺腺癌的细胞病理学特点。方法回顾性分析2011年9月至2015年4月在复旦大学

  19. Clinicopathological features of lung adenocarcinoma harboring anaplastic lymphoma kinase rearrangements%间变性淋巴瘤激酶融合基因阳性肺腺癌的临床病理特征

    Institute of Scientific and Technical Information of China (English)

    董宇杰; 周立娟; 王敬慧; 蔡毅然; 穆晶; 张海青

    2015-01-01

    Objective To analyze the clinicopathological characteristics of patients with anaplastic lymphoma kinase( ALK) rearrangements in lung adenocarcinoma, and the clinical therapy and prognosis of the patients. Methods Clinicopathological data of 34 cases of ALK⁃positive patients treated in the Beijing Chest Hospital from 2005 to 2014 were reviewed. The expression of ALK proteins in the resected tumors was detected by immunohistochemistry, and EGFR mutations were examined by polymerase chain reaction and a direct DNA sequencing method. Results Among the 34 patients, 20 were male and 14 were female, the median age was 49, and 11 were smokers and 23 were never smokers. The clinical stages of the patients were stage ⅠA in 5 patients,ⅠB in one patient,ⅡA in two patients,ⅢA in 16 patients,ⅢB in 5 patients,Ⅳin 4 patients, and one patient of unknown stage. ALK⁃positive tumors showed strong granular staining in cell cytoplasm by immunohistochemistry. Forteen patients were solid predominant subtype with mucin production, 10 of acinar predominant subtype, 6 of papillary predominant subtype, 3 of micropapillary predominant subtype, and one was of colloid variant. There were 18 cases with mucin production, 6 cases had signet⁃ring cell morphology, and 10 cases showed cribriform pattern. Only one patient had coexistence of ALK rearrangement and EGFR mutation ( L858R at exon 21) . Of the 34 patients, 24 patients were followed up. The median follow up of the 24 patients was 11.0 months (1.7⁃48.7 months). Conclusions ALK⁃positive tumors as a molecular subtype of lung adenocarcinoma have distinct clinicopathological features. The histological findings of ALK⁃positive tumors are characterized by solid predominant subtype with mucin production, acinar predominant subtype, signet⁃ring cells and cribriform structures. They were rarely co⁃mutated with EGFR mutation.%目的:探讨间变性淋巴瘤激酶( ALK)融合基因阳性肺腺癌的临床病理特征

  20. Systemic Capillary Leak Syndrome as an Initial Presentation of ALK-Negative Anaplastic Large Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Laura S. Lourdes

    2012-01-01

    Full Text Available Systemic capillary leak syndrome (SCLS is a rare disease characterized by third spacing of plasma into the extravascular compartment, leading to anasarca, hemoconcentration, and hypovolemic shock. It has been rarely associated with lymphomas, and reports usually indicate that it occurs after antineoplastic treatment. We present the case of a patient with ALK-negative anaplastic large cell lymphoma who presented with SCLS as the initial manifestation of her lymphoma. The SCLS resolved with treatment of the malignancy with steroids and chemotherapy.

  1. Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)

    Energy Technology Data Exchange (ETDEWEB)

    Cui, J Jean; Tran-Dube,; #769; Michelle,; Shen, Hong; Nambu, Mitchell; Kung, Pei-Pei; Pairish, Mason; Jia, Lei; Meng, Jerry; Funk, Lee; Botrous, Iriny; McTigue, Michele; Grodsky, Neil; Ryan, Kevin; Padrique, Ellen; Alton, Gordon; Timofeevski, Sergei; Yamazaki, Shinji; Li, Qiuhua; Zou, Helen; Christensen, James; Mroczkowski, Barbara; Bender, Steve; Kania, Robert S; Edwards, Martin P [Pfizer

    2011-08-03

    Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.

  2. NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma.

    Science.gov (United States)

    Galietta, Annamaria; Gunby, Rosalind H; Redaelli, Sara; Stano, Paola; Carniti, Cristiana; Bachi, Angela; Tucker, Philip W; Tartari, Carmen J; Huang, Ching-Jung; Colombo, Emanuela; Pulford, Karen; Puttini, Miriam; Piazza, Rocco G; Ruchatz, Holger; Villa, Antonello; Donella-Deana, Arianna; Marin, Oriano; Perrotti, Danilo; Gambacorti-Passerini, Carlo

    2007-10-01

    The oncogenic fusion tyrosine kinase nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) induces cellular transformation in anaplastic large-cell lymphomas (ALCLs) carrying the t(2;5) chromosomal translocation. Protein-protein interactions involving NPM/ALK are important for the activation of downstream signaling pathways. This study was aimed at identifying novel NPM/ALK-binding proteins that might contribute to its oncogenic transformation. Using a proteomic approach, several RNA/DNA-binding proteins were found to coimmunoprecipitate with NPM/ALK, including the multifunctional polypyrimidine tract binding proteinassociated splicing factor (PSF). The interaction between NPM/ALK and PSF was dependent on an active ALK kinase domain and PSF was found to be tyrosine-phosphorylated in NPM/ALK-expressing cell lines and in primary ALK(+) ALCL samples. Furthermore, PSF was shown to be a direct substrate of purified ALK kinase domain in vitro, and PSF Tyr293 was identified as the site of phosphorylation. Y293F PSF was not phosphorylated by NPM/ALK and was not delocalized in NPM/ALK(+) cells. The expression of ALK fusion proteins induced delocalization of PSF from the nucleus to the cytoplasm and forced overexpression of PSF-inhibited proliferation and induced apoptosis in cells expressing NPM/ALK. PSF phosphorylation also increased its binding to RNA and decreased the PSF-mediated suppression of GAGE6 expression. These results identify PSF as a novel NPM/ALK-binding protein and substrate, and suggest that PSF function may be perturbed in NPM/ALK-transformed cells.

  3. Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report and Literature Review.

    Science.gov (United States)

    Letter, Haley; Rop, Baiywo; Edison, Michele N; Turner, Patricia

    2016-03-26

    Introduction Anaplastic large cell lymphoma is a very rare T-cell lymphoma that has only recently been found to be associated with breast implants. It has been described in the literature mainly in the form of case reports. This article focuses on the imaging characteristics of this rare disease. We hope to increase awareness of breast imagers and referring physicians to improve early detection rates. Case Report We present the case of a 32-year-old female who presented with several weeks of pain and firmness in her right breast. MRI and ultrasound demonstrated a peri-implant fluid collection. Ultrasound-guided aspiration revealed anaplastic large cell lymphoma. The patient was treated with implant removal alone and has now been in remission for 3 years.  Conclusion Anaplastic large cell lymphoma of the breast is a very rare entity that has mainly been described in the literature as case reports. As in the case of our patient, imaging findings can be very non-specific, and it is important for surgeons, breast imagers, and oncologists to be aware of this rare disease to ensure prompt diagnosis.

  4. NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma.

    Science.gov (United States)

    Pearson, Joel D; Lee, Jason K H; Bacani, Julinor T C; Lai, Raymond; Ingham, Robert J

    2011-01-30

    Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive non-Hodgkin lymphoma of T/null immunophenotype that is most prevalent in children and young adults. The normal cellular counterpart of this malignancy is presumed to be the cytotoxic T lymphocyte (CTL), and this presumption is partly based on the observation that these tumour cells often express cytotoxic granules containing Granzyme B (GzB) and Perforin. Chromosomal translocations involving the gene encoding for the ALK tyrosine kinase are also characteristic of ALK+ ALCL, and the resulting fusion proteins (e.g. NPM-ALK) initiate signalling events important in ALK+ ALCL pathogenesis. These events include the elevated expression of JunB; an AP-1 family transcription factor that promotes ALK+ ALCL proliferation. In this report we demonstrate that JunB is a direct transcriptional activator of GzB and that GzB transcription is also promoted by NPM-ALK. We found that Perforin expression was not regulated by JunB, but was promoted by NPM-ALK in some cell lines and inhibited by it in others. In conclusion, our study makes the novel observation that signalling through NPM-ALK and JunB affect the expression of cytotoxic molecules in ALK+ ALCL. Moreover, these findings demonstrate the expression of GzB and Perforin in this lymphoma is not solely due its presumed CTL origin, but that oncogenic signalling is actively influencing the expression of these proteins.

  5. Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK(+) anaplastic large cell lymphoma.

    Science.gov (United States)

    Hamedani, Farid Saei; Cinar, Munevver; Mo, Zhicheng; Cervania, Melissa A; Amin, Hesham M; Alkan, Serhan

    2014-04-01

    Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product with tyrosine kinase activity and is expressed in substantial subset of anaplastic large cell lymphomas (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3). Although NPM-ALK(+) ALCL overall shows a better prognosis, there is a sub-group of patients who relapses and is resistant to conventional chemotherapeutic regimens. NPM-ALK is a potential target for small molecule kinase inhibitors. Crizotinib (PF-2341066) is a small, orally bioavailable molecule that inhibits growth of tumors with ALK activity as shown in a subgroup of non-small lung cancer patients with EML4-ALK expression. In this study, we have investigated the in vitro effects of Crizotinib in ALCL cell line with NPM-ALK fusion. Crizotinib induced marked downregulation of STAT3 phosphorylation, which was associated with significant apoptotic cell death. Apoptosis induction was attributed to caspase-3 cleavage and marked downregulation of the Bcl-2 family of proteins including MCL-1. These findings implicate that Crizotinib has excellent potential to treat patients with NPM-ALK(+) ALCL through induction of apoptotic cell death and downregulation of major oncogenic proteins in this aggressive lymphoma.

  6. Primary central nervous system anaplastic large-cell lymphoma mimicking lymphomatosis cerebri.

    Science.gov (United States)

    Sugino, Toshiya; Mikami, Takeshi; Akiyama, Yukinori; Wanibuchi, Masahiko; Hasegawa, Tadashi; Mikuni, Nobuhiro

    2013-01-01

    Primary central nervous system lymphoma (PCNSL) is usually diffuse large B-cell lymphoma. Anaplastic large-cell lymphoma (ALCL) rarely occurs in the central nervous system. PCNSL always presents as single or multiple nodular contrast-enhancing mass lesions within T2-hyperintense areas on magnetic resonance imaging (MRI). Infrequently, diffuse infiltrating change with little contrast enhancement called lymphomatosis cerebri can be seen in PCNSL. In this report, we describe a 75-year-old immunocompetent man who had progressive dementia. On MRI, diffuse white matter lesions with little contrast enhancement were observed to gradually progress, which was clinically consistent with his worsening condition. A biopsy specimen revealed non-destructive, diffusely infiltrating, anaplastic large CD30-positive lymphoma, indicating a diagnosis of ALCL. After the biopsy, he was treated by whole brain irradiation (total 46 Gy) and focal boost irradiation (total 14 Gy). However, his performance status worsened and there was no symptom improvement. The patient died 8 months after symptom onset. The clinical course, diagnostic workup, pathologic correlates, and treatment outcomes are described herein.

  7. Cardiac Tamponade Associated with the Presentation of Anaplastic Large Cell Lymphoma in a 2-Year-Old Child

    Directory of Open Access Journals (Sweden)

    Gema Mira-Perceval Juan

    2015-01-01

    Full Text Available The anaplastic large cell lymphoma is a rare entity in pediatric patients. We present an unusual case of pericardial involvement, quite uncommon as extranodal presentation of this type of disorder, that provoked a life-risk situation requiring an urgent pericardiocentesis. To our knowledge, this is the first report on a child with pericardial involvement without an associated cardiac mass secondary to anaplastic large cell lymphoma in pediatric age. We report the case of a 21-month-old Caucasian male infant with cardiac tamponade associated with the presentation of anaplastic large cell lymphoma. Initially, the child presented with 24-day prolonged fever syndrome, cutaneous lesions associated with hepatomegaly, inguinal adenopathies, and pneumonia. After a 21-day asymptomatic period, polypnea and tachycardia were detected in a clinical check-up. Chest X-ray revealed a remarkable increase of the cardiothoracic index. The anaplastic large cell lymphoma has a high incidence of extranodal involvement but myocardial or pericardial involvements are rare. For this reason, we recommend a close monitoring of patients with a differential diagnosis of anaplastic large cell lymphoma.

  8. Isolated cutaneous involvement in a child with nodal anaplastic large cell lymphoma

    Directory of Open Access Journals (Sweden)

    Vibhu Mendiratta

    2016-01-01

    Full Text Available Non-Hodgkin lymphoma is a common childhood T-cell and B-cell neoplasm that originates primarily from lymphoid tissue. Cutaneous involvement can be in the form of a primary extranodal lymphoma, or secondary to metastasis from a non-cutaneous location. The latter is uncommon, and isolated cutaneous involvement is rarely reported. We report a case of isolated secondary cutaneous involvement from nodal anaplastic large cell lymphoma (CD30 + and ALK + in a 7-year-old boy who was on chemotherapy. This case is reported for its unusual clinical presentation as an acute febrile, generalized papulonodular eruption that mimicked deep fungal infection, with the absence of other foci of systemic metastasis.

  9. Downregulation of NPM-ALK by siRNA causes anaplastic large cell lymphoma cell growth inhibition and augments the anti cancer effects of chemotherapy in vitro.

    Science.gov (United States)

    Hsu, Faye Yuan-yi; Zhao, Yi; Anderson, W French; Johnston, Patrick B

    2007-06-01

    The fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), results from the chromosome translocation t(2;5)(p23;q25) and is present in 50-70 percent of anaplastic large-cell lymphomas (ALCLs). NPM-ALK is a constitutively activated kinase that transforms cells through stimulating several mitogenic signaling pathways. To examine if the NPM-ALK is a potential therapeutic target in ALCL, we used siRNA to specifically downregulate the expression of the NPM-ALK in ALCL cell lines. In this report, we demonstrated viability loss in t(2;5)-positive ALCL cell lines, SUDHL-1 and Karpas 299 cells, but not in lymphoma cell lines without the chromosome translocation, Jurkat and Granta 519 cells. Further study demonstrated that the downregulation of NPM-ALK resulted in decreased cell proliferation and increased cell apoptosis. When used in combination with chemotherapeutic agents, such as doxorubicin, the inhibition of the NPM-ALK augments the chemosensitivity of the tumor cells. These results revealed the importance of continuous expression of NPM-ALK in maintaining the growth of ALCL cells. Our data also suggested that the repression of the fusion gene might be a potential novel therapeutic strategy for NPM-ALK positive ALCLs.

  10. Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas.

    Science.gov (United States)

    Colomba, A; Courilleau, D; Ramel, D; Billadeau, D D; Espinos, E; Delsol, G; Payrastre, B; Gaits-Iacovoni, F

    2008-04-24

    The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60(c-src), Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

  11. Primary pancreatic anaplastic large cell lymphoma, ALK negative:A case report

    Institute of Scientific and Technical Information of China (English)

    Christos G Savopoulos; NE Tsesmeli; GD Kaiafa; AT Zantidis; MT Bobos; AI Hatzitolios; ST Papavramidis; IS Kostopoulos

    2005-01-01

    We present the fourth case of a primary pancreatic anaplastic large cell lymphoma (ALCL), ALK-. An 80-year-old man was admitted to our clinic for further investigation of a fever of unknown origin. He noted anorexia, weight loss and fatigue. His laboratory tests showed anemia and a great elevation of ESR, LDH, and β2 microglobulin. In CT and MRI scan, a soft tissue mass in the pancreas was observed. A repeated endoscopy after his admission revealed an ulcerated mass-like deformity of the duodenal bulb. Explorative laparotomy confirmed a diffuse spread of an unresectable malignant pancreatic mass extending to the adjacent organs. Duodenal and surgical biopsies identified an ALCL of T-cell lineage, ALK-. The patient died in the Intensive Care Unit due to hemodynamic instability.Our case is the first one indicating that primary pancreatic lymphoma should be suspected in a patient with pancreatic mass and elevated serum LDH and β2 microglobulin.

  12. Acute spontaneous tumor lysis in anaplastic large T-cell lymphoma presenting with hyperuricemic acute renal failure.

    Science.gov (United States)

    Hsu, Hsiang-Hao; Huang, Chiu-Ching

    2004-01-01

    Acute spontaneous tumor lysis (ASTL) syndrome, an extremely rare disease, requires prompt recognition and aggressive management because it is fulminant at its outset, associated with severe metabolic derangement, and potentially reversible. We describe an unusual case in which spontaneous tumor lysis occurred in anaplastic large T-cell lymphoma associated with acute uric acid nephropathy, persistent oliguria, and shock. This case contrasts markedly with previously reported cases of ASTL syndrome, which developed mainly in the pathologic type of Burkitt lymphoma. To our knowledge, this is the first reported occurrence of ASTL syndrome associated with anaplastic large T-cell type lymphoma. This report also chronicles our successful experience with continuous renal replacement therapy in the presence of compromised hemodynamic status.

  13. Implant-associated anaplastic large cell lymphoma of the breast: Insight into a poorly understood disease.

    Science.gov (United States)

    Weathers, William M; Wolfswinkel, Erik M; Hatef, Daniel A; Lee, Edward I; Hollier, Larry H; Brown, Rodger H

    2013-01-01

    Implant-associated anaplastic large cell lymphoma (ALCL) is the subject of much debate in the field of plastic surgery. Only a few published cases have been reported and the rarity of the disease may make proving causality exceedingly difficult. Despite this, it is of utmost importance that full attention be devoted to this subject to ensure the safety and well-being of patients. The authors report one new case of implant-associated ALCL that recently presented to their institution. Implant-associated ALCL is a poorly understood disease. It should likely be considered its own clinical entity and categorized into two subtypes: one presenting as a seroma and the other as a distinct mass or masses. When reported, only textured implants have been associated with ALCL. The United States Food and Drug Administration and American Society of Plastic Surgeons have initiated a registry and have collected critical data to gain further understanding of this disease.

  14. Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma.

    Science.gov (United States)

    Damm-Welk, Christine; Mussolin, Lara; Zimmermann, Martin; Pillon, Marta; Klapper, Wolfram; Oschlies, Ilske; d'Amore, Emanuele S G; Reiter, Alfred; Woessmann, Wilhelm; Rosolen, Angelo

    2014-01-16

    Detection of minimal disseminated disease (MDD) at diagnosis correlates with relapse risk in children with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL). We investigated whether minimal residual disease (MRD) positivity by qualitative reverse-transcriptase polymerase chain reaction (RT-PCR) for Nucleophosmin (NPM)-ALK during treatment identifies patients at the highest relapse risk. Blood and/or bone marrow of 180 patients with NPM-ALK-positive ALCL treated with Berlin-Frankfurt-Münster-type protocols were screened for NPM-ALK transcripts at diagnosis; 103 were found to be MDD-positive. MRD before the second therapy course could be evaluated in 52 MDD-positive patients. MRD positivity correlated with uncommon histology. The cumulative incidence of relapses (CIR) of 26 MDD-positive/MRD-positive patients (81% ± 8%) was significantly higher than the CIR of 26 MDD-positive/MRD-negative (31% ± 9%) and 77 MDD-negative patients (15% ± 5%) (P NPM-ALK-positive ALCL identifies patients with a very high relapse risk and inferior survival.

  15. Brentuximab vedotin in children and adolescents with Hodgkin’s lymphoma and anaplastic large cell lymphoma – literature review and own experience

    Directory of Open Access Journals (Sweden)

    N. V. Myakova

    2016-01-01

    Full Text Available Despite significant advances in the treatment of lymphomas in children remain a small proportion of patients with refractory or recurrent disease. An effective approach to the treatment of such patients – not only is the second line chemotherapy, but the use of the new targeted therapies. An example of this approach is the use of brentuximab vedotin (antibody-drug conjugate directed to the CD30 in relapsed Hodgkin’s lymphoma and anaplastic large cell lymphoma. Literature review and own experience of using this drug in children are describes in this article.

  16. Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma

    Science.gov (United States)

    Wurster, K D; Hummel, F; Richter, J; Giefing, M; Hartmann, S; Hansmann, M-L; Kreher, S; Köchert, K; Krappmann, D; Klapper, W; Hummel, M; Wenzel, S-S; Lenz, G; Janz, M; Dörken, B; Siebert, R; Mathas, S

    2017-01-01

    Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), activator protein-1 (AP-1) and interferon regulatory factor (IRF) transcription factors (TFs) that are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein levels in the majority of cHL cell lines and Hodgkin and Reed–Sternberg (HRS) cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B-cell lines, small interfering RNA-mediated PDLIM2 knockdown results in superactivation of TFs NF-κB and AP-1 following phorbol 12-myristate 13-acetate (PMA) stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL) that shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis. PMID:27538486

  17. miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma.

    Science.gov (United States)

    Matsuyama, Hironori; Suzuki, Hiroshi I; Nishimori, Hikaru; Noguchi, Masaaki; Yao, Takashi; Komatsu, Norio; Mano, Hiroyuki; Sugimoto, Koichi; Miyazono, Kohei

    2011-12-22

    Many transformed lymphoma cells show immune-phenotypes resembling the corresponding normal lymphocytes; thus, they provide a guide for proper diagnosis and present promising routes to improve their pathophysiologic understanding and to identify novel therapeutic targets. However, the underlying molecular mechanism(s) of these aberrant immune-phenotypes is largely unknown. Here, we report that microRNA-135b (miR-135b) mediates nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-driven oncogenicity and empowers IL-17-producing immunophenotype in anaplastic large cell lymphoma (ALCL). NPM-ALK oncogene strongly promoted the expression of miR-135b and its host gene LEMD1 through activation of signal transducer and activator of transcription (STAT) 3. In turn, elevated miR-135b targeted FOXO1 in ALCL cells. miR-135b introduction also decreased chemosensitivity in Jurkat cells, suggesting its contribution to oncogenic activities of NPM-ALK. Interestingly, miR-135b suppressed T-helper (Th) 2 master regulators STAT6 and GATA3, and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells, indicating that miR-135b-mediated Th2 suppression may lead to the skewing to ALCL immunophenotype overlapping with Th17 cells. Furthermore, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, demonstrating significance of this "Th17 mimic" pathway as a therapeutic target. These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment.

  18. Successful Treatment in a Child with Anaplastic Large Cell Lymphoma and Coexistence of Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    Margarita Baka

    2013-01-01

    Full Text Available A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL, whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months, pyrazinamide (the first 2 months, and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time.

  19. Infectious Mimicry Complicates Diagnosis in Hemophagocytic Syndrome Caused by Anaplastic Large-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Michael J. Peluso

    2012-01-01

    Full Text Available Hemophagocytic syndrome (HPS arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL. This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified.

  20. PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

    Directory of Open Access Journals (Sweden)

    Esperanza Martín-Sánchez

    Full Text Available Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL. The Proviral Integration site of Moloney murine leukemia virus (PIM kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs and pharmacologically (mainly with the pan-PIM inhibitor (PIMi ETP-39010 in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

  1. A Case of an Unusually Aggressive Cutaneous Anaplastic Large T-Cell Lymphoma in an HIV Patient Treated with CHOP

    Directory of Open Access Journals (Sweden)

    Jorge Hurtado-Cordovi

    2011-01-01

    Full Text Available Anaplastic large cell lymphoma (ALCL is the second most common malignancy of T-cell phenotype. This case report describes an unusual rapidly progressing cutaneous anaplastic large T-cell lymphoma in an HIV patient. Our patient is a twenty-year-old African American male with perinatally acquired HIV who presented with a 2×2 centimeter necrotic lesion in the right 1st toe; however, 2-3 weeks later multiple smaller lesions appeared on the anterior aspect of the right foot, ankle, and thigh. Biopsy showed cells strongly positive for CD3 and CD30 and negative for CD56 and the ALK gene product. CT of the chest, abdomen, and pelvis was negative for extracutaneous involvement favoring cutaneous ALCL. Patient was treated with 6 cycles of CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone chemotherapy and went into complete remission. Due to the aggressive course that this malignancy follows in HIV patients we suggest prompt treatment with systemic therapy.

  2. Transformation of Sézary syndrome into CD30+ anaplastic large T-cell lymphoma after alemtuzumab therapy with evidence of clonal unity.

    Science.gov (United States)

    Nevet, Mariela Judith; Zuckerman, Tsila; Sahar, Dvora; Bergman, Reuven

    2015-01-01

    Alemtuzumab is a humanized mouse antibody targeting the CD52 cell surface, which has been effective in patients with advanced stage mycosis fungoides (MF) including erythrodermic MF and Sézary syndrome. There are a few descriptions of large cell transformation after its administration. A young patient with an acute onset of Sézary syndrome treated initially unsuccessfully with fludarabine and cyclophosphamide and later on successfully with alemtuzumab has been described. Three weeks after the beginning of therapy, however, she developed transformed T-cell lymphoma indistinguishable from CD30 anaplastic large-cell lymphoma. After bone marrow transplantation, the transformed CD30 cutaneous T-cell lymphoma recurred as a transformed CD30 plaque MF. All 3 types of lesions showed the same T-cell receptor clonal gene rearrangement, which supports the notion that Sézary syndrome, CD30 anaplastic large-cell lymphoma, and MF are interrelated.

  3. 全自动免疫组化筛查ALK基因融合非小细胞肺癌及其病理特征%Screen of Non-small Cell Lung Cancer with Anaplastic Lymphoma Kinase Fusion Gene by Automatic Immunohistochemical Method and Its Pathological Features

    Institute of Scientific and Technical Information of China (English)

    冯强; 彭森; 刘霞

    2016-01-01

    目的 探讨全自动免疫组化筛查间变性淋巴瘤激酶(ALK)基因融合非小细胞肺癌的临床特点及病理特征.方法 选取经病理检查确诊的554例非小细胞肺癌组织,采用Ventana抗ALK试剂和全自动免疫组化(IHC)染色检测ALK状态,分析ALK基因融合非小细胞肺癌的临床特点和病理特征.结果 本次研究的554例非小细胞肺癌患者组织中,共筛选出34例ALK阳性,占6.14%;年龄0.05).组织形态学方面,34例ALK阳性非小细胞肺癌中28例为肺腺癌,6例为非肺腺癌.16例实体型为主腺癌合并黏液产生,7例腺泡型为主腺癌,1例为乳头型为主腺癌,4例为浸润性黏液腺癌,4例为鳞状细胞癌.EGFR基因突变检测显示:仅有1例合并该基因突变,其余均为野生型.9例IHC阳性样本,9例ALK基因融合非小细胞肺癌,9例IHC阴性样本经荧光原位杂交技术检测和RT-PCR检测均为阴性结果,6例IHC染色可能为阳性,经荧光原位杂交技术检测均显示为ALK融合阴性.结论 ALK基因融合肺癌是非小细胞肺癌一新的分子亚型,具有独特的临床表现和病理形态;Ventana抗ALK试剂和IHC染色是检测ALK阳性非小细胞肺癌首选方法,对提高该类型肺癌的检出率及个体化治疗具有重要意义.%Objective To explore the automatic immunohistochemical method for the screen of non-small cell lung cancer with anaplastic lymphoma kinase( ALK) and its clinical pathological features.Methods 554 cases of non-small cell lung cancer diagnosed by pathological examination were enrolled in this study.The status of ALK was detected by Ventana anti ALK reagent and IHC staining, and the clinical characteristics and pathological features of ALK gene were analyzed.Results Among of 554 patients with non-small cell lung cancer,34 cases showed positive ALK(6.14%).The positive rate of the patients under 60 years old(8.69%) was significantly higher than that of the elder patients ( 3 .62%) ( P0.05).The results of

  4. U.S. Food and Drug Administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma.

    Science.gov (United States)

    de Claro, R Angelo; McGinn, Karen; Kwitkowski, Virginia; Bullock, Julie; Khandelwal, Aakanksha; Habtemariam, Bahru; Ouyang, Yanli; Saber, Haleh; Lee, Kyung; Koti, Kallappa; Rothmann, Mark; Shapiro, Marjorie; Borrego, Francisco; Clouse, Kathleen; Chen, Xiao Hong; Brown, Janice; Akinsanya, Lara; Kane, Robert; Kaminskas, Edvardas; Farrell, Ann; Pazdur, Richard

    2012-11-01

    The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65-83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23-42%). For patients with sALCL, ORR was 86% (95% CI, 77-95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44-70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen.

  5. Locally advanced breast implant associated anaplastic large cell lymphoma: A case report of successful treatment with radiation and chemotherapy

    Directory of Open Access Journals (Sweden)

    Christopher Fleighton Estes

    2015-02-01

    Full Text Available The development of breast implant associated anaplastic large cell lymphoma (ALCL is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can become more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surgery, chemotherapy, and external beam radiotherapy. This is a case report of breast implant ALCL with pathologically proven lymph node involvement, the fifth such patient reported. Our patient experienced a favorable outcome with radiation therapy and chemotherapy.

  6. The heat shock protein-90 co-chaperone, Cyclophilin 40, promotes ALK-positive, anaplastic large cell lymphoma viability and its expression is regulated by the NPM-ALK oncoprotein

    Directory of Open Access Journals (Sweden)

    Pearson Joel D

    2012-06-01

    Full Text Available Abstract Background Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL is a T cell lymphoma defined by the presence of chromosomal translocations involving the ALK tyrosine kinase gene. These translocations generate fusion proteins (e.g. NPM-ALK with constitutive tyrosine kinase activity, which activate numerous signalling pathways important for ALK+ ALCL pathogenesis. The molecular chaperone heat shock protein-90 (Hsp90 plays a critical role in allowing NPM-ALK and other signalling proteins to function in this lymphoma. Co-chaperone proteins are important for helping Hsp90 fold proteins and for directing Hsp90 to specific clients; however the importance of co-chaperone proteins in ALK+ ALCL has not been investigated. Our preliminary findings suggested that expression of the immunophilin co-chaperone, Cyclophilin 40 (Cyp40, is up-regulated in ALK+ ALCL by JunB, a transcription factor activated by NPM-ALK signalling. In this study we examined the regulation of the immunophilin family of co-chaperones by NPM-ALK and JunB, and investigated whether the immunophilin co-chaperones promote the viability of ALK+ ALCL cell lines. Methods NPM-ALK and JunB were knocked-down in ALK+ ALCL cell lines with siRNA, and the effect on the expression of the three immunophilin co-chaperones: Cyp40, FK506-binding protein (FKBP 51, and FKBP52 examined. Furthermore, the effect of knock-down of the immunophilin co-chaperones, either individually or in combination, on the viability of ALK+ ALCL cell lines and NPM-ALK levels and activity was also examined. Results We found that NPM-ALK promoted the transcription of Cyp40 and FKBP52, but only Cyp40 transcription was promoted by JunB. We also observed reduced viability of ALK+ ALCL cell lines treated with Cyp40 siRNA, but not with siRNAs directed against FKBP52 or FKBP51. Finally, we demonstrate that the decrease in the viability of ALK+ ALCL cell lines treated with Cyp40 siRNA does not appear to

  7. The ALK inhibitor ASP3026 eradicates NPM-ALK⁺ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model.

    Science.gov (United States)

    George, Suraj Konnath; Vishwamitra, Deeksha; Manshouri, Roxsan; Shi, Ping; Amin, Hesham M

    2014-07-30

    NPM-ALK⁺ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK⁺ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK⁺ solid tumors. However, NPM-ALK⁺ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK⁺ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK⁺ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK⁺ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK⁺ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.

  8. Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant–Associated Anaplastic Large-Cell Lymphoma

    Science.gov (United States)

    Clemens, Mark W.; Medeiros, L. Jeffrey; Butler, Charles E.; Hunt, Kelly K.; Fanale, Michelle A.; Horwitz, Steven; Weisenburger, Dennis D.; Liu, Jun; Morgan, Elizabeth A.; Kanagal-Shamanna, Rashmi; Parkash, Vinita; Ning, Jing; Sohani, Aliyah R.; Ferry, Judith A.; Mehta-Shah, Neha; Dogan, Ahmed; Liu, Hui; Thormann, Nora; Di Napoli, Arianna; Lade, Stephen; Piccolini, Jorge; Reyes, Ruben; Williams, Travis; McCarthy, Colleen M.; Hanson, Summer E.; Nastoupil, Loretta J.; Gaur, Rakesh; Oki, Yasuhiro; Young, Ken H.

    2016-01-01

    Purpose Breast implant–associated anaplastic large-cell lymphoma (BI-ALCL) is a rare type of T-cell lymphoma that arises around breast implants. The optimal management of this disease has not been established. The goal of this study is to evaluate the efficacy of different therapies used in patients with BI-ALCL to determine an optimal treatment approach. Patients and Methods In this study, we applied strict criteria to pathologic findings, assessed therapies used, and conducted a clinical follow-up of 87 patients with BI-ALCL, including 50 previously reported in the literature and 37 unreported. A Prentice, Williams, and Peterson model was used to assess the rate of events for each therapeutic intervention. Results The median and mean follow-up times were 45 and 30 months, respectively (range, 3 to 217 months). The median overall survival (OS) time after diagnosis of BI-ALCL was 13 years, and the OS rate was 93% and 89% at 3 and 5 years, respectively. Patients with lymphoma confined by the fibrous capsule surrounding the implant had better event-free survival (EFS) and OS than did patients with lymphoma that had spread beyond the capsule (P = .03). Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014) than did patients who received partial capsulectomy, systemic chemotherapy, or radiation therapy. Conclusion Surgical management with complete surgical excision is essential to achieve optimal EFS in patients with BI-ALCL. PMID:26628470

  9. A Unique “Composite” PTLD with Diffuse Large B-Cell and T/Anaplastic Large Cell Lymphoma Components Occurring 17 Years after Transplant

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    Kristin La Fortune

    2013-01-01

    Full Text Available Posttransplant lymphoproliferative disorder (PTLD comprises a spectrum ranging from polyclonal hyperplasia to aggressive monoclonal lymphomas. The majority of PTLDs are of B-cell origin while T-cell PTLDs and Hodgkin lymphoma-like PTLDs are uncommon. Here, we report a unique case of a 56-year-old man in whom a lymphoma with two distinct components developed as a duodenal mass seventeen years following a combined kidney-pancreas transplant. This PTLD, which has features not previously reported in the literature, consisted of one component of CD20 positive and EBV negative monomorphic diffuse large B-cell lymphoma. The other component showed anaplastic morphology, expressed some but not all T-cell markers, failed to express most B-cell markers except for PAX5, and was diffusely EBV positive. Possible etiologies for this peculiar constellation of findings are discussed and the literature reviewed for “composite-like” lymphomas late in the posttransplant setting.

  10. Extrinsic apoptotic pathways: A new potential "Target" for more sufficient therapy in a case of cutaneous anaplastic large CD30+ ALK-T--cell lymphoma

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    Georgi Tchernev

    2011-01-01

    Full Text Available The primary cutaneous T-cell lymphomas (CTCL represent a clonal T-lymphocyte proliferation infiltrating the skin. CD30+ T-cell lymphomas present clinically as nodules with a diameter between 1 and 15 cm, mostly in elderly patients. The role of the CD30 molecule in patients suffering from T-cell lymphomas is not completely clear yet. The signal transduction pathway which includes CD30 seems to play a key role in tumor progression. In certain forms of T-cellular lymphomas, the interaction between CD30/CD30-ligand is able to provoke apoptosis of the "tumor lymphocytes". The modern conceptions of the pathogenesis of T-cell lymphomas include disorders in the pathways involved in programmed cellular death and disregulation in the expression of certain of its regulatory molecules. We are presenting an unusual case of a female patient with a primary cutaneous form of CD30 + /ALK− anaplastic large T-cell lymphoma. Upon the introduction of systemic PUVA, (psoralen plus ultraviolet light radiation combined with beam therapy, a complete remission could be noticed. Eight months later, we observed a local recurrence, which was overcome by CHOP chemotherapy (Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin, Vincristin (Oncovin®, Predniso(lon. Six months later, new cutaneous lesions had been noticed again. A new therapeutic hope for the patients with anaplastic large CTCL is actually based on the influence of the activity of the different apoptotic pathways. Death ligands, including tumor necrosis factor (TNF-α, CD95L/FasL, and TRAIL, mediate also some important safeguard mechanisms against tumor growth in patients with CD30 + cutaneous anaplastic large T-cell lymphomas and critically contribute to lymphocyte homeostasis.

  11. Occurrence of anaplastic large cell lymphoma following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma.

    Science.gov (United States)

    Ishida, Mitsuaki; Hodohara, Keiko; Yoshida, Keiko; Kagotani, Akiko; Iwai, Muneo; Yoshii, Miyuki; Okuno, Hiroko; Horinouchi, Akiko; Nakanishi, Ryota; Harada, Ayumi; Yoshida, Takashi; Okabe, Hidetoshi

    2013-01-01

    IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Recently, the association between IgG4-related sclerosing disease and the risk of malignancies has been suggested. IgG4-related autoimmune pancreatitis with pancreatic cancer has been reported. Further, a few cases of extraocular malignant lymphoma in patients with IgG4-related sclerosing disease have also been documented. Herein, we describe the first documented case of anaplastic large cell lymphoma (ALCL) following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma (DLBCL). A 61-year-old Japanese male, with a past history of DLBCL, was detected with swelling of the pancreas and tumorous lesions in the gallbladder. Histopathological study of the resected gallbladder specimen revealed diffuse lymphoplasmacytic infiltration with fibrosclerosis in the entire gallbladder wall. Eosinophilic infiltration and obliterative phlebitis were also noted. Immunohistochemically, many IgG4-positive plasma cells had infiltrated into the lesion, and the ratio of IgG4/IgG-positive plasma cells was 71.6%. Accordingly, a diagnosis of IgG4-related cholecystitis was made. Seven months later, he presented with a painful tumor in his left parotid gland. Histopathological study demonstrated diffuse or cohesive sheet-like proliferation of large-sized lymphoid cells with rich slightly eosinophilic cytoplasm and irregular-shaped large nuclei. These lymphoid cells were positive for CD30, CD4, and cytotoxic markers, but negative for CD3 and ALK. Therefore, a diagnosis of ALK-negative ALCL was made. It has been suggested that the incidence of malignant lymphoma may be high in patients with IgG4-related sclerosing disease, therefore, intense medical follow-up is important in patients with this disorder.

  12. NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells.

    Science.gov (United States)

    Ambrogio, Chiara; Martinengo, Cinzia; Voena, Claudia; Tondat, Fabrizio; Riera, Ludovica; di Celle, Paola Francia; Inghirami, Giorgio; Chiarle, Roberto

    2009-11-15

    Transformed cells in lymphomas usually maintain the phenotype of the postulated normal lymphocyte from which they arise. By contrast, anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma with aberrant phenotype because of the defective expression of the T-cell receptor and other T-cell-specific molecules for still undetermined mechanisms. The majority of ALCL carries the translocation t(2;5) that encodes for the oncogenic tyrosine kinase NPM-ALK, fundamental for survival, proliferation, and migration of transformed T cells. Here, we show that loss of T-cell-specific molecules in ALCL cases is broader than reported previously and involves most T-cell receptor-related signaling molecules, including CD3epsilon, ZAP70, LAT, and SLP76. We further show that NPM-ALK, but not the kinase-dead NPM-ALK(K210R), downregulated the expression of these molecules by a STAT3-mediated gene transcription regulation and/or epigenetic silencing because this downregulation was reverted by treating ALCL cells with 5-aza-2-deoxycytidine or by knocking down STAT3 through short hairpin RNA. Finally, NPM-ALK increased the methylation of ZAP70 intron 1-exon 2 boundary region, and both NPM-ALK and STAT3 regulated the expression levels of DNA methyltransferase 1 in transformed T cells. Thus, our data reveal that oncogene-deregulated tyrosine kinase activity controls the expression of molecules that determine T-cell identity and signaling.

  13. ALK and c-myc gene of anaplastic large cell lymphoma%间变性大细胞淋巴瘤的ALK和c-myc基因研究

    Institute of Scientific and Technical Information of China (English)

    于冉; 周春菊; 陈刚; 高子芬; 时云飞; 石岩; 谢建兰; 周小鸽; 宫丽平

    2010-01-01

    目的 探讨间变性大细胞淋巴瘤(ALCL)中间变性淋巴瘤激酶(ALK)基因与c-myc基因的分子遗传学改变.方法 收集原发系统性ALCL石蜡包埋组织标本72例,利用间期荧光原位杂交(FISH)技术检测ALCL肿瘤组织中ALK和c-myc基因结构与数目的变化.结果 72例ALCL中,ALK阳性者42例,40例存在涉及ALK基因的染色体易位,其中17例同时伴有ALK基因的多拷贝;ALK阴性的30例均未发现ALK基因的易位,但其中14例存在ALK基因的多拷贝.ALK基因多拷贝的发生率在ALK阳性与阴性组中的差异无统计学意义(P>0.05).72例病例中,均未发现涉及c-myc基因的染色体易位,但其中24例存在c-myc基因的多拷贝.结论 大部分ALCL伴有ALK基因的异常(75.0%).以涉及ALK基因的染色体易位最为多见(55.6%),ALK基因多拷贝也是ALCL较为常见的遗传学改变(43.1%).前者只出现于ALK阳性ALCL中,后者既可出现在ALK阳性也可出现在ALK阴性的ALCL中.ALCL中不见或罕见涉及c-myc基因的染色体易位,但c-myc基因多拷贝的现象较为常见(33.3%).%Objective To investigate the molecular genetic changes of anaplastic lymphoma kinase (ALK) gene and c-myc gene in anaplastic large cell lymphoma (ALCL). Methods The structural aberrations and changes of copy numbers in ALK and c-myc genes in 72 paraffin-embedded ALCL specimens were detected by interphase fluorescence in situ hybridization (FISH). Results Among 72 ALCL specimens, ALK protein was expressed in 42, ALK gene translocation was detected in 40 specimens in which extra copies of ALK gene were detected in 17. ALK gene translocation was not found in all 30 ALK negative specimens, but extra copies of ALK gene were detected in 14 cases. The difference of incidence rates of extra copies in ALK gene between ALK positive and ALK negative specimens was not significant (P>0.05). c-myc gene translocation was not found in any of 72 ALCL specimens, but extra copies were detected in 24

  14. Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Long-Term Follow-Up of 60 Patients

    Science.gov (United States)

    Miranda, Roberto N.; Aladily, Tariq N.; Prince, H. Miles; Kanagal-Shamanna, Rashmi; de Jong, Daphne; Fayad, Luis E.; Amin, Mitual B.; Haideri, Nisreen; Bhagat, Govind; Brooks, Glen S.; Shifrin, David A.; O'Malley, Dennis P.; Cheah, Chan Y.; Bacchi, Carlos E.; Gualco, Gabriela; Li, Shiyong; Keech, John A.; Hochberg, Ephram P.; Carty, Matthew J.; Hanson, Summer E.; Mustafa, Eid; Sanchez, Steven; Manning, John T.; Xu-Monette, Zijun Y.; Miranda, Alonso R.; Fox, Patricia; Bassett, Roland L.; Castillo, Jorge J.; Beltran, Brady E.; de Boer, Jan Paul; Chakhachiro, Zaher; Ye, Dongjiu; Clark, Douglas; Young, Ken H.; Medeiros, L. Jeffrey

    2014-01-01

    Purpose Breast implant–associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown. Patients and Methods We reviewed the literature for all published cases of breast implant–associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up. Results The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively). Conclusion Most patients with breast implant–associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants. PMID:24323027

  15. Loss of CD30 Expression in Anaplastic Large Cell Lymphoma Following Brentuximab Therapy.

    Science.gov (United States)

    Nielson, Colton; Fischer, Ryan; Fraga, Garth; Aires, Daniel

    2016-07-01

    Monoclonal antibody therapy is a new innovation in cancer therapy. Binding of monoclonal antibodies to tumor cells facilitates their destruction by the immune system. Tumor cells with mutated target antigens may escape detection by monoclonal antibodies and exhibit a selective growth advantage. This phenomenon was first recognized in CD20-negative B-cell lymphomas in patients previously treated with the anti-CD20 monoclonal antibody rituximab. We report a cutaneous recurrence of systemic ALCL with an anomalous CD30-negative immunophenotype. The patient had been previously treated with the anti-CD30 monoclonal antibody brentuximab. To our knowledge, we present the first reported case of a cutaneous recurrence of systemic ALCL with an anomalous CD30-negative immunophenotype following chronic brentuximab therapy. J Drugs Dermatol. 2016;15(7):894-895.

  16. Relationship between expression of anaplastic lymphoma kinase in pleural effusion and clinicopathological features of patients with lung adenocarcinoma and the response to crizotinib%肺腺癌胸腔积液沉渣间变性淋巴瘤激酶融合基因蛋白表达与临床病理特征的关系及克唑替尼疗效观察

    Institute of Scientific and Technical Information of China (English)

    穆晶; 曲杨; 赵丹; 董宇杰; 王重利; 张晨; 张莉; 张海青

    2015-01-01

    Objective To explore the expression of anaplastic lymphoma kinase (ALK) protein in pleural effusion cells from patients with lung adenocarcinoma and to investigate the relationship between ALK status and the clinicopathological features,and the response to crizotinib.Methods Eighty-five cases were reviewed from Sept.2013-Nov.2014 at Beijing Chest Hospital.There were 42 males and 43 females,with a median age of 58 (30-87).ALK rearrangements were screened by using immunohistochemistry on Benchmark XT auto-stainer.Results The frequency of ALK positive reactivity was 15.3% among the 85 patients.The incidence of ALK expression was more frequent in patients < 60 years as compared with patients≥60 years of age(26.1%,2.6%,x2 =9.015,P =0.002).Among the ALK-positive patients,8 were males and 5 were females (19.1%,11.6%,x2 =0.903,P =0.259).There were 8 never-smokers and 5 smokers harboring ALK rearrangement(17.0%,13.5%,x2 =0.379,P =0.827).Among patients with ALK rearrangement,6 received EGFR detection,and 5 showed no EGFR mutation,and 1 showed 19del EGFR mutation.Among the 13 ALK-positive patients,4 received crizotinib therapy,and all showed partial response.Conclusion Patients with lung adenocarcinoma with ALK rearrangement were significantly younger than those with ALK wild-type,and ALK rearrangement was rarely concur with EGFR mutation.Screening ALK fusion protein expression in patients with lung adenocarcinoma by paraffin-embedded sediments of pleural effusion was useful in guide of crizotinib therapy.%目的 探讨原发性肺腺癌胸腔积液沉渣间变性淋巴瘤激酶(ALK)蛋白表达与临床病理特征的关系及克唑替尼的治疗效果.方法 回顾性分析2013年9月至2014年1 1月首都医科大学附属北京胸科医院以胸腔积液沉渣包埋标本进行ALK基因重排检测的原发性肺腺癌病例85例,男42例,女43例,年龄30~87岁,平均58岁.采用Ventana全自动免疫组织化学染色和D5F3抗体试剂盒检测ALK

  17. Silicone-induced granuloma of breast implant capsule (SIGBIC): similarities and differences with anaplastic large cell lymphoma (ALCL) and their differential diagnosis

    Science.gov (United States)

    Fleury, Eduardo de Faria Castro; Rêgo, Milena Morais; Ramalho, Luciana Costa; Ayres, Veronica Jorge; Seleti, Rodrigo Oliveira; Ferreira, Carlos Alberto Pecci; Roveda, Decio

    2017-01-01

    Primary breast lymphoma is a rare disease and accounts for 0.5% of cases of breast cancer. Most primary breast lymphomas develop from B cells, and the involvement of T cells is rare. Anaplastic large cell lymphoma (ALCL) is a recently discovered T-cell lymphoma associated with breast implants. Only a few cases have been reported to date. It is believed that the incidence of ALCL is increasing because of the increasing number of breast implants. The clinical presentation is variable and can manifest as a palpable mass in the breast or armpit, breast pain, or capsular contracture. Because of the rarity of the disease and the lack of knowledge to date, clinical diagnosis is often delayed, with consequent delays in treatment. The cause and pathogenesis have not been fully elucidated, and there are no evidence-based guidelines for diagnosis, treatment, or follow-up of this disease. We present a review of cases of patients with silicone breast implants, including ALCL, a rare type of breast cancer that is still under study, and silicone-induced granuloma of breast implant capsule and its differential diagnosis, and discuss if a silicone-induced granuloma of breast implant capsule could be the precursor of the disease.

  18. Pseudocarcinomatous hyperplasia in anaplastic large cell lymphoma, a mimicker of poorly differentiated squamous cell carcinoma: report of a case and review of the literature.

    Science.gov (United States)

    Price, Alexandra; Miller, Jason H; Junkins-Hopkins, Jacqueline M

    2015-11-01

    Pseudocarcinomatous hyperplasia can occasionally be observed in biopsies of CD30-positive lymphoproliferative disorders. It is important to be cognizant of this association, because epithelial hyperproliferation can overshadow large atypical lymphoid cells, leading to an erroneous diagnosis of squamous cell carcinoma (SCC) or keratoacanthoma. Herein, we present a case of anaplastic large cell lymphoma (ALCL) with pseudocarcinomatous hyperplasia simulating a poorly differentiated carcinoma and review the literature on this subject. Immunohistochemical staining with p63 helped delineate the infiltrating tongues of pseudocarcinomatous hyperplasia from the malignant infiltrate. We present this case to raise awareness of the potential for pseudocarcinomatous hyperplasia to occur in the setting of CD30+ lymphoproliferative disorders. Clinicians and dermatopathologists should consider the possibility of ALCL or lymphomatoid papulosis when examining lesions with features of inflamed SCC, especially if the tumor presents on a site or in a patient that is not typical of SCC.

  19. [Molecular abnormalities in lymphomas].

    Science.gov (United States)

    Delsol, G

    2010-11-01

    Numerous molecular abnormalities have been described in lymphomas. They are of diagnostic and prognostic value and are taken into account for the WHO classification of these tumors. They also shed some light on the underlying molecular mechanisms involved in lymphomas. Overall, four types of molecular abnormalities are involved: mutations, translocations, amplifications and deletions of tumor suppressor genes. Several techniques are available to detect these molecular anomalies: conventional cytogenetic analysis, multicolor FISH, CGH array or gene expression profiling using DNA microarrays. In some lymphomas, genetic abnormalities are responsible for the expression of an abnormal protein (e.g. tyrosine-kinase, transcription factor) detectable by immunohistochemistry. In the present review, molecular abnormalities observed in the most frequent B, T or NK cell lymphomas are discussed. In the broad spectrum of diffuse large B-cell lymphomas microarray analysis shows mostly two subgroups of tumors, one with gene expression signature corresponding to germinal center B-cell-like (GCB: CD10+, BCL6 [B-Cell Lymphoma 6]+, centerine+, MUM1-) and a subgroup expressing an activated B-cell-like signature (ABC: CD10-, BCL6-, centerine-, MUM1+). Among other B-cell lymphomas with well characterized molecular abnormalies are follicular lymphoma (BCL2 deregulation), MALT lymphoma (Mucosa Associated Lymphoid Tissue) [API2-MALT1 (mucosa-associated-lymphoid-tissue-lymphoma-translocation-gene1) fusion protein or deregulation BCL10, MALT1, FOXP1. MALT1 transcription factors], mantle cell lymphoma (cycline D1 [CCND1] overexpression) and Burkitt lymphoma (c-Myc expression). Except for ALK (anaplastic lymphoma kinase)-positive anaplastic large cell lymphoma, well characterized molecular anomalies are rare in lymphomas developed from T or NK cells. Peripheral T cell lymphomas not otherwise specified are a heterogeneous group of tumors with frequent but not recurrent molecular abnormalities

  20. Primary cutaneous CD8 + CD30 + anaplastic large cell lymphoma: An unusual case with a high Ki-67 index-A short review

    Directory of Open Access Journals (Sweden)

    Jitendra G Nasit

    2015-01-01

    Full Text Available Primary cutaneous anaplastic large cell lymphoma (PCALCL is a part of the spectrum of CD30 + cutaneous lymphoproliferative disorder, characterized by variable degrees of CD2, CD3, CD4 and CD5 expression by lymphoid cells. PCALCLs with an expression of cytotoxic phenotype (CD8 + and cytotoxic proteins are uncommon. Cutaneous CD8 + CD30 + lymphoproliferative lesions are difficult to classify, diagnose and may be the cause of misdiagnose. CD8 + PCALCL must be distinguished from CD8 + mycosis fungoides, lymphomatoid papulosis type D and primary cutaneous aggressive epidermotropic CD8 + T-cell lymphoma. Usually CD8 + PCALCL is an indolent disease with a favorable prognosis, except few cases can show poor outcomes. The high Ki-67 index points toward advanced PCALCL. Treatment modalities include surgical excision, radiotherapy and clinical monitoring. Chemotherapy is reserved for disseminated disease. We report a 59-year-old male presented with rapid development of multiple painful reddish-brown plaques and nodular ulcerative skin lesions over the left thigh region since 2 months. A diagnosis of CD8 + PCALCL with a high Ki-67 index was made on the basis of histology and immunohistochemistry, in co-relation with clinical presentation.

  1. 间变性淋巴瘤激酶抑制剂的研究进展%Advances in research on anaplastic lympgoma kinase inhibitors

    Institute of Scientific and Technical Information of China (English)

    陈雅琳; 李巍; 汪天洋; 周雪琴; 刘东志

    2016-01-01

    研究发现非小细胞肺癌的形成与多种致癌突变密切相关,其中间变性淋巴瘤激酶重排备受关注,针对棘皮动物微管相关蛋白质4-间变性淋巴瘤激酶融合基因的抑制剂克唑替尼对于治疗晚期ALK阳性非小细胞肺癌患者是有效的,2011年获得美国食品药品监督管理局批准上市,但出现了耐药性,第二代间变性淋巴瘤激酶抑制剂的出现,克服了耐药机制,并显示出治疗非小细胞肺癌患者的活性。本论文按化学结构的不同介绍了克唑替尼、Ceritinib、Alectinib 、Brigatinib、RXDX-101、PF-06463922、ASP3026、X-396、CEP-37440等间变性淋巴瘤激酶抑制剂及临床研究等,为非小细胞肺癌的靶向治疗药物的开发提供了参考。%Researchers have found that multiple oncogenic driver multations are closely related with the progression and prognosis of NSCLC.In the era of molecular targeted treatment,rearrangements in anaplastic lymphoma kinase(ALK)gene and echinoderm microtubule-associated protein-like 4 (EML4)gene were applied in patients with non-small cell lung cancer(NSCLC). Crizotinib,an ALK inhibitor,is effective in treating advanced ALK-positive NSCLC,and the US Food and Drug Administration(FDA)approved it for treating ALK-positive NSCLC. Several mechanisms of acquired resistance to crizotinib have recently been reported. Second-generation ALK inhibitors were developed to overcome these resistance mechanisms and showed activity againstALKpositive NSCLC. The latest development of crizotinib,ceritinib,alectinibetc. were reviewed.

  2. The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration

    DEFF Research Database (Denmark)

    Voena, Claudia; Conte, Chiara; Ambrogio, Chiara;

    2007-01-01

    in the activation loop of Src, resulting in impaired ALCL cell proliferation and growth disadvantage. Finally, migration of ALCL cells was reduced by Shp2 shRNA. These findings show a direct involvement of Shp2 in NPM-ALK lymphomagenesis, highlighting its critical role in lymphoma cell proliferation and migration....

  3. Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex.

    Science.gov (United States)

    Piazza, Rocco; Magistroni, Vera; Mogavero, Angela; Andreoni, Federica; Ambrogio, Chiara; Chiarle, Roberto; Mologni, Luca; Bachmann, Petra S; Lock, Richard B; Collini, Paola; Pelosi, Giuseppe; Gambacorti-Passerini, Carlo

    2013-05-01

    BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.

  4. Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex

    Directory of Open Access Journals (Sweden)

    Rocco Piazza

    2013-05-01

    Full Text Available BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2 corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.

  5. Case report: a unique pediatric case of a primary CD8 expressing ALK-1 positive anaplastic large cell lymphoma of skeletal muscle

    Directory of Open Access Journals (Sweden)

    Gaiser Timo

    2012-04-01

    Full Text Available Abstract Primary involvement of skeletal muscle is a very rare event in ALK-1 positive anaplastic large cell lymphoma (ALCL. We describe a case of a 10-year old boy presenting with a three week history of pain and a palpable firm swelling at the dorsal aspect of the left thigh. Histological examination of the lesion revealed a tumoral and diffuse polymorphic infiltration of the muscle by large lymphoid cells. Tumor cells displayed eccentric, lobulated "horse shoe" or "kidney-shape" nuclei. The cells showed immunohistochemical positivity for CD30, ALK-1, CD2, CD3, CD7, CD8, and Perforin. Fluorescence in situ hybridization analysis revealed a characteristic rearrangement of the ALK-1 gene in 2p23 leading to the diagnosis of ALK-1 positive ALCL. Chemotherapy according to the ALCL-99-NHL-BFM protocol was initiated and resulted in a complete remission after two cycles. This case illustrates the unusual presentation of a pediatric ALCL in soft tissue with a good response to chemotherapy.

  6. Sub-megabase resolution tiling (SMRT array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines

    Directory of Open Access Journals (Sweden)

    Lam Wan L

    2008-01-01

    Full Text Available Abstract Background Hodgkin lymphoma (HL and Anaplastic Large Cell Lymphoma (ALCL, are forms of malignant lymphoma defined by unique morphologic, immunophenotypic, genotypic, and clinical characteristics, but both overexpress CD30. We used sub-megabase resolution tiling (SMRT array-based comparative genomic hybridization to screen HL-derived cell lines (KMH2 and L428 and ALCL cell lines (DEL and SR-786 in order to identify disease-associated gene copy number gains and losses. Results Significant copy number gains and losses were observed on several chromosomes in all four cell lines. Assessment of copy number alterations with 26,819 DNA segments identified an average of 20 genetic alterations. Of the recurrent minimally altered regions identified, 11 (55% were within previously published regions of chromosomal alterations in HL and ALCL cell lines while 9 (45% were novel alterations not previously reported. HL cell lines L428 and KMH2 shared gains in chromosome cytobands 2q23.1-q24.2, 7q32.2-q36.3, 9p21.3-p13.3, 12q13.13-q14.1, and losses in 13q12.13-q12.3, and 18q21.32-q23. ALCL cell lines SR-786 and DEL, showed gains in cytobands 5p15.32-p14.3, 20p12.3-q13.11, and 20q13.2-q13.32. Both pairs of HL and ALCL cell lines showed losses in 18q21.32-18q23. Conclusion This study is considered to be the first one describing HL and ALCL cell line genomes at sub-megabase resolution. This high-resolution analysis allowed us to propose novel candidate target genes that could potentially contribute to the pathogenesis of HL and ALCL. FISH was used to confirm the amplification of all three isoforms of the trypsin gene (PRSS1/PRSS2/PRSS3 in KMH2 and L428 (HL and DEL (ALCL cell lines. These are novel findings that have not been previously reported in the lymphoma literature, and opens up an entirely new area of research that has not been previously associated with lymphoma biology. The findings raise interesting possibilities about the role of signaling

  7. Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination.

    Science.gov (United States)

    Colomba, A; Giuriato, S; Dejean, E; Thornber, K; Delsol, G; Tronchère, H; Meggetto, F; Payrastre, B; Gaits-Iacovoni, F

    2011-06-01

    Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM-ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM-ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM-ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas.

  8. The correlation of clinical pathological features with the expressions of epidermal growth factor receptor gene and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene in non-small-cell lung cancer patient%非小细胞肺癌患者表皮生长因子受体和棘皮动物微管相关蛋白样4-间变性淋巴瘤激酶与病理特征的相关性

    Institute of Scientific and Technical Information of China (English)

    徐利芬; 陈佳; 龙昭玲; 宋翼

    2016-01-01

    目的 检测表皮生长因子受体(EGFR)基因、棘皮动物微管相关蛋白样4(EML4)-间变性淋巴瘤激酶(ALK)基因在非小细胞肺癌(NSCLC)患者中的突变率,并分析其与临床病理特征的关系. 方法 应用Taqman-ARMS方法检测119例NSCLC患者石蜡组织中EGFR基因与53例EML4-ALK基因改变情况,并对其临床病理特征进行相关性分析. 结果 119例NSCLC中EGFR基因总突变率为44.5 %(53/119),外显子18、19、20和21单突变率分别为1.7%(2/119)、25.2%(30/119)、0.8%(1/119)和13.4%(16/119);EGFR基因各外显子之间双重突变共4例(3.4%);ALK融合基因总阳性率为15.1% (8/53);EGFR基因突变与ALK融合基因阳性共存型1例(0.8%),其临床病理特征表现为腺癌高于非腺癌;不吸烟患者高于吸烟患者;女性患者高于男性患者. 结论 NSCILC患者中,EGFR基因19和21外显子突变和ALK融合基因均存在较高的突变率,基因突变亚型分类能指导精准医学的个体化靶向治疗,而基因双突变共存型基因突变率虽低但不容忽视.EGFR及EML4-ALK阳性患者在临床病理上有一些相同或相似的特征,即女性、非吸烟、腺癌患者中较为多见,但也有一些不同的特征:EML4-ALK阳性患者中,腺癌中多伴有黏液产生的腺泡样结构,不同时合并EGFR突变.%Objective To detect the mutation rates of epidermal growth factor receptor(EGFR) gene and echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase(ALK) gene in non-small-cell lung cancer (NSCLC)patients and to analyze their relation with clinical pathological features.Methods EGFR gene of 119 NSCLC patients and EML4-ALK gene of 53 NSCLC patients were detected using gene mutation detection kits(Taqman-ARMS),and the correlation analysis on their clinical pathological features was taken.Results The total mutation rate of the EGFR gene was 44.5%(53/119),and a single mutation rate of the 18th,19th,20th and 21st exons was 1.7%(2

  9. CTOP/ITE/MTX Compared With CHOP as the First-line Therapy for Newly Diagnosed Young Patients With T Cell Lymphoma

    Science.gov (United States)

    2013-11-24

    ALK-negative Anaplastic Large Cell Lymphoma; Peripherial T Cell Lymphoma,Not Otherwise Specified; Angioimmunoblastic T Cell Lymphoma; Enteropathy Associated T Cell Lymphoma; Hepatosplenic T Cell Lymphoma; Subcutaneous Panniculitis Like T Cell Lymphoma

  10. Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma

    DEFF Research Database (Denmark)

    Krejsgaard, Thorbjørn; Vetter-Kauczok, Claudia S; Woetmann, Anders;

    2009-01-01

    B-lymphoid kinase (Blk) is exclusively expressed in B cells and thymocytes. Interestingly, transgenic expression of a constitutively active form of Blk in the T-cell lineage of mice results in the development of T-lymphoid lymphomas. Here, we demonstrate nuclear factor-kappa B (NF......-kappaB)-mediated ectopic expression of Blk in malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL). Importantly, Blk is also expressed in situ in lesional tissue specimens from 26 of 31 patients with CTCL. Already in early disease the majority of epidermotropic T cells express Blk...... phosphorylated in malignant CTCL cell lines and spontaneously active in kinase assays. Furthermore, targeting Blk activity and expression by Src kinase inhibitors and small interfering RNA (siRNA) inhibit the proliferation of the malignant T cells. In conclusion, this is the first report of Blk expression...

  11. Analysis on the clinicopathology characteristics of anaplastic large cell lymphoma%间变性大细胞淋巴瘤临床病理分析

    Institute of Scientific and Technical Information of China (English)

    王刚平; 田胜花; 梁粉花

    2009-01-01

    目的 研究间变性大细胞淋巴瘤(ALCL)的临床病理特征、免疫表型,以提高诊断水平.方法 回顾性分析19例ALCL的临床、病理形态学资料和免疫组织化学,CD30、ALK、CD43、CD45RO、EMA和TIA-1检测结果.结果 19例均为原发系统型ALCL,其中男性11例,女性8例,年龄2~71岁,平均26岁.16例(84.2%)出现B症状,14例(73.7%)结外侵犯.肿瘤细胞沿淋巴窦生长或散在分布,均可见标志性肿瘤细胞,CD+3019例(100%),ALK(+)15例(78.9%),EMA(+)10例(52.6%),TIA-1(+)14例(73.7%),ALK、EMA和TIA-1同时阴性2例(10.5%).重新诊断17例(89.5%)正确.结论 ALCL表现多样,大部分患者经临床、组织病理学和免疫标记特征综合判断可作出相应诊断,CD30、ALK、EMA、TIA-1对鉴别诊断有帮助.%Objective To investigate the clinicopathology characteristics, immunopheotypic of anaplastic large cell lymphoma (ALCL) in order to improve its diagnostic and therapeutic accuracy. Methods The clinical, immunophenotypic and histopathologie features of 19 cases ALCL were retrospectively studied. The expression of CD30, ALK, CD43, CD45RO, EMA and TIA-1 was detected using EnVision immunohistochemical technique. Results All patients were primary systemic ALCL. Among the 19 patients, 11 were males and 8were females. The age ranged from 2 to 71 years, average age 26 years old. It shows a broad morphologic spectrum of the tumor cell and the hallmark cells characterized by sheets of large lymphoid cells withchromatin-poor horseshoe-shaped nuclei containing multiple nucleoli were encountered in all ALCL variants. 16patients (84.2 %) showed B-symptoms, and extranodal involvement was present in 14 (73.7 % ).Immunohistochemical study showed that the tumor cells expressed CD30 (100 %), ALK (78.9 %), EMA(52.6 %), TIA-1 (73.7 %) and 2 cases (10.5 %) neither expressed ALK, nor EMA,TIA-1.17 cases were reached the correct diagnosis according to combination of clinic, histological and immunological features

  12. Primary anaplastic large T cell lymphoma of central nervous system%中枢神经系统原发性间变性大细胞淋巴瘤

    Institute of Scientific and Technical Information of China (English)

    刘腾飞; 韩慧霞; 黎相照; 张彦

    2013-01-01

    are similar to the systemic ALCL and the anaplastic lymphoma kinase-1 (ALK-1) can be positive or negative. Being misdiagnosed as meningitis, hormone therapy with glucocorticoid before biopsy is always used, and massive necrosis and a lot of histocyte proliferation and phagocytosis can be found under histological findings. Therefore, when the material is not enough, primary ALCL of CNS is often misdiagnosed as cerebral infarction or malignant histocytosis and so on. This paper reports a case of primary ALCL of CNS and makes a review of relevant literature, so as to summarize the clinical manifestations and elevate the recognition of clinicians and pathologists on this disease. Methods and Results A 12-year-old boy was admitted because of fever, worsening headache, numbness and weakness of right limbs. MRI showed local gyri swelling and abnormal enhancement of pia mater in the right parietal lobe, expanding to the right temporal lobe, and pia mater enhancement in the left parietal lobe. The right temporo-parietal lobe lesion biopsy revealed irregularly shaped tumor cells of large size, rich and eosinophilic cytoplasm and horseshoe-shaped or kidney-shaped nuclei. Immunohistochemical examination showed tumor cells positive for CD3, CD45RO, CD30, ALK-1 and epithelial membrane antigen (EMA), and negative for CD20 and CD79a. Conclusion Primary ALCL of CNS is an extremely rare tumor which is usually misdiagnosed as meningitis according to clinical and imaging examinations. Therefore, for those patients who are considered as meningitis but with poor treatment effect and replase of illness, brain tissue biopsy, which is an important means for diagnosis, or cerebrospinal fluid cytologic examination, should be carried out as soon as possible.

  13. Efficacy and safety of crizotinib vs. platinum-containing two-drug-regimens in advanced non-small-cell lung cancer patients with positive echinoderm microtubule-associated protein-like 4-anaplastic ;lymphoma kinase fusion gene%克唑替尼与含铂两药方案治疗棘皮动物微管结合蛋白4-间变性淋巴瘤激酶融合基因阳性晚期非小细胞肺癌疗效与安全性比较

    Institute of Scientific and Technical Information of China (English)

    姚舒洋; 张毅; 胡牧; 王若天; 支修益

    2016-01-01

    Objective To compare the efficacY and safetY between crizotinib and platinum-containing two-drug regimens in advanced non-small-cell lung cancer( nsCLC ) patients with positive echinoderm microtubule-associated protein-liKe 4(EML4)-anaplastic lYmphoma Kinase(ALK)fusion gene. Methods The hospitalization records and outpatient follow-up data of all advanced nsCLC patients with positive EML4-ALK fusion gene in Department of Thoracic surgerY,Xuanwu Hospital of Capital Medical universitY from December 2013 to FebruarY 2015 were collected for retrospective analYsis. The patients were divided into the crizotinib group( crizotinib 250 mg twice dailY,28 daYs as a cYcle,continuing to taKe crizotinib as long as progression of disease or could not tolerate due to adverse reactions)and the platinum-containing two-drug regimens group(docetaxel plus carboplatin or pemetrexed plus carboplatin,21daYs as a cYcle,no more than 6 cYcles,continuing to taKe platinum two-drug regimen as long as progression of disease or could not tolerate due to adverse reactions). The efficacY[ complete response( CR),partial response ( PR),stable disease( sD),progressive disease( PD),overall response rate( ORR),disease control rate ( DCR)and progression free survival( PFs)]and adverse reactions between the two groups were compared. Results A total of 31 patients were enrolled in the studY. The crizotinib group comprised 11 and the platinum two-drug regimen group 20 patients,respectivelY. The difference of the general clinical data was not significant between the 2 groups. After the treatment for 2-18 cYcles( median treatment cYcle:8 ), among 11 patients in the crizotinib group,the best responses as PR,sD,and PD were 8(72. 7%),2 (18. 2%)and 1(9. 1%),respectivelY. The ORR and DCR were 72. 7% and 90. 9%. After the treatment of 2-6 cYcles( median treatment cYcle:6 ),among 20 patients in the platinum two-drug regimen group,the best responses as PR,sD,and PD were 7(35. 0%),7(35. 0%),and 6(30. 0%),respectivel

  14. Anaplastic thyroid cancer

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/000352.htm Anaplastic thyroid cancer To use the sharing features on this page, ... of cancer of the thyroid gland. Causes Anaplastic thyroid cancer is an invasive type of thyroid cancer that ...

  15. The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling.

    Science.gov (United States)

    Staber, Philipp B; Vesely, Paul; Haq, Naznin; Ott, Rene G; Funato, Kotaro; Bambach, Isabella; Fuchs, Claudia; Schauer, Silvia; Linkesch, Werner; Hrzenjak, Andelko; Dirks, Wilhelm G; Sexl, Veronika; Bergler, Helmut; Kadin, Marshall E; Sternberg, David W; Kenner, Lukas; Hoefler, Gerald

    2007-11-01

    Anaplastic large cell lymphomas (ALCLs) are highly proliferating tumors that commonly express the AP-1 transcription factor JunB. ALK fusions occur in approximately 50% of ALCLs, and among these, 80% have the t(2;5) translocation with NPM-ALK expression. We report greater activity of JunB in NPM-ALK-positive than in NPM-ALK-negative ALCLs. Specific knockdown of JUNB mRNA using small interfering RNA and small hairpin RNA in NPM-ALK-expressing cells decreases cellular proliferation as evidenced by a reduced cell count in the G2/M phase of the cell cycle. Expression of NPM-ALK results in ERK1/2 activation and transcriptional up-regulation of JUNB. Both NPM-ALK-positive and -negative ALCL tumors demonstrate active ERK1/2 signaling. In contrast to NPM-ALK-negative ALCL, the mTOR pathway is active in NPM-ALK-positive lymphomas. Pharmacological inhibition of mTOR in NPM-ALK-positive cells down-regulates JunB protein levels by shifting JUNB mRNA translation from large polysomes to monosomes and ribonucleic particles (RNPs), and decreases cellular proliferation. Thus, JunB is a critical target of mTOR and is translationally regulated in NPM-ALK-positive lymphomas. This is the first study demonstrating translational control of AP-1 transcription factors in human neoplasia. In conjunction with NPM-ALK, JunB enhances cell cycle progression and may therefore represent a therapeutic target.

  16. Among diffuse large B-cell lymphomas, T-cell-rich/histiocyte-rich BCL and CD30+anaplastic B-cell subtypes exhibit distinct clinical features

    NARCIS (Netherlands)

    Maes, B; Anastasopoulou, A; Kluin-Nelemans, JC; Teodorovic, [No Value; Achten, R; Carbone, A; De Wolf-Peeters, C

    2001-01-01

    Background: The EORTC clinical trial 20901, activated in 1990, was designed to treat non-Hodgkin's lymphomas (NHL) of intermediate/high-grade malignancy according to the Working Formulation. Established in 1994, the R.E.A.L. Classification on NHL has now replaced all former classifications. Patients

  17. Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma.

    Science.gov (United States)

    Damm-Welk, Christine; Busch, Kerstin; Burkhardt, Birgit; Schieferstein, Jutta; Viehmann, Susanne; Oschlies, Ilske; Klapper, Wolfram; Zimmermann, Martin; Harbott, Jochen; Reiter, Alfred; Woessmann, Willi

    2007-07-15

    Clinical and histopathological characteristics have limited prognostic value for children with anaplastic large-cell lymphoma (ALCL). We evaluated the presence, extent, and prognostic impact of circulating tumor cells in bone marrow (BM) and peripheral blood (PB) of children and adolescents with NPM-ALK-positive ALCL at diagnosis using qualitative and quantitative polymerase chain reaction (PCR) for NPM-ALK. Numbers of NPM-ALK transcripts were normalized to 10(4) copies ABL (NCNs). BM was analyzed from 80 patients and PB from 52. BM was positive for NPM-ALK in 47.5% of patients, and positivity was significantly correlated with clinical stage, mediastinal or visceral involvement, microscopic BM involvement, and histologic subtype. Qualitative and quantitative PCR results in BM and PB strongly correlated. BM PCR was associated with the cumulative incidence of relapses (CI-Rs): CI-R was 50% +/- 10% for 38 PCR-positive and 15% +/- 7% for 42 PCR-negative patients (P NPM-ALK in BM had a CI-R of 71% +/- 14% compared with a CI-R of 18% +/- 6% for 59 patients with 10 or fewer NCNs (P < .001). PB PCR results led to a similar grouping. Thus, quantitative PCR in BM or PB allows identification of 20% of patients experiencing 60% of all relapses with an event-free survival of 20%.

  18. Quantitative PCR detection of NPM/ALK fusion gene and CD30 gene expression in patients with anaplastic large cell lymphoma--residual disease monitoring and a correlation with the disease status.

    Science.gov (United States)

    Kalinova, Marketa; Krskova, Lenka; Brizova, Helena; Kabickova, Edita; Kepak, Tomas; Kodet, Roman

    2008-01-01

    Anaplastic large cell lymphoma (ALCL) represents a heterogeneous group of malignant lymphoproliferative diseases with a consistent expression of the cytokine receptor CD30. ALCL is frequently associated with a NPM/ALK fusion gene which is found in up to 75% of pediatric ALCLs. Real-time quantitative RT-PCR (RQ-RT-PCR) of NPM/ALK and CD30 gene expression was employed to analyze minimal residual disease (MRD) in 10 patients with NPM/ALK positive ALCL in 79 follow-up bone marrow (BM) and/or peripheral blood (PB) samples. In all BM samples from relapses and/or closely before a relapse, BM samples revealed NPM/ALK and CD30 positivity in at least one of the iliac BM trephines. Five out of nine relapses were preceded or were accompanied by minimally half log increased NPM/ALK levels in the BM. We found that RQ-RT-PCR of the CD30 expression is not suitable for MRD detection--only two relapses were accompanied by an increase of the CD30 level above a level which was detected in BM/PB samples from healthy individuals. RQ-RT-PCR of NPM/ALK expression is a promising and rapid approach for monitoring MRD.

  19. Everolimus and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma

    Science.gov (United States)

    2016-04-18

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

  20. Investigation of Rho-Kinase Expressions and Polymorphisms in Mantle Cell Lymphoma Patients

    Directory of Open Access Journals (Sweden)

    Didar Yanardağ Açık

    2016-05-01

    Full Text Available Objective: Mantle cell lymphoma (MCL is a rare but aggressive form of B-cell non-Hodgkin lymphoma characterized by excessive expression of cyclin D1. Intracellular signaling enzyme Rho-kinase (ROCK can contribute to cellular migration, proliferation, and differentiation, as well as tumor development and metastasis. However, ROCK gene and protein expressions or polymorphisms have never been investigated in MCL patients. The purpose of this study was to investigate the role of ROCK gene and protein expressions in MCL patients. We also examined ROCK2 gene polymorphisms in this study. Materials and Methods: A total of 60 patients with MCL and 60 healthy controls were included in this retrospective study. Hematoxylin and eosin-stained lymph node tissue slides in the entire archive were reevaluated and used for immunohistochemistry, gene expression, and polymerase chain reaction studies. Results: In immunohistochemical studies, there were significant increases in ROCK1 (p=0.0009 and ROCK2 (p<0.0001 protein expressions in MCL patients when compared with the control group. Although a marked increase in ROCK1 gene expression (p=0.0215 was noted, no significant change was observed in ROCK2 gene expression in MCL patients. Seven ROCK2 polymorphisms were studied, but the results showed no significant differences between the groups. Conclusion: This is the first study to show that ROCK1 gene and ROCK protein expressions may contribute to the development of MCL.

  1. Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells

    Directory of Open Access Journals (Sweden)

    Ji Yeon Lim

    2015-01-01

    Full Text Available Aberrant regulation of phosphatidylinositol-3-kinases (PI3Ks is known to be involved in the progression of cancers. PI3K-binding flavonoids such as quercetin and myricetin have been shown to inhibit PI3K activity, but the direct targeting of fisetin to PI3K has not been established. Here, we carried out an in silico investigation of fisetin binding to PI3K and determined fisetin’s inhibitory activity in enzymatic and cell-based assays. In addition, fisetin induced apoptosis in human Burkitt’s lymphoma Raji cells by inhibiting both PI3Ks and mammalian target of rapamycin (mTOR. Our results indicate that fisetin may serve as a natural backbone for the development of novel dual inhibitors of PI3Ks and mTOR for the treatment of cancer.

  2. Cytological Diagnosis of Bilateral Breast Implant-Associated Lymphoma of the ALK-Negative Anaplastic Large-Cell Type. Clinical Implications of Peri-Implant Breast Seroma Cytological Reporting.

    Science.gov (United States)

    Granados, Rosario; Lumbreras, Eva M; Delgado, Manuel; Aramburu, José A; Tardío, Juan C

    2016-07-01

    The cytological examination of peri-prosthetic breast effusions allowed the diagnosis of bilateral breast-implant ALK-negative anaplastic large cell lymphoma (BI-ALCL) in the case reported. Ten years after reconstructive surgery with bilateral breast implants, a large unilateral seroma developed and was cytologically analyzed. The presence of CD30 and CD4-positive large-sized atypical lymphoid cells exhibiting horseshoe-shaped nuclei and a brisk mitotic activity rendered the diagnosis of BI-ALCL. Similar cells were seen in the peri-prosthetic fluid intraoperatively collected from the contralateral breast. Although initial histological analysis of the capsulectomy specimens showed unilateral tumor, the cytological findings prompted a more thorough tissue sampling, resulting in the diagnosis of bilateral disease. BI-ALCL usually follows an indolent clinical course; however, there are reported cases with an aggressive behavior. While the presence of bilateral disease is a putative risk factor for a bad prognosis, the small number of cases reported precludes a definitive assessment of this risk. Since most BI-ALCL present with late seromas, cytologic analysis of these effusions in women with breast implants should be mandatory. Cytology is a safe tool for diagnosis and follow-up of patients with breast implant-related late seromas, sometimes proven more sensitive than histological analysis. Complete bilateral capsulectomy and a detailed histological analysis should follow a cytological diagnosis of BI-ALCL in a breast effusion in order to avoid false negative diagnoses. Our case constitutes the first published report of a bilateral BI-ALCL diagnosed by cytology. Diagn. Cytopathol. 2016;44:623-627. © 2016 Wiley Periodicals, Inc.

  3. Purely Cortical Anaplastic Ependymoma

    Directory of Open Access Journals (Sweden)

    Flávio Ramalho Romero

    2012-01-01

    Full Text Available Ependymomas are glial tumors derived from ependymal cells lining the ventricles and the central canal of the spinal cord. It may occur outside the ventricular structures, representing the extraventicular form, or without any relationship of ventricular system, called ectopic ependymona. Less than fifteen cases of ectopic ependymomas were reported and less than five were anaplastic. We report a rare case of pure cortical ectopic anaplastic ependymoma.

  4. Chidamide in the treatment of peripheral T-cell lymphoma

    Science.gov (United States)

    Chan, Thomas S; Tse, Eric; Kwong, Yok-Lam

    2017-01-01

    Mature T-cell lymphomas are aggressive malignancies. Treatment outcome is poor with conventional chemotherapy. They are about twice as common in Asia as compared with other non-Asian countries. Histone proteins form the basic structure of chromatin, and their acetylation at lysine residues relaxes chromatin structure, facilitating gene transcription. Conversely, histone deacetylation, catalyzed by histone deacetylases, compacts chromatin and represses gene transcription. Histone deacetylase inhibitors are an important class of antineoplastic agents. Chidamide is a novel orally active benzamide-type histone deacetylase inhibitor that has shown in vitro activities against a wide array of neoplasms. In Phase I trials, chidamide showed preferential efficacy in mature T-cell lymphomas. In a pivotal Phase II trial of chidamide in 79 patients with relapsed or refractory mature T-cell lymphomas, an overall response rate of 28% (complete remission/complete remission unconfirmed: 14%) was achieved, with most responses occurring within the first 6 weeks of treatment. The median duration of response (DOR) was 9.9 (1.1–40.8) months. Of 22 responders, 19 patients (86%) had a DOR of ≥3 months and eight patients (36%) had a DOR of >12 months. Angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma (anaplastic lymphoma kinase-negative) showed better response rates, with the most durable responses observed in angioimmunoblastic T-cell lymphoma patients. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. Chidamide is approved by the China Food and Drug Administration for the treatment of relapsed and refractory peripheral T-cell lymphomas. PMID:28138258

  5. Lenalidomide Therapy for Patients With Relapsed and/or Refractory, Peripheral T-Cell Lymphomas

    Science.gov (United States)

    2012-04-18

    Peripheral T-cell Lymphomas; Adult T-cell Leukemia; Adult T-cell Lymphoma; Peripheral T-cell Lymphoma Unspecified; Angioimmunoblastic T-cell Lymphoma; Anaplastic Large Cell Lymphoma; T/Null Cell Systemic Type; Cutaneous t-Cell Lymphoma With Nodal/Visceral Disease

  6. Lymphoma in acquired generalized lipodystrophy.

    Science.gov (United States)

    Brown, Rebecca J; Chan, Jean L; Jaffe, Elaine S; Cochran, Elaine; DePaoli, Alex M; Gautier, Jean-Francois; Goujard, Cecile; Vigouroux, Corinne; Gorden, Phillip

    2016-01-01

    Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression.

  7. Controversies on Hodgkin's disease and anaplastic large cell lymphoma. Hematopathology Study Group of the Società Italiana di Anatomia Patologica.

    Science.gov (United States)

    Pileri, S

    1994-01-01

    Just one year ago the Italian Society of Pathology (S.I.A.P.) created a Study Group which included members of the most active Italian hematopathology teams. Prof. Pasquale Calapso was asked to chair the Group and Prof. Stefano Pileri to take care of secretarial duties. The aim of the Group is to spread hematopathologic knowledge among young pathologists and to promote activities that can contribute to updating Italian pathologists on topics of both speculative and diagnostic interest. The first Workshop of the S.I.A.P. Hematopathology Group was held at the Palazzo dei Congressi in Bologna, November 20, 1993. About 150 pathologists from all over Italy took part in the meeting, which consisted of two sections devoted to: a) discussion of the boundaries between Hodgkin's disease and non-Hodgkin's lymphomas, and b) a case seminar illustrating the impact of immunohistochemistry in the diagnosis of bone-marrow biopsy. The first section included 5 presentations and a Round Table chaired by Prof. Luciano Fiore-Donati. Below, the contributors to this section summarize the content of their presentations, which were aimed at answering specific questions the Organizers had put to them.

  8. Conditional TPM3-ALK and NPM-ALK transgenic mice develop reversible ALK-positive early B-cell lymphoma/leukemia.

    Science.gov (United States)

    Giuriato, Sylvie; Foisseau, Marianne; Dejean, Emilie; Felsher, Dean W; Al Saati, Talal; Demur, Cécile; Ragab, Ashraf; Kruczynski, Anna; Schiff, Claudine; Delsol, Georges; Meggetto, Fabienne

    2010-05-20

    NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) and TPM3-ALK (nonmuscular tropomyosin 3-anaplastic lymphoma kinase) are oncogenic tyrosine kinases implicated in the pathogenesis of human ALK-positive lymphoma. We report here the development of novel conditional mouse models for ALK-induced lymphomagenesis, with the use of the tetracycline regulatory system under the control of the EmuSRalpha enhancer/promoter. The expression of either oncogene resulted in the arrest of the differentiation of early B cells and lymphomagenesis. We also observed the development of skin keratoacanthoma lesions, probably because of aberrant ALK expression in keratinocytes. The inactivation of the ALK oncogene on doxycycline treatment was sufficient to induce sustained regression of both hematopoietic tumors and skin disease. Importantly, treatment with the specific ALK inhibitor (PF-2341066) also reversed the pathologic states, showing the value of these mouse models for the validation of ALK tyrosine kinase inhibitors. Thus, our results show (1) that NPM-ALK and TPM3-ALK oncogenes are sufficient for lymphoma/leukemia development and required for tumor maintenance, hence validating ALK as potentially effective therapeutic target; and (2) for the first time, in vivo, the equal tumorigenic potential of the NPM-ALK and TPM3-ALK oncogenic tyrosine kinases. Our models offer a new tool to investigate in vivo the molecular mechanisms associated with ALK-induced lymphoproliferative disorders.

  9. Salvia Hispanica Seed in Reducing Risk of Disease Recurrence in Patients With Non-Hodgkin Lymphoma

    Science.gov (United States)

    2017-01-26

    Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Adult T-Cell Leukemia/Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; B Lymphoblastic Leukemia/Lymphoma; Blastic Plasmacytoid Dendritic Cell Neoplasm; Burkitt Leukemia; Central Nervous System Lymphoma; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Associated T-Cell Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3 Follicular Lymphoma; Hepatosplenic T-Cell Lymphoma; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Mycosis Fungoides; Nasal Type Extranodal NK/T-Cell Lymphoma; Nodal Marginal Zone Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise Specified; Post-Transplant Lymphoproliferative Disorder; Primary Cutaneous Anaplastic Large Cell Lymphoma; Primary Effusion Lymphoma; Sezary Syndrome; Splenic Marginal Zone Lymphoma; Subcutaneous Panniculitis-Like T-Cell Lymphoma; Systemic Anaplastic Large Cell Lymphoma; T Lymphoblastic Leukemia/Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

  10. A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma

    NARCIS (Netherlands)

    F. Morschhauser; J.F. Seymour; H.C. Kluin-Nelemans (Hanneke); A. Grigg; M. Wolf; M. Pfreundschuh (Michael); H. Tilly (Herve); J. Raemaekers; M.B. van 't Veer (Mars); N. Milpied; G. Cartron; A. Pezzutto; A. Spencer; F. Reyes; M. Dreyling (Martin)

    2008-01-01

    textabstractBackground: Protein kinase C beta (PKCβ), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses

  11. A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma

    NARCIS (Netherlands)

    Morschhauser, F.; Seymour, J. F.; Kluin-Nelemans, H. C.; Grigg, A.; Wolf, M.; Pfreundschuh, M.; Tilly, H.; Raemaekers, J.; van 't Veer, M. B.; Milpied, N.; Cartron, G.; Pezzutto, A.; Spencer, A.; Reyes, F.; Dreyling, M.

    2008-01-01

    Background: Protein kinase C beta (PKC beta), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signali

  12. MHC-I-induced apoptosis in human B-lymphoma cells is dependent on protein tyrosine and serine/threonine kinases

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Bregenholt, S; Johansen, B;

    1999-01-01

    B lymphoma cells, is dependent on protein tyrosine kinases and the phosphatidylinositol 3 (PI-3) kinase. Functional studies showed that MHC-I crosslinking induced almost complete inhibition of the spontaneous proliferation of the B lymphoma cells as early as 6 h post-crosslinking and apoptosis 24 h...... post-crosslinking. Preincubation with either protein tyrosine kinase or protein serine/threonine kinase inhibitors reduced the MHC-I-induced apoptosis to background levels, whereas inhibition of PI-3 kinase had no effect. These data demonstrate a pivotal role for protein tyrosine and serine....../threonine kinases in MHC-I-mediated apoptosis in human B-cells and suggest the presence of several MHC-I signaling pathways leading to diverse effects in these cells....

  13. PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.

    Science.gov (United States)

    Laimer, Daniela; Dolznig, Helmut; Kollmann, Karoline; Vesely, Paul W; Schlederer, Michaela; Merkel, Olaf; Schiefer, Ana-Iris; Hassler, Melanie R; Heider, Susi; Amenitsch, Lena; Thallinger, Christiane; Staber, Philipp B; Simonitsch-Klupp, Ingrid; Artaker, Matthias; Lagger, Sabine; Turner, Suzanne D; Pileri, Stefano; Piccaluga, Pier Paolo; Valent, Peter; Messana, Katia; Landra, Indira; Weichhart, Thomas; Knapp, Sylvia; Shehata, Medhat; Todaro, Maria; Sexl, Veronika; Höfler, Gerald; Piva, Roberto; Medico, Enzo; Ruggeri, Bruce A; Cheng, Mangeng; Eferl, Robert; Egger, Gerda; Penninger, Josef M; Jaeger, Ulrich; Moriggl, Richard; Inghirami, Giorgio; Kenner, Lukas

    2012-11-01

    Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.

  14. Deltex1 promotes protein kinase Cθ degradation and sustains Casitas B-lineage lymphoma expression.

    Science.gov (United States)

    Hsu, Tzu-Sheng; Hsiao, Huey-Wen; Wu, Pei-Jung; Liu, Wen-Hsien; Lai, Ming-Zong

    2014-08-15

    The generation of T cell anergy is associated with upregulation of ubiquitin E3 ligases including Casitas B-lineage lymphoma (Cbl-b), Itch, gene related to anergy in lymphocyte, and deltex1 (DTX1). These E3 ligases attenuate T cell activation by targeting to signaling molecules. For example, Cbl-b and Itch promote the degradation of protein kinase Cθ (PKCθ) and phospholipase C-γ1 (PLC-γ1) in anergic Th1 cells. How these anergy-associated E3 ligases coordinate during T cell anergy remains largely unknown. In the current study, we found that PKCθ and PLC-γ1 are also downregulated by DTX1. DTX1 interacted with PKCθ and PLC-γ1 and stimulated the degradation of PKCθ and PLC-γ1. T cell anergy-induced proteolysis of PKCθ was prevented in Dtx1(-/-) T cells, supporting the essential role of DTX1 in PKCθ downregulation. Similar to Cbl-b and Itch, DTX1 promoted monoubiquitination of PKCθ. Proteasome inhibitor did not inhibit DTX1-directed PKCθ degradation, but instead DTX1 directed the relocalization of PKCθ into the lysosomal pathway. In addition, DTX1 interacted with Cbl-b and increased the protein levels of Cbl-b. We further demonstrated the possibility that, through the downregulation of PKCθ, DTX1 prevented PKCθ-induced Cbl-b degradation and increased Cbl-b protein stability. Our results suggest the coordination between E3 ligases during T cell anergy; DTX1 acts with Cbl-b to assure a more extensive silencing of PKCθ, whereas DTX1-mediated PKCθ degradation further stabilizes Cbl-b.

  15. Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

    Science.gov (United States)

    2016-06-27

    Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Waldenström Macroglobulinemia

  16. Malignant lymphoma and the thyroid gland

    Energy Technology Data Exchange (ETDEWEB)

    Becker, W.; Reiners, C.; Boerner, W.; Mueller, H.A.; Wuensch, P.H.; Schaeffer, R.; Gunzer, U.

    1983-04-01

    Among 4325 goiter patients first examined in the period from February 1980 to April 1982, 5 cases of lymphoma appearing primarily in the thyroid gland were discovered incidentally. During the same period 13 patients with anaplastic thyroid carcinoma were observed. 5 of 23 systematically examined patients who had already known extrahyroidal malignant non-Hodgkin's lymphomas and lymphoma patient examined by chance exhibited a secondary thyroid gland lymphoma, that is, a secondary infiltration of the enlarged thyroid. Altogether, 29 patients with malignant non-Hodgkin's lymphoma (Kiel classification) were examined. Of 8 Hodgkin's disease patients none showed clinical or cytological evidence of thyroid infiltration. The clinical symptoms of primary lymphoma of the thyroid gland corresponded to those of anaplastic thyroid carcinoma. A positive differential diagnosis of the two tumours succeeded cytologically. The secondary lymphoma of the thyroid also could only be diagnosed cytologically. Patients with Hodgkin's lymphoma and non-Hodgkin's lymphoma were always found to be euthyroid. Autoimmunological phenomena (antimicrosomal and antithyreoglobulin autoantibodies) as an indicator of lymphocytic thyroiditis could only be examined among 11 patients. Two patients with secondary lymphoma of the thyroid showed positive titers. A small cell anaplastic thyroid carcinoma could not be diagnosed in any of 37 patients with anaplastic thyroid cancer out of an enlarged patient collective (period under consideration: 1976-1982).

  17. 皮肤原发性CD30阳性间变性大细胞淋巴瘤%Primary cutaneous CD30-positive anaplastic large cell lymphoma analysis

    Institute of Scientific and Technical Information of China (English)

    石群立; 周晓军; 燕晓雯; 印洪林; 徐新宇; 张彤; 社本擀博; 钱斌

    2002-01-01

    目的对10例皮肤原发性CD30阳性间变性大细胞淋巴瘤(ALCL)进行临床及组织病理学研究,为临床病理早期诊断提供依据.方法采用组织病理学及免疫组织化学法(LCA、 CD20、CD30、CD45RO、CD68、EMA、CK和HMB45)对10例皮肤原发性CD30阳性ALCL进行观察.结果组织病理学示瘤细胞体积大,呈多形性、圆形或椭圆形,胞浆丰富,核大,核分裂像多,常见R-S样细胞和多核巨细胞,核仁明显.免疫组化标记CD30 阳性,其中6例同时表达CD45RO, 1例表达CD20,非T非B表达3例.随访发现2例因肿瘤转移死亡,2例复发,6例无复发.结论皮肤原发性CD30阳性ALCL是具有独特形态特点且预后较好的肿瘤.组织病理学特征及CD30阳性在鉴别诊断时具有重要意义.%Objective To examine 10 cases with primary cutaneous CD30-positive anaplastic large cell lymphoma (ALCL), analyze their clinical manifestations and pathological and immunohistochemical features, and improve early diagnosis of this disease. Methods We studied the morphological characteristics of primary cutaneous CD30-positive ALCL using histopathological methods. Leukocyte common antigen (LCA), CD20, CD30, CD45RO, CD68, epithelial membrane antigen (EMA), cytokeratin (CK) and HMB45 antibodies were used to determine the expression of their respective antigens from routine paraffin samples of the patients. Results Ten patients (7 men and 3 women, aged 31 to 84 years) complained of subcutaneous masses or papular eruptions over their lower trunks and extremities. Histopathologically, the lesions were composed of numerous large round or oval pleomorphic cells. The cytoplasm was usually abundant, amphophilic or basophilic, and finely vacuolated. Nuclei were commonly eccentrically localized and lobated or horseshoed in shape, and multinucleated giant cells and Reed-Sternberg-like cells were seen. Nucleoli were generally multiple and large. Of the 10 patients, tumor cells displayed positive antigen

  18. Genetically Modified Peripheral Blood Stem Cell Transplant in Treating Patients With HIV-Associated Non-Hodgkin or Hodgkin Lymphoma

    Science.gov (United States)

    2015-05-06

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Small Noncleaved Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I AIDS-related Lymphoma; Stage II AIDS-related Lymphoma; Stage III AIDS-related Lymphoma; Stage IV AIDS-related Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  19. NPM-ALK: The Prototypic Member of a Family of Oncogenic Fusion Tyrosine Kinases

    Directory of Open Access Journals (Sweden)

    Joel D. Pearson

    2012-01-01

    Full Text Available Anaplastic lymphoma kinase (ALK was first identified in 1994 with the discovery that the gene encoding for this kinase was involved in the t(2;5(p23;q35 chromosomal translocation observed in a subset of anaplastic large cell lymphoma (ALCL. The NPM-ALK fusion protein generated by this translocation is a constitutively active tyrosine kinase, and much research has focused on characterizing the signalling pathways and cellular activities this oncoprotein regulates in ALCL. We now know about the existence of nearly 20 distinct ALK translocation partners, and the fusion proteins resulting from these translocations play a critical role in the pathogenesis of a variety of cancers including subsets of large B-cell lymphomas, nonsmall cell lung carcinomas, and inflammatory myofibroblastic tumours. Moreover, the inhibition of ALK has been shown to be an effective treatment strategy in some of these malignancies. In this paper we will highlight malignancies where ALK translocations have been identified and discuss why ALK fusion proteins are constitutively active tyrosine kinases. Finally, using ALCL as an example, we will examine three key signalling pathways activated by NPM-ALK that contribute to proliferation and survival in ALCL.

  20. 506U78 in Treating Patients With Lymphoma

    Science.gov (United States)

    2013-01-15

    Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Small Intestine Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome

  1. MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells.

    Science.gov (United States)

    Mukherjee, P; Tinder, T L; Basu, G D; Gendler, S J

    2005-01-01

    MUC1 (CD227) is a large transmembrane epithelial mucin glycoprotein, which is aberrantly overexpressed in most adenocarcinomas and is a target for immune therapy for epithelial tumors. Recently, MUC1 has been detected in a variety of hematopoietic cell malignancies including T and B cell lymphomas and myelomas; however, its function in these cells is not clearly defined. Using the Jurkat T cell lymphoma cell line and normal human T cells, we demonstrate that MUC1 is not only expressed in these cells but is also phosphorylated upon T cell receptor (TCR) ligation and associates with the Src-related T cell tyrosine kinase, p56lck. Upon TCR-mediated activation of Jurkat cells, MUC1 is found in the low-density membrane fractions, where linker of T cell activation is contained. Abrogation of MUC1 expression in Jurkat cells by MUC1-specific small interfering RNA resulted in defects in TCR-mediated downstream signaling events associated with T cell activation. These include reduction in Ca2+ influx and extracellular signal-regulated kinase 1/2 phosphorylation, leading to a decrease in CD69 expression, proliferation, and interleukin-2 production. These results suggest a regulatory role of MUC1 in modulating proximal signal transduction events through its interaction with proteins of the activation complex.

  2. Dose Monitoring of Busulfan and Combination Chemotherapy in Hodgkin or Non-Hodgkin Lymphoma Undergoing Stem Cell Transplant

    Science.gov (United States)

    2015-08-12

    Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult

  3. Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

    Science.gov (United States)

    2016-07-12

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  4. Successful treatment of hepatic oligometastases with stereotactic ablative radiotherapy and radiofrequency ablation in an anaplastic lymphoma kinase fusion-positive lung cancer patient

    DEFF Research Database (Denmark)

    Weber, Britta; Liu, Mitchell; Sobkin, Paul;

    2016-01-01

    Local ablative therapy with stereotactic ablative radiotherapy may improve survival in oncogene‐addicted lung cancer patients with extracranial oligometastatic disease treated with targeted therapies. There is limited data on the use of radiofrequency ablation (RFA) in this same setting. We present...

  5. Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1.

    Directory of Open Access Journals (Sweden)

    Sharmila Mallya

    Full Text Available Inhibitors of the mechanistic target of rapamycin (mTOR hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive "active-site" mTOR inhibitors produce more complete mTOR inhibition and are more effective than rapamycin in preclinical models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials of active-site mTOR inhibitors, it will be important to identify resistance mechanisms that might limit drug efficacy in certain patients. From a panel of diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is particularly resistant to apoptosis in the presence of active-site mTOR inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic initiation factor 4E-binding protein-1 (4EBP1, a key negative regulator of translation controlled by mTOR. Although VAL cells express the related protein 4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with active-site mTOR inhibitors. These findings provide a naturally occurring example of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR inhibitors.

  6. Phorbol esters, but not the hormonal form of vitamin D, induce changes in protein kinase C during differentiation of human histiocytic lymphoma cell line (U-937)

    Energy Technology Data Exchange (ETDEWEB)

    Mezzetti, G.; Bagnara, G.P.; Monti, M.G.; Casolo, L.P.; Bonsi, l.; Brunelli, M.A.

    1987-05-25

    Human histiocytic lymphoma cells (U-937) undergo similar differentiation when incubated with the phorbol ester 12-0-tetradecanoyl phorbol-13-acetate (TPA) and 1,25-dihydroxycholecalciferol. In this action, TPA somehow implicates calcium-sensitive and phospholipid-dependent protein kinase (protein kinase C), which is rapidly and significantly affected by this inducer. On the contrary, 1,25-dihydroxy-cholecalciferol in its differentiating action does not involve protein kinase C thus suggesting that the secosteroid induces monocytic differentiation possibly through a different mechanism of that of phorbol ester. 13 references, 2 figures, 1 table.

  7. FAU in Treating Patients With Advanced Solid Tumors or Lymphoma

    Science.gov (United States)

    2014-01-06

    Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell

  8. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas

    Science.gov (United States)

    Palomero, Teresa; Couronné, Lucile; Khiabanian, Hossein; Kim, Mi-Yeon; Ambesi-Impiombato, Alberto; Perez-Garcia, Arianne; Carpenter, Zachary; Abate, Francesco; Allegretta, Maddalena; Haydu, J. Erika; Jiang, Xiaoyu; Lossos, Izidore S.; Nicolas, Concha; Balbin, Milagros; Bastard, Christian; Bhagat, Govind; Piris, Miguel Angel; Campo, Elias; Bernard, Olivier; Rabadan, Raul; Ferrando, Adolfo

    2014-01-01

    Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non Hodgkin lymphomas1,2. Here we combined whole exome sequencing of 12 tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA p.Gly17Val (NM_001664) mutation present in 22/35 (67%) of angioimmunoblastic T-cell lymphomas (AITL) and in 8/44 (18%) not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated Guanine Exchange Factor (GEF) proteins. In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL. PMID:24413734

  9. Protein tyrosine kinases p53/56lyn and p72syk in MHC class I-mediated signal transduction in B lymphoma cells

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Bregenholt, S; Skov, S;

    1998-01-01

    Crosslinking of major histocompatibility complex class I (MHC-I) molecules on the surface of human B lymphoma cells was shown to induce protein tyrosine phosphorylation and mobilization of intracellular free calcium. Immunoprecipitations indicated that the protein tyrosine kinases p53/56lyn and p72......syk are among the tyrosine-phosphorylated proteins. The kinetics of phosphorylation of these kinases after MHC-I crosslinking differ from the kinetics observed after crosslinking of the B cell antigen receptor (BCR). Additional experiments were performed with chicken lyn- and syk-negative DT40 B cells...... and the results indicate that these two kinases have different substrate specificity and regulate intracellular free calcium differently in response to MHC-I crosslinking. In addition MHC-I crosslinking of a sIgM-negative DT40 chicken B cell variant results in less activity of tyrosine kinases and less...

  10. Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas.

    Science.gov (United States)

    Naylor, Tara L; Tang, Huaping; Ratsch, Boris A; Enns, Andreas; Loo, Alice; Chen, Liqing; Lenz, Peter; Waters, Nigel J; Schuler, Walter; Dörken, Bernd; Yao, Yung-Mae; Warmuth, Markus; Lenz, Georg; Stegmeier, Frank

    2011-04-01

    The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-κB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-κB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-κB pathway inhibition and were mediated by induction of G₁-phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities.

  11. Pediatric lymphomas in Brazil

    Directory of Open Access Journals (Sweden)

    Gabriela Gualco

    2010-01-01

    Full Text Available OBJECTIVE: This study provides the clinical pathological characteristics of 1301 cases of pediatric/adolescent lymphomas in patients from different geographic regions of Brazil. METHODS: A retrospective analyses of diagnosed pediatric lymphoma cases in a 10-year period was performed. We believe that it represents the largest series of pediatric lymphomas presented from Brazil. RESULTS: Non-Hodgkin lymphomas represented 68% of the cases, including those of precursor (36% and mature (64% cell origin. Mature cell lymphomas comprised 81% of the B-cell phenotype and 19% of the T-cell phenotype. Hodgkin lymphomas represented 32% of all cases, including 87% of the classical type and 13% of nodular lymphocyte predominant type. The geographic distribution showed 38.4% of the cases in the Southeast region, 28.7% in the Northeast, 16.1% in the South, 8.8% in the North, and 8% in the Central-west region. The distribution by age groups was 15-18 years old, 33%; 11-14 years old, 26%; 6-10 years old, 24%; and 6 years old or younger, 17%. Among mature B-cell lymphomas, most of the cases were Burkitt lymphomas (65%, followed by diffuse large B-cell lymphomas (24%. In the mature T-cell group, anaplastic large cell lymphoma, ALK-positive was the most prevalent (57%, followed by peripheral T-cell lymphoma, then not otherwise specified (25%. In the group of classic Hodgkin lymphomas, the main histological subtype was nodular sclerosis (76%. Nodular lymphocyte predominance occurred more frequently than in other series. CONCLUSION: Some of the results found in this study may reflect the heterogeneous socioeconomical status and environmental factors of the Brazilian population in different regions.

  12. Patients harboring EGFR mutation after primary resistance to crizotinib and response to EGFR-tyrosine kinase inhibitor

    Directory of Open Access Journals (Sweden)

    Wang WX

    2016-01-01

    Full Text Available Wenxian Wang,1 Xiaowen Jiang,1 Zhengbo Song,1,2 Yiping Zhang1,2 1Department of Chemotherapy, Zhejiang Cancer Hospital, 2Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou, Zhejiang, People’s Republic of China Abstract: Anaplastic lymphoma kinase (ALK rearrangement lung cancer responds to ALK tyrosine kinase inhibitors. It is known that many cases ultimately acquired resistance to crizotinib. However, a case of primary resistance is rare. We present a case of harboring exon 19 deletion in epidermal growth factor receptor in ALK rearranged lung adenocarcinoma, who experienced a partial tumor response to icotinib after failure with crizotinib therapy and chemotherapy. Considering the partial response, we conclude that it is important to find the cause of resistance to crizotinib. We detected gene mutations with plasma by the next-generation sequencing; the next-generation sequencing demonstrates an attractive system to identify mutations improving the outcome of patients with a deadly disease. Keywords: non-small cell lung cancer, anaplastic lymphoma kinase, crizotinib, epidermal growth factor receptor

  13. The NPM-ALK tyrosine kinase mimics TCR signalling pathways, inducing NFAT and AP-1 by RAS-dependent mechanisms.

    Science.gov (United States)

    Turner, Suzanne D; Yeung, Debra; Hadfield, Kathryn; Cook, Simon J; Alexander, Denis R

    2007-04-01

    Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expression is associated with the lymphoid malignancy anaplastic large cell lymphoma (ALCL) and results from a t(2;5) chromosomal translocation. We show that NPM-ALK induces Ras activation and phosphorylation of the ERK MAP Kinase consistent with activation of the Ras-MAP Kinase pathway. Furthermore, we demonstrate that activation of Ras is necessary for inducing transcription via NFAT/AP-1 composite transcriptional binding sites. This activity is dependent on NPM-ALK forming complexes with proteins that bind to autophosphorylated tyrosine residues at positions 156, 567 and 664, associated with binding to IRS-1, Shc and PLCgamma, respectively. Specifically, NPM-ALK activates transcription from the TRE promoter element, an AP-1 binding region, an activity dependent on both Ras and Shc activity. Our results show that NPM-ALK mimics activated T-cell receptor signalling by inducing pathways associated with the activation of NFAT/AP-1 transcription factors that bind to promoter elements found in a broad array of cytokine genes.

  14. A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK.

    Science.gov (United States)

    Fawal, Mohamad; Armstrong, Florence; Ollier, Severine; Dupont, Henri; Touriol, Christian; Monsarrat, Bernard; Delsol, Georges; Payrastre, Bernard; Morello, Dominique

    2006-10-15

    Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a chimeric protein expressed in a subset of cases of anaplastic large cell lymphoma (ALCL) for which constitutive expression represents a key oncogenic event. The ALK signaling pathway is complex and probably involves functional redundancy between various signaling substrates of ALK. Despite numerous studies on signaling mediators, the molecular mechanisms contributing to the distinct oncogenic features of NPM-ALK remain incompletely understood. The search for additional interacting partners of NPM-ALK led to the discovery of AUF1/hnRNPD, a protein implicated in AU-rich element (ARE)-directed mRNA decay. AUF1 was immunoprecipitated with ALK both in ALCL-derived cells and in NIH3T3 cells stably expressing NPM-ALK or other X-ALK fusion proteins. AUF1 and NPM-ALK were found concentrated in the same cytoplasmic foci, whose formation required NPM-ALK tyrosine kinase activity. AUF1 was phosphorylated by ALK in vitro and was hyperphosphorylated in NPM-ALK-expressing cells. Its hyperphosphorylation was correlated with increased stability of several AUF1 target mRNAs encoding key regulators of cell proliferation and with increased cell survival after transcriptional arrest. Thus, AUF1 could function in a novel pathway mediating the oncogenic effects of NPM-ALK. Our data establish an important link between oncogenic kinases and mRNA turnover, which could constitute a critical aspect of tumorigenesis.

  15. Extraneural metastases in anaplastic ependymoma

    Directory of Open Access Journals (Sweden)

    Kumar Pavan

    2007-01-01

    Full Text Available Ependymoma are rare glial neoplasm, it rarely metastasize outside the central nervous system. We present a case of anaplastic ependymoma with extraneural metastases with review of literature. A ten-year-old male child presented with anaplastic ependymoma of choroid plexus and treated with craniospinal radiotherapy in 1998. He had intracranial recurrence in 2004, confirmed by biopsy. He was given adjuvant chemotherapy in form of PCV. At 10 months after completion of chemotherapy, he developed extracranial scalp metastasis and so was treated with palliative local radiation therapy to the scalp metastasis and systemic chemotherapy with oral Etoposide. Scalp metastasis completely disappeared and ataxia improved. After five cycles of chemotherapy, the patient had progression of disease in form of scalp and cervical lymph node metastasis confirmed by fine needle aspiration cytology, biopsy and immunohistochemistry. He was given salvage chemotherapy (carboplatin + ifosfamide + etoposide at 3-weekly. He had partial response and was still on chemotherapy till May 2007.

  16. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.

    Science.gov (United States)

    Pizzi, Marco; Piazza, Francesco; Agostinelli, Claudio; Fuligni, Fabio; Benvenuti, Pietro; Mandato, Elisa; Casellato, Alessandro; Rugge, Massimo; Semenzato, Gianpietro; Pileri, Stefano A

    2015-03-30

    Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.

  17. CD30-positive cutaneous lymphoma: report of four cases with an emphasis on clinicopathological correlations*

    Science.gov (United States)

    Vargas, Thiago Jeunon de Sousa; Jorge, Samira Barroso; Gonzaga, Yung Bruno de Mello

    2017-01-01

    The classification of cutaneous lymphomas is multidisciplinary and requires the correlation between clinical, histopathological, immunohistochemical, and molecular diagnostic elements. In this article, we present four different cases of CD30-positive T-cell lymphoma with cutaneous manifestations. We compare cases with definitive diagnosis of papulosis lymphomatoid type C, primary cutaneous anaplastic large T-cell lymphoma, systemic anaplastic large T-cell lymphoma with secondary skin involvement, and mycosis fungoides with large cell transformation, highlighting the importance of clinicopathological correlation to classify these cases. PMID:28225962

  18. Bortezomib and Fenretinide Induce Synergistic Cytotoxicity in Mantle Cell Lymphoma Via Apoptosis, Cell Cycle Dysregulation, and IκBα Kinase Down-regulation

    Science.gov (United States)

    Cowan, Andrew J.; Frayo, Shani L.; Press, Oliver W.; Palanca-Wessels, Maria C.; Pagel, John M.; Green, Damian J.; Gopal, Ajay K.

    2015-01-01

    Background Mantle cell lymphoma (MCL) remains incurable for most patients and proteasome inhibitors like bortezomib induce responses in a minority of patients with relapsed disease. Fenretinide is a retinoid that has shown preclinical activity in B-cell lymphomas. We hypothesized that these agents could yield augmented anti-tumor activity. Methods Mantle cell lymphoma lines (Granta-519, Jeko-1, Rec-1) were treated with escalating concentrations of bortezomib and fenretinide singly and in combination. Cytotoxicity was assessed using the MTT assay. Flow cytometric methods assessed apoptosis and necrosis with annexin V-FITC/propidium iodide and G1 and G2 cell cycle changes with DAPI staining. Changes in Cyclin D1, Cyclin B, IκBα, and IKKα expression were quantified by Western blot. Results Cytotoxicity was mediated via apoptosis; both agents showed observed vs expected cytotoxicity in Granta-519 of 92.2% vs 55.1%, in Jeko-1 of 87.6% vs 36.3%, and in Rec-1 of 63.2% vs 29.8%. Isobolographic analysis confirmed synergy in Jeko-1 and Rec-1. Bortezomib induced G2 phase arrest with a 1.7 fold-increase over control, and fenretinide resulted in G1 phase arrest, with an increase of 1.3 fold over control. In combination G2 phase arrest predominated, with a 1.4 fold-increase compared to control, and reduced expression of Cyclin D1 to 24%, Cyclin B to 52% and 64%, Cyclin D3 to 25% and 43%, IκBα to 23% and 46%, and IκBα kinase to 34% and 44%. Conclusions Bortezomib and fenretinide exhibit synergistic cytotoxicity against MCL cell lines. This activity is mediated by IκBα kinase modulation, decreased cyclin expression, cell cycle dysregulation, and apoptotic cell death. PMID:26237500

  19. Etoposide, Filgrastim, and Plerixafor in Improving Stem Cell Mobilization in Treating Patients With Non-Hodgkin Lymphoma

    Science.gov (United States)

    2016-09-15

    Adult Acute Lymphoblastic Leukemia in Remission; Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  20. Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV)+ B cell lymphomas.

    Science.gov (United States)

    Hatton, Olivia; Lambert, Stacie L; Krams, Sheri M; Martinez, Olivia M

    2012-01-01

    The B lymphotrophic γ-herpesvirus EBV is associated with a variety of lymphoid- and epithelial-derived malignancies, including B cell lymphomas in immunocompromised and immunosuppressed individuals. The primary oncogene of EBV, latent membrane protein 1 (LMP1), activates the PI3K/Akt pathway to induce the autocrine growth factor, IL-10, in EBV-infected B cells, but the mechanisms underlying PI3K activation remain incompletely understood. Using small molecule inhibition and siRNA strategies in human B cell lines expressing a chimeric, signaling-inducible LMP1 protein, nerve growth factor receptor (NGFR)-LMP1, we show that NGFR-LMP1 utilizes Syk to activate PI3K/Akt signaling and induce IL-10 production. NGFR-LMP1 signaling induces phosphorylation of BLNK, a marker of Syk activation. Whereas Src kinases are often required for Syk activation, we show here that PI3K/Akt activation and autocrine IL-10 production by NGFR-LMP1 involves the Src family kinase Fyn. Finally, we demonstrate that NGFR-LMP1 induces phosphorylation of c-Cbl in a Syk- and Fyn-dependent fashion. Our results indicate that the EBV protein LMP1, which lacks the canonical ITAM required for Syk activation, can nevertheless activate Syk, and the Src kinase Fyn, resulting in downstream c-Cbl and PI3K/Akt activation. Fyn, Syk, and PI3K/Akt antagonists thus may present potential new therapeutic strategies that target the oncogene LMP1 for treatment of EBV+ B cell lymphomas.

  1. Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV+ B cell lymphomas.

    Directory of Open Access Journals (Sweden)

    Olivia Hatton

    Full Text Available The B lymphotrophic γ-herpesvirus EBV is associated with a variety of lymphoid- and epithelial-derived malignancies, including B cell lymphomas in immunocompromised and immunosuppressed individuals. The primary oncogene of EBV, latent membrane protein 1 (LMP1, activates the PI3K/Akt pathway to induce the autocrine growth factor, IL-10, in EBV-infected B cells, but the mechanisms underlying PI3K activation remain incompletely understood. Using small molecule inhibition and siRNA strategies in human B cell lines expressing a chimeric, signaling-inducible LMP1 protein, nerve growth factor receptor (NGFR-LMP1, we show that NGFR-LMP1 utilizes Syk to activate PI3K/Akt signaling and induce IL-10 production. NGFR-LMP1 signaling induces phosphorylation of BLNK, a marker of Syk activation. Whereas Src kinases are often required for Syk activation, we show here that PI3K/Akt activation and autocrine IL-10 production by NGFR-LMP1 involves the Src family kinase Fyn. Finally, we demonstrate that NGFR-LMP1 induces phosphorylation of c-Cbl in a Syk- and Fyn-dependent fashion. Our results indicate that the EBV protein LMP1, which lacks the canonical ITAM required for Syk activation, can nevertheless activate Syk, and the Src kinase Fyn, resulting in downstream c-Cbl and PI3K/Akt activation. Fyn, Syk, and PI3K/Akt antagonists thus may present potential new therapeutic strategies that target the oncogene LMP1 for treatment of EBV+ B cell lymphomas.

  2. RNAi阻断NPM-ALK基因表达及对大细胞间变性淋巴瘤细胞的影响%Effects of RNA interference on NPM-ALK fusion gene expression in anaplastic large-cell lymphoma cells

    Institute of Scientific and Technical Information of China (English)

    赵艳霞; 顾龙君; 叶启东; 赵金彩

    2005-01-01

    目的应用RNA干扰技术抑制大细胞间变性淋巴瘤细胞系(Karpas299)中NPM-ALK融合基因表达,观察其对肿瘤细胞生长的影响.方法针对NPM-ALK融合位点设计两个siRNA序列siRNA-I与siRNA-II, 经PCR反应构建含U6启动子siRNA正义和反义线性表达载体,通过脂质体转染Karpas299细胞,应用实时荧光定量RT-PCR、Western blot检测siRNA片段对NPM-ALK mRNA和蛋白表达的抑制作用,MTT、Hoechst荧光染色检测siRNA对肿瘤细胞生长的影响.结果 siRNA-I可导致NPM-ALK mRNA下降约75%(P<0.05),转染72 h后可导致蛋白表达下降;转染siRNA-II细胞NPM-ALK mRNA下降为35%(P<0.05),但蛋白水平无明显改变.转染siRNA-I的细胞可抑制Karpas299细胞的增殖和诱导凋亡发生,siRNA-II则无明显的抑制增殖和诱导凋亡作用.结论含有针对NPM-ALK融合位点特异siRNA序列 的U6表达载体,可特异地抑制NPM-ALK基因mRNA和蛋白的表达,并能抑制大细胞间变性淋巴瘤肿瘤细胞株Karpas299细胞的增殖,导致肿瘤细胞凋亡增加,提示NPM-ALK融合基因的异常表达与大细胞间变性淋巴瘤形成密切相关,为研究NPM-ALK基因功能和大细胞间变性淋巴瘤基因靶向治疗提供了新策略.%Objective To evaluate two small interfering RNAs (siRNAs) on the NPM-ALK fusion gene expression in anaplastic large-cell lymphoma cell line Karpas299, and to study the effect of RNA interference on Karpas299 cells proliferation. Methods Two siRNAs sequences (siRNA- I and siRNA-II) were designed to target the NPM-ALK fusion site in anaplastic large-cell lymphoma cell line Karpas299. An siRNA U6 expression system including U6 RNA-based polymerase III promoter was set up. The two siRNAs designed for down-regulation of the NPM-ALK fusion mRNA were transfected into Karpas299 cells by liposomal transfection reagents. The effect of RNAi on NPM-ALK mRNA expression was detected by real-time RT-PCR and Western blot. The anti-proliferative effects of the si

  3. [Gene expression profiling by suppression subtractive hybridization (SSH): a example for its application to the study of lymphomas].

    Science.gov (United States)

    Villalva, C; Trempat, P; Zenou, R C; Delsol, G; Brousset, P

    2001-03-01

    Suppression subtractive hybridization (SSH) was used to isolate genes that were differentially expressed in anaplastic lymphoma kinase (ALK)-positive and ALK-negative anaplastic large cell lymphoma. In addition, this approach was applied to Hodgkin's disease cases with different clinical outcomes. SSH combines a normalization step that equalizes the abundance of cDNAs within the sequences to be tested and a subtraction step that excludes the common sequences between the target and the control. In a model system, the SSH technique enriches for rare sequences up to 5,000-fold in one round. We have isolated several genes whose expression varied significantly with regard to the tumour subtypes. There were different genes with known or unknown functions. We aim to compare the results of the SSH approach with those obtained with high density filters. In a near future, we would like to design DNA chips specific of each pathology that could be used for clinical purposes (evaluation of prognosis and therapeutic response).

  4. ABNORMAL PROTEIN TYROSINE KINASES ASSOCIATED WITH HUMAN HAEMATOLOGICAL MALIGNANCIES

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoproteins and their causative role in some leukemias and lymphomas. Results: Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiations. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) plays an etiologic role in several clonal hematopoietic malignancies. For example, the PTK product of the BCR-ABL fusion gene resulting from the t (9; 22) translocation exhibits several fold higher tyrosine kinase activity than the product of the ABL gene. Evidence suggests that the BCR-ABL oncoprotein alone is sufficient to case chronic myelogenous leukemia (CML) and other Ph positive acute leukemia. PTK over-activity resulting from chromosomal translocations creating TEL-ABL, TEL-JAK2 and TEL-PDGFR( fusion proteins plays an important role in the pathogenesis of other types of leukemia. Another example occurs in anaplastic large cell lymphoma (ALCL). Experimental and clinical evidences indicate that translocations involving ALK gene on chromosome 2p23, most commonly resulting in an NPM-ALK fusion oncogene, result in constitutive activation of ALK and cause ALCL. This group of lymphomas is now named ALK positive lymphoma or ALKoma. Conclusion: Genetic lesions creating aberrant fusion proteins that result in excessive PTK activity are increasingly being recognized as central to the pathogenesis of hemotopoietic malignancies. These chimeric PTK molecules represent attractive disease-specific targets against which new classes therapeutic agents are being developed.

  5. Combined Modality Treatment for PET-Positive Non-Hodgkin Lymphoma: Favorable Outcomes of Combined Modality Treatment for Patients With Non-Hodgkin Lymphoma and Positive Interim or Postchemotherapy FDG-PET

    Energy Technology Data Exchange (ETDEWEB)

    Halasz, Lia M. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Jacene, Heather A. [Department of Imaging, Dana-Farber Cancer Institute, and Department of Radiology, Brigham and Women' s Hospital, Boston, Massachusetts (United States); Catalano, Paul J. [Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Van den Abbeele, Annick D. [Department of Imaging, Dana-Farber Cancer Institute, and Department of Radiology, Brigham and Women' s Hospital, Boston, Massachusetts (United States); LaCasce, Ann [Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Mauch, Peter M. [Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, Massachusetts (United States); Ng, Andrea K., E-mail: ang@lroc.harvard.edu [Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, Massachusetts (United States)

    2012-08-01

    Purpose: To evaluate outcomes of patients treated for aggressive non-Hodgkin lymphoma (NHL) with combined modality therapy based on [{sup 18}F]fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) response. Methods and Materials: We studied 59 patients with aggressive NHL, who received chemotherapy and radiation therapy (RT) from 2001 to 2008. Among them, 83% of patients had stage I/II disease. Patients with B-cell lymphoma received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-based chemotherapy, and 1 patient with anaplastic lymphoma kinase-negative anaplastic T-cell lymphoma received CHOP therapy. Interim and postchemotherapy FDG-PET or FDG-PET/computed tomography (CT) scans were performed for restaging. All patients received consolidated involved-field RT. Median RT dose was 36 Gy (range, 28.8-50 Gy). Progression-free survival (PFS) and local control (LC) rates were calculated with and without a negative interim or postchemotherapy FDG-PET scan. Results: Median follow-up was 46.5 months. Thirty-nine patients had negative FDG-PET results by the end of chemotherapy, including 12 patients who had a negative interim FDG-PET scan and no postchemotherapy PET. Twenty patients were FDG-PET-positive, including 7 patients with positive interim FDG-PET and no postchemotherapy FDG-PET scans. The 3-year actuarial PFS rates for patients with negative versus positive FDG-PET scans were 97% and 90%, respectively. The 3-year actuarial LC rates for patients with negative versus positive FDG-PET scans were 100% and 90%, respectively. Conclusions: Patients who had a positive interim or postchemotherapy FDG-PET had a PFS rate of 90% at 3 years after combined modality treatment, suggesting that a large proportion of these patients can be cured with consolidated RT.

  6. Anaplastic thyroid cancer, tumorigenesis and therapy.

    LENUS (Irish Health Repository)

    O'Neill, J P

    2010-03-01

    Anaplastic thyroid cancer (ATC) is a fatal endocrine malignancy. Current therapy fails to significantly improve survival. Recent insights into thyroid tumorigenesis, post-malignant dedifferentiation and mode of metastatic activity offer new therapeutic strategies.

  7. The importance of Notch signaling in peripheral T-cell lymphomas

    DEFF Research Database (Denmark)

    Kamstrup, Maria Rørbæk; Biskup, Edyta; Gjerdrum, Lise Mette Rahbek

    2014-01-01

    Peripheral T-cell lymphomas (PTLs) represent an area of high medical need. Previously, we demonstrated high expression of Notch, a known oncogene, in primary cutaneous anaplastic large cell lymphoma (ALCL). In this study, we performed immunohistochemical staining for Notch1 in lymph nodes from PT...

  8. Clinical significance of cyclin-dependent kinase inhibitor p27Kip1 expression and proliferation in non-Hodgkin's lymphoma

    DEFF Research Database (Denmark)

    Møller, Michael Boe; Skjødt, Karsten; Mortensen, Leif Spange;

    1999-01-01

    between p27Kip1 and Ki-67 expression. Low expression of p27Kip1, defined as nuclear p27Kip1 expression in ... expression tended to do better. Likewise, a high proliferation rate (Ki-67 >40%) was associated with poor survival in indolent and aggressive lymphomas. Multivariate analysis using the proportional hazards model showed that only p27Kip1, and not Ki-67, maintained independent prognostic significance...

  9. Primary Cutaneous Lymphoma-Associated Pseudoepitheliomatous Hyperplasia Masquerading as Squamous Cell Carcinoma in a Young Adult.

    Science.gov (United States)

    Ansari, Mahsa; Azmoodeh Ardalan, Farid; Najafi, Masoumeh; Goodarzi, Azadeh; Ghanadan, Alireza

    2015-12-01

    Primary cutaneous anaplastic large cell lymphoma is a T-cell malignancy with atypical CD30 positive lymphocytes. Pseudoepitheliomatous hyperplasia is an uncommon finding in primary cutaneous anaplastic large cell lymphoma, and may mimic squamous cell carcinoma as pseudomalignancy. Careful attention of a pathologist to correct diagnosis of pseudoepitheliomatous hyperplasia and its underlying causes will help physicians to avoid inappropriate management. Here, we present a 22-year-old man referred to our hospital with a solitary nodule persistent on his forearm which was diagnosed as squamous cell carcinoma in the first biopsy. The lesion recurred after two months and histopathologic and immunohistochemistry examination revealed anaplastic large cell lymphoma with florid pseudoepitheliomatous hyperplasia which masquerading as well-differentiated squamous cell carcinoma. Diagnosis of pseudoepitheliomatous hyperplasia must guide the pathologist to search for underlying causes, such as primary cutaneous lymphoma. Pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma and this can result in inappropriate diagnosis and management.

  10. Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors.

    Science.gov (United States)

    Ceribelli, Michele; Kelly, Priscilla N; Shaffer, Arthur L; Wright, George W; Xiao, Wenming; Yang, Yibin; Mathews Griner, Lesley A; Guha, Rajarshi; Shinn, Paul; Keller, Jonathan M; Liu, Dongbo; Patel, Paresma R; Ferrer, Marc; Joshi, Shivangi; Nerle, Sujata; Sandy, Peter; Normant, Emmanuel; Thomas, Craig J; Staudt, Louis M

    2014-08-01

    In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-κB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IκB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-κB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.

  11. Pleomorphic xanthoastrocytoma with anaplastic features

    Directory of Open Access Journals (Sweden)

    Cheng ZHI

    2015-08-01

    Full Text Available Objective  To explore the clinical pathological characteristics, immunophenotyping, diagnosis and differential diagnosis and prognosis of pleomorphic xanthoastrocytoma (PXA with anaplastic features.  Methods  HE staining was used for histological observation. The expressions of glial fibrillary acidic protein (GFAP, vimentin (Vim, CD34, epithelial membrane antigen (EMA, progestrone receptor (PR, neurofilment protein (NF, neuronal nuclei (NeuN, synaptophysin (Syn, Nestin (Nes, S-100 protein (S-100, P53 and Ki-67 labeling index were detected by immunohistochemical method. BRAF mutation was detected by polymerase chain reaction (PCR amplification.  Results  A 43-year-old male patient presented with repeatedly paroxysmal tic of limbs and disturbance of consciousness. Cranial MRI revealed multiple abnormal signals in left temporo-occipito-parietal lobe and posterior horn of lateral ventricle, with unclear borderline and cystic degeneration. Surgical removal of the lesion was performed. Histologically, the tumor was biphasic. One part was composed of spindle cells arranged in fascicles or as running water, with weird multinuclear giant cells. Abundant vacuolated lipidized cytoplasm could be seen. Mitosis and "map"-like necrosis were noted. Another part revealed the tumor cells were consistent in size and uniform in distribution, with loose background tissue. Immunohistochemistry showed tumor cells were diffusely positive for GFAP, Vim, S-100, Nes, CD34 and P53, and negative for EMA, Syn, NeuN and NF. Ki-67 labeling index was about 15%. Reticular fiber staining showed abundant reticular fibers in the tumor tissue. BRAF mutation detected by PCR amplification was not found.  Conclusions  Classified as grade Ⅱ in the World Health Organization (WHO classification, the prognosis of PXA is good. A diagnosis of PXA with anaplastic features should be considered when the tumor demonstrates mitotic activity > 5/10 high power field (HPF and/or areas of

  12. Prognostic significance of the NPM-ALK fusion gene in bone marrow and peripheral blood for patients with anaplastic large cell lymphoma%间变性大细胞淋巴瘤患者骨髓及外周血NPM-ALK融合基因表达与预后的关系

    Institute of Scientific and Technical Information of China (English)

    杨菁; 赵晓曦; 金铃; 段彦龙; 黄爽; 张梦; 张蕊; 周春菊; 张永红

    2013-01-01

    Objective To investigate the expression of NPM-ALK fusion gene in bone marrow (BM) and peripheral blood (PB) in anaplastic large cell lymphoma (ALCL) patients and its prognostic significance.Methods NPM-ALK fusion gene of 21 BM and 15 PB samples from patients with NPMALK positive ALCL was detected by RT-PCR,and the relationship between NPM-ALK expression and prognosis and clinical characters was evaluated.Results Of the 21 patients,12 cases were male and 9 case were female with a median age of 9 (range,2-14) years old.The median follow-up was 31months.Patients with a positive NPM-ALK expression in BM had a 3-years EFS of (35.6± 18.6)%,compared with (91.7±8.0)% for patients with negative NPM-ALK (P=0.038).The incidence of positive expression in BM was significantly higher in patients who had more than 3 organs involved by tumor (P=0.032).86.7%patients had a concordant results of NPM-ALK expression in PB and BM.Conclusion We could evaluate the minimal disseminated disease of NPM-ALK positive ALCL patients by screening the NPM-ALK fusion gene in BM and PB by RT-PCR.The positive expression is associated with a poor prognosis and could be used for stratification of ALCL.%目的 探讨间变性大细胞淋巴瘤(ALCL)患者骨髓及外周血NPM-ALK融合基因的表达与预后的关系.方法 应用RT-PCR法检测21例ALCL患者骨髓(21份标本)及外周血(15份标本)细胞NPM-ALK融合基因的表达,并对其与患者的预后及临床特征之间的关系进行统计学分析.结果 21例患者中男12例,女9例,中位年龄9(2~14)岁.21例患者中位随访时间31个月.骨髓细胞NPM-ALK阳性患者3年无事件生存率为(35.6±18.6)%,阴性患者为(91.7士8.0)%,差异有统计学意义(P=0.038).患者骨髓细胞NPM-ALK阳性与其有3个以上器官受累(P=0.032)有相关性.86.7%的患者外周血与骨髓NPM-ALK检测结果一致.结论 通过RT-PCR法检测ALCL患者骨髓及外周血NPM-ALK融合基因表达,可以证实患者血

  13. The pathobiology of the oncogenic tyrosine kinase NPM-ALK: a brief update.

    Science.gov (United States)

    Lai, Raymond; Ingham, Robert J

    2013-04-01

    Extensive research has been carried out in the past two decades to study the pathobiology of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which is an oncogenic fusion protein found exclusively in a specific type of T-cell lymphoid malignancy, namely ALK-positive anaplastic large cell lymphoma. Results from these studies have provided highly useful insights into the mechanisms by which a constitutively tyrosine kinase, such as NPM-ALK, promotes tumorigenesis. Several previous publications have comprehensively summarized the advances in this field. In this review, we provide readers with a brief update on specific areas of NPM-ALK pathobiology. In the first part, the NPM-ALK/signal transducer and activator of transcription 3 (STAT3) signaling axis is discussed, with an emphasis on the existence of multiple biochemical defects that have been shown to amplify the oncogenic effects of this signaling axis. Specifically, findings regarding JAK3, SHP1 and the stimulatory effects of several cytokines including interleukin (IL)-9, IL-21 and IL-22 are summarized. New concepts stemming from recent observations regarding the functional interactions among the NPM-ALK/STAT3 axis, β catenin and glycogen synthase kinase 3β will be postulated. Lastly, new mechanisms by which the NPM-ALK/STAT3 axis promotes tumorigenesis, such as its modulations of Twist1, hypoxia-induced factor 1α, CD274, will be described. In the second part, we summarize recent data generated by mass spectrometry studies of NPM-ALK, and use MSH2 and heat shock proteins as examples to illustrate the use of mass spectrometry data in stimulating new research in this field. In the third part, the evolving field of microRNA in the context of NPM-ALK biology is discussed.

  14. Serine phosphorylation of NPM-ALK, which is dependent on the auto-activation of the kinase activation loop, contributes to its oncogenic potential.

    Science.gov (United States)

    Wang, Peng; Wu, Fang; Zhang, Jingdong; McMullen, Todd; Young, Leah C; Ingham, Robert J; Li, Liang; Lai, Raymond

    2011-02-01

    It is well established that the tumorigenic potential of nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK), an oncogenic tyrosine kinase, is dependent on its tyrosine phosphorylation. Using tandem affinity purification-mass spectrometry, we found evidence of phosphorylation of three serine residues of NPM-ALK (Serine¹³⁵, Serine¹⁶⁴ and Serine⁴⁹⁷) ectopically expressed in GP293 cells. Using a specific anti-phosphoserine antibody and immunoprecipitation, we confirmed the presence of serine phosphorylation of NPM-ALK in all three NPM-ALK-expressing cell lines examined. Similar to the tyrosine phosphorylation, phosphorylation of these serine residues was dependent on the activation status of the kinase activation loop of ALK. All of these three serine residues are biologically important as mutation of any one of these residues resulted in a significant reduction in the tumorigenicity of NPM-ALK (assessed by cell viability and clonogenic assay), which correlated with a substantial reduction in the phosphorylation of extracellular signal-regulated kinase 1/2, c-jun N-terminal kinase and signal transducer and activator of transcription 6. Serine phosphorylation of NPM-ALK appears to be regulated by multiple serine kinases since it was markedly reduced by pharmacologic inhibitors for glycogen synthase kinase-3, casein kinase I or mitogen-activated protein kinases. In summary, our study is the first to identify serine phosphorylation of NPM-ALK and to provide evidence that it enhances the tumorigenic potential of this oncogenic protein.

  15. Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

    Science.gov (United States)

    2015-10-30

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

  16. ALK-positive diffuse large B-cell lymphoma: two more cases and a brief literature review.

    Science.gov (United States)

    Rudzki, Zbigniew; Rucińska, Małgorzata; Jurczak, Wojciech; Skotnicki, Aleksander B; Maramorosz-Kurianowicz, Magdalena; Mruk, Andrzej; Piróg, Krystyna; Utych, Graźyna; Bodzioch, Piotr; Srebro-Stariczyk, Maria; Włodarska, Iwona; Stachura, Jerzy

    2005-01-01

    Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare, recently defined tumor distinct in many aspects from ALK-positive anaplastic large cell lymphoma (ALCL). We present two additional cases of ALK+DLBCL recently diagnosed in our department and a review of literature. A 48-year old man presented with a large upper neck mass growing slowly over 18 months. Histologically the tumor was diagnosed as an ALK-positive diffuse large B-cell lymphoma. with plasmablastic features. Large, frequently intrasinusoidal tumor cells expressed CD138, EMA, weakly IgA and kappa, but were negative for other B-cell markers, T-cell markers and CD30. The ALK staining was cytoplasmic with the increased intensity in the Golgi area. At the diagnosis the patient manifested with the stage IIIB. Three courses of CHOP resulted in partial and only transient remission. The patient died of massive bleeding from his decomposing tumor 3 months after the diagnosis. A 49-year old man complaining of abdominal pain revealed abdominal lymphadenomegaly and a gastric infiltrate, involving the deep portions of the gastric wall. The tumor showed immunoblastic/anaplastic morphology, with some Reed-Sternberg-like cells positive for ALK. ALK immunostaining was cytoplasmic, weak in a routine immunostain, enhanced with double (proteinase + pressure cooker) antigen retrieval. FISH was consistent with the t(2;5)/nucleophosmin(NPM)-ALK rearrangement. The tumor demonstrated similar "null" B/T phenotype with positivity for IgA, lambda, EMA and LCA. The patient (stage IVB) currently undergoes chemotherapy. ALK-positive DLBCL affects mostly middle-aged men, shows generally poor but stage-dependent prognosis (at least 60% mortality rate), presents typically as a lymph node-based disseminated disease, and very rarely involves the bone marrow. Genetic studies showed that the majority of ALK+DLBCL cases are characterized by the clathrin (CLTC)-ALK fusion and in a few cases the NPM

  17. Primary and Secondary T-cell Lymphomas of the Breast: Clinico-pathologic Features of 11 Cases

    Science.gov (United States)

    Gualco, Gabriela; Chioato, Lucimara; Harrington, William J.; Weiss, Lawrence M.; Bacchi, Carlos E.

    2009-01-01

    Breast involvement by non-Hodgkin lymphomas is rare, and exceptional for T-cell lymphomas; we studied the morphologic, immunophenotypic, and clinical features of 11 patients with T-cell non-Hodgkin lymphomas involving the breast. Four cases fulfilled the definition criteria for primary breast lymphomas, 3 females and 1 male, with a median age of 51 years. One primary breast lymphomas was T-cell lymphoma unspecified, other was subcutaneous panniculitis-like T-cell lymphoma, and 2 cases were anaplastic large cell lymphomas. One of the anaplastic large cell lymphoma cases was found surrounding a silicone breast implant and presented as clinically as mastitis; whereas the other case occurred in a man. T-cell lymphoma secondarily involved the breast in 7 patients, all women and 1 bilateral, with a median age of 29 years. These secondary breast lymphomas occurred as part of widespread nodal or leukemic disease. Three patients had adult T-cell leukemia/lymphoma, including the patient with bilateral lesions, 3 others had precursor T-lymphoblastic lymphoma/leukemia, and the other presented with a peripheral-T-cell lymphoma nonotherwise specified type. Breast T-cell lymphomas are very infrequent and are morphologically and clinically heterogeneous. PMID:19318917

  18. Primary and secondary T-cell lymphomas of the breast: clinico-pathologic features of 11 cases.

    Science.gov (United States)

    Gualco, Gabriela; Chioato, Lucimara; Harrington, William J; Weiss, Lawrence M; Bacchi, Carlos E

    2009-07-01

    Breast involvement by non-Hodgkin lymphomas is rare, and exceptional for T-cell lymphomas; we studied the morphologic, immunophenotypic, and clinical features of 11 patients with T-cell non-Hodgkin lymphomas involving the breast. Four cases fulfilled the definition criteria for primary breast lymphomas, 3 females and 1 male, with a median age of 51 years. One primary breast lymphomas was T-cell lymphoma unspecified, other was subcutaneous panniculitis-like T-cell lymphoma, and 2 cases were anaplastic large cell lymphomas. One of the anaplastic large cell lymphoma cases was found surrounding a silicone breast implant and presented as clinically as mastitis; whereas the other case occurred in a man. T-cell lymphoma secondarily involved the breast in 7 patients, all women and 1 bilateral, with a median age of 29 years. These secondary breast lymphomas occurred as part of widespread nodal or leukemic disease. Three patients had adult T-cell leukemia/lymphoma, including the patient with bilateral lesions, 3 others had precursor T-lymphoblastic lymphoma/leukemia, and the other presented with a peripheral-T-cell lymphoma non otherwise specified type. Breast T-cell lymphomas are very infrequent and are morphologically and clinically heterogeneous.

  19. Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation

    DEFF Research Database (Denmark)

    Biskup, Edyta; Naym, David Gram; Gniadecki, Robert

    2016-01-01

    and require more aggressive therapies. OBJECTIVE: The aim of this project was to investigate whether inhibition of Ataxia Telangiectasia and Rad3 related kinase (ATR) may enhance efficacy of phototherapy. METHODS: CTCL cell lines (MyLa2000, SeAx and Mac2a) served as in vitro cell models. ATR and Chk1 were...

  20. Anaplastic giant cell thyroid carcinoma.

    Science.gov (United States)

    Wallin, G; Lundell, G; Tennvall, J

    2004-01-01

    Anaplastic (giant cell) thyroid carcinoma (ATC), is one of the most aggressive malignancies in humans with a median survival time after diagnosis of 3-6 months. Death from ATC was earlier seen because of local growth and suffocation. ATC is uncommon, accounting for less than 5 % of all thyroid carcinomas. The diagnosis can be established by means of multiple fine needle aspiration biopsies, which are neither harmful nor troublesome for the patient. The cytological diagnosis of this high-grade malignant tumour is usually not difficult for a well trained cytologist. The intention to treat patients with ATC is cure, although only few of them survive. The majority of the patients are older than 60 years and treatment must be influenced by their high age. We have by using a combined modality regimen succeeded in achieving local control in most patients. Every effort should be made to control the primary tumour and thereby improve the quality of remaining life and it is important for patients, relatives and the personnel to know that cure is not impossible. Different treatment combinations have been used since 30 years including radiotherapy, cytostatic drugs and surgery, when feasible. In our latest combined regimen, 22 patients were treated with hyper fractionated radiotherapy 1.6Gy x 2 to a total target dose of 46 Gy given preoperatively, 20 mg doxorubicin was administered intravenously once weekly and surgery was carried out 2-3 weeks after the radiotherapy. 17 of these 22 patients were operated upon and none of these 17 patients got a local recurrence. In the future we are awaiting the development of new therapeutic approaches to this aggressive type of carcinoma. Inhibitors of angiogenesis might be useful. Combretastatin has displayed cytotoxicity against ATC cell lines and has had a positive effect on ATC in a patient. Sodium iodide symporter (NIS) genetherapy is also being currently considered for dedifferentiated thyroid carcinomas with the ultimate aim of

  1. Romidepsin and Lenalidomide in Treating Patients With Previously Untreated Peripheral T-Cell Lymphoma

    Science.gov (United States)

    2016-10-06

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Peripheral T-cell Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome

  2. Pathobiology of Hodgkin Lymphoma

    Directory of Open Access Journals (Sweden)

    Pier Paolo Piccaluga

    2011-01-01

    Full Text Available Despite its well-known histological and clinical features, Hodgkin's lymphoma (HL has recently been the object of intense research activity, leading to a better understanding of its phenotype, molecular characteristics, histogenesis, and possible mechanisms of lymphomagenesis. There is complete consensus on the B-cell derivation of the tumor in most cases, and on the relevance of Epstein-Barr virus infection and defective cytokinesis in at least a proportion of patients. The REAL/WHO classification recognizes a basic distinction between lymphocyte predominance HL (LP-HL and classic HL (cHL, reflecting the differences in clinical presentation and behavior, morphology, phenotype, and molecular features. cHL has been classified into four subtypes: lymphocyte rich, nodular sclerosing, with mixed cellularity, and lymphocyte depleted. The borders between cHL and anaplastic large-cell lymphoma have become sharper, whereas those between LP-HL and T-cell-rich B-cell lymphoma remain ill defined. Treatments adjusted to the pathobiological characteristics of the tumor in at-risk patients have been proposed and are on the way to being applied.

  3. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients.

    Science.gov (United States)

    Chang, Betty Y; Francesco, Michelle; De Rooij, Martin F M; Magadala, Padmaja; Steggerda, Susanne M; Huang, Min Mei; Kuil, Annemieke; Herman, Sarah E M; Chang, Stella; Pals, Steven T; Wilson, Wyndham; Wiestner, Adrian; Spaargaren, Marcel; Buggy, Joseph J; Elias, Laurence

    2013-10-03

    Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

  4. NPM-ALK signals through glycogen synthase kinase 3β to promote oncogenesis.

    Science.gov (United States)

    McDonnell, S R P; Hwang, S R; Basrur, V; Conlon, K P; Fermin, D; Wey, E; Murga-Zamalloa, C; Zeng, Z; Zu, Y; Elenitoba-Johnson, K S J; Lim, M S

    2012-08-01

    Anaplastic large cell lymphoma (ALCL) is the most common type of pediatric peripheral T-cell lymphoma. In 70-80% of cases, the chromosomal aberration t(2;5)(p23;q35) results in the juxtaposition of anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM) and the subsequent expression of the NPM-ALK fusion protein. NPM-ALK is a chimeric tyrosine kinase, which induces numerous signaling pathways that drive proliferation and abrogate apoptosis. However, the mechanisms that lead to activation of downstream growth regulatory molecules have not been completely elucidated. Using a mass spectrometry-based phosphoproteomic screen, we identified GSK3β as a signaling mediator of NPM-ALK. Using a selective inhibitor of ALK, we demonstrated that the tyrosine kinase activity of ALK regulates the serine-9 phosphorylation of GSK3β. Expression of NPM-ALK in 293T cells led to an increase of pS(9)-GSK3β (glycogen synthase kinase 3 beta) compared with kinase-defective K210R mutant NPM-ALK, but did not affect total GSK3β levels. Phosphorylation of pS(9)-GSK3β by NPM-ALK was mediated by the PI3K/AKT signaling pathway. ALK inhibition resulted in degradation of GSK3β substrates Mcl-1 and CDC25A, which was recovered upon chemical inhibition of the proteasome (MG132). Furthermore, the degradation of Mcl-1 was recoverable with inhibition of GSK3β. ALK inhibition also resulted in decreased cell viability, which was rescued by GSK3β inhibition. Furthermore, stable knockdown of GSK3β conferred resistance to the growth inhibitory effects of ALK inhibition using viability and colony formation assays. pS(9)-GSK3β and CDC25A were selectively expressed in neoplastic cells of ALK+ALCL tissue biopsies, and showed a significant correlation (PNPM-ALK regulates the phosphorylation of S(9)-GSK3β by PI3K/AKT. The subsequent inhibition of GSK3β activity results in accumulation of CDC25A and Mcl-1, which confers the advantage of growth and protection from apoptosis. These findings provide

  5. p53 immunoreactivity is uncommon in primary cutaneous lymphoma.

    Science.gov (United States)

    McGregor, J M; Dublin, E A; Levison, D A; MacDonald, D M; Smith, N P; Whittaker, S

    1995-03-01

    p53 gene mutation appears to play an important role in the development of systemic lymphoma, and may be associated with tumour progression. Its role in cutaneous lymphoma is currently unknown. We examined p53 expression in 55 biopsies of cutaneous lymphoma, including patch-, plaque- and tumour-stage mycosis fungoides (MF), T- and B-cell lymphoma and lymphomatoid papulosis. Strong, homogeneous p53 expression, thought to correlate most closely with p53 gene mutation, was seen in only three cases; in a plaque and tumour from a patient with tumour-stage MF, in plaque-stage MF in a patient without tumours, and in one case of CD30+ large-cell anaplastic lymphoma. These data suggest that p53 gene mutation is not a critical step in the development of the majority of primary cutaneous lymphomas.

  6. Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors.

    Science.gov (United States)

    Davare, Monika A; Vellore, Nadeem A; Wagner, Jacob P; Eide, Christopher A; Goodman, James R; Drilon, Alexander; Deininger, Michael W; O'Hare, Thomas; Druker, Brian J

    2015-09-29

    Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1(G2032R) mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.

  7. Aggressive primary thyroid lymphoma: imaging features of two elderly patients

    Directory of Open Access Journals (Sweden)

    Eu Hyun Kim

    2014-10-01

    Full Text Available

    We report two cases of aggressive thyroid lymphoma in elderly patients that presented as Epub ahead of print large infiltrative thyroid masses with extensive invasion to adjacent structures including trachea, esophagus, and common carotid artery. Ultrasonography displayed irregular shaped, heterogeneous hypoechoic mass, mimicking anaplastic carcinoma. Computed tomography showed heterogeneously enhancing mass compared to surrounding muscles without calcification and hemorrhage. After biopsy, the masses were histopathologically diagnosed as lymphoma. Aggressive primary thyroid lymphoma is rare; therefore, here we report its image features, with emphasis on ultrasonographic findings, and discuss its differential diagnosis.

  8. Aggressive primary thyroid lymphoma: imaging features of two elderly patients

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eu Hyun; Kim, Jee Young; Kim, Tae Jung [Yeouido St. Mary' s Hospital, The Catholic University College of Medicine, Seoul (Korea, Republic of)

    2014-12-15

    We report two cases of aggressive thyroid lymphoma in elderly patients that presented as Epub ahead of print large infiltrative thyroid masses with extensive invasion to adjacent structures including trachea, esophagus, and common carotid artery. Ultrasonography displayed irregular shaped, heterogeneous hypoechoic mass, mimicking anaplastic carcinoma. Computed tomography showed heterogeneously enhancing mass compared to surrounding muscles without calcification and hemorrhage. After biopsy, the masses were histopathologically diagnosed as lymphoma. Aggressive primary thyroid lymphoma is rare; therefore, here we report its image features, with emphasis on ultrasonographic findings, and discuss its differential diagnosis.

  9. 胃原发间变性大细胞淋巴瘤4例临床病理学特点及预后分析%Analysis of clinicopthologic features and prognosis of 4 cases primary gastric anaplastic large cell lymphomas

    Institute of Scientific and Technical Information of China (English)

    赖玉梅; 黄欣; 刘翠苓; 王小燕; 李敏; 孙琳; 陆伟; 高子芬

    2012-01-01

    目的 探讨胃原发间变性大细胞淋巴瘤( ALCL)的临床病理学特点及预后.方法 收集经北京大学医学部基础医学院病理学系确诊的4例胃原发ALCL,通过HE染色、免疫组织化学、EB病毒( EBV)编码的小核RNA(EBV-EBER)原位杂交、间期荧光原位杂交技术并结合文献复习,分析其临床病理学特点及预后.结果 男性3例,女性1例;年龄27~87岁,中位年龄58.5岁.大体标本均为胃部巨大溃疡型肿物;镜下见肿瘤细胞多形性明显、体积大的肿瘤细胞弥漫性浸润并破坏胃壁.肿瘤细胞一致性强表达LCA和CD30、CD3e阳性率75%(3/4).ALK蛋白水平及基因水平检测均为阴性(4/4),亦未检测到EBV感染.2例患者接受手术+CHOP方案化疗,1例接受CHOP方案化疗+自体干细胞移植,此3例患者均获得临床完全缓解出院,随访截至2011年11月30日,均未出现肿瘤复发或进展.另1例患者未接受治疗,于确诊后22个月死亡.结论 胃原发ALCL多为ALK阴性,其临床病理学特点及预后与其他部位原发的ALK阴性ALCL基本相同,但CD3e阳性率较高,早期诊断和积极治疗有助于改善患者的预后.%Objective To evaluate clinicopathologic features and prognosis of primary gastric anaplastic large cell lymphomas (ALCL).Methods Clinical data and parafiin blocks of 4 patients diagnosed with primary gastric ALCL were obtained. The diagnosis of all cases was based on the criteria of WHO classification of hematolymphoid neoplasm.Furthermore,chromosomal rearrangement involving ALK gene was detected by interphase fluorescence in situ hybridization (FISH) and Epstein-Barr virus (EBV) status was determined by in situ hybridization(ISH) for EBV-encoded small RNAs (EBERs).Results The patients (3 males and 1 female) were from 27 to 87 years old, with a median age of 58.5 years. All the four cases presented with a solitary ulcerative mass in stomach. Morphologically, the normal architecture of gastric wall was

  10. Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway.

    Science.gov (United States)

    Marzec, M; Kasprzycka, M; Liu, X; El-Salem, M; Halasa, K; Raghunath, P N; Bucki, R; Wlodarski, P; Wasik, M A

    2007-08-16

    The mechanisms of cell transformation mediated by the nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) tyrosine kinase are only partially understood. Here, we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma display persistent activation of mammalian target of rapamycin (mTOR) as determined by phosphorylation of mTOR targets S6rp and 4E-binding protein 1 (4E-BP1). The mTOR activation is serum growth factor-independent but nutrient-dependent. It is also dependent on the expression and enzymatic activity of NPM/ALK as demonstrated by cell transfection with wild-type and functionally deficient NPM/ALK, small interfering RNA (siRNA)-mediated NPM/ALK depletion and kinase activity suppression using the inhibitor WHI-P154. The NPM/ALK-induced mTOR activation is transduced through the mitogen-induced extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway and, to a much lesser degree, through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Accordingly, whereas the low-dose PI3K inhibitor wortmannin and Akt inhibitor III profoundly inhibited Akt phosphorylation, they had a very modest effect on S6rp and 4E-BP1 phosphorylation. In turn, MEK inhibitors U0126 and PD98059 and siRNA-mediated depletion of either ERK1 or ERK2 inhibited S6rp phosphorylation much more effectively. Finally, the mTOR inhibitor rapamycin markedly decreased proliferation and increased the apoptotic rate of ALK+TCL cells. These findings identify mTOR as a novel key target of NPM/ALK and suggest that mTOR inhibitors may prove effective in therapy of ALK-induced malignancies.

  11. Anaplastic thyroid carcinoma: a new approach.

    Science.gov (United States)

    Simpson, W J

    1980-01-01

    Less than 10% of patients with anaplastic thyroid carcinoma survive 5 years when treated by operation and conventional irradiation, but survivors who are disease-free at 2 years appear to be cured. The administration of a small number of large radiation fractions (350 to 800 rads) failed to eradicate the local disease in 14 patients, all of whom died within 9 months. Hyperfractionation (100 rads qid at 3-hour intervals) caused complete tumour regression of 6 of 14 patients and partial regression in 7 others; the 1 patient whose tumour failed to respond was treated only once daily. However, the cost was high: two patients died of spinal cord necrosis and a third of pneumonitis due to the unexpected increase in radiation toxicity caused by the concurrent administration of Adriamycin. If an effective systemic treatment can be devised for this disease, hyperfractionation may be capable of eradicating the massive local tumour masses so characteristic of anaplastic thyroid carcinoma.

  12. Incidental anaplastic thyroid carcinoma: A case report

    Directory of Open Access Journals (Sweden)

    Pembegül GÜNEŞ

    2008-01-01

    Full Text Available Anaplastic thyroid carcinoma is one of the most aggressive of all human malignant diseases. It has an unfavorable prognosis and responsible for most of the mortality and morbidity rates due to thyroid carcinomas. We present a case of incidental anaplastic thyroid carcinoma and discuss the epidemiology, biology, risk factors, prognostic factors of the disease and the approach to treatment, in the light of the current medical literature. The prognosis is much better in cases with incidental carcinoma compared to the classical type and surgical excision of the tumor has a favorable effect on the results. Our case was followed-up for 1.5 years with no evidence of recurrence or metastasis.

  13. Poorly differentiated (anaplastic) seminoma of the testis.

    Science.gov (United States)

    Cockburn, A G; Vugrin, D; Batata, M; Hajdu, S; Whitmore, W F

    1984-05-01

    Anaplastic seminoma constitutes approximately 17% of total experience with seminoma at Memorial Sloan-Kettering Cancer Center. Among 25 previously untreated patients, 11 (44%) were clinical Stage I, and 14 (56%) were clinical Stage II or III. Treatment of these 25 patients with the same regimens employed for classical seminoma yielded an overall 80% 5-year apparent cure rate. Survival rates were poor in eight previously treated patients referred with recurrence.

  14. Extensive Growth of an Anaplastic Meningioma

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    Hajrullah Ahmeti

    2013-01-01

    Full Text Available We present the case of a 30-year-old male patient with an almost complete destruction of the calvarial bone through an anaplastic meningioma diagnosed in line with dizziness. Neuroimaging revealed an extensive growing, contrast enhancing lesion expanding at the supra- and infratentorial convexity, infiltrating and destroying large parts of the skull, and infiltrating the skin. Due to progressive ataxia and dysarthria with proven tumor growth in the posterior fossa in the continuing course, parts of the tumor were resected. A surgical procedure with the aim of complete tumor resection in a curative manner was not possible. Six months after the first operation, due to a new tumor progression, most extensive tumor resection was performed. Due to the aggressive and destructive growth with a high rate of recurrence and tendency of metastases, anaplastic meningiomas can be termed as malignant tumors. The extrinsic growth masks the tumor until they reach a size, which makes these tumors almost unresectable. In the best case scenarios, the five-year survival is about 50%. With the presented case, we would like to show the aggressive behavior of anaplastic meningiomas in a very illustrative way. Chemotherapy, radiotherapy, and surgery reach their limits in this tumor entity.

  15. Clinical analysis of primary anaplastic carcinoma of the small intestine

    Institute of Scientific and Technical Information of China (English)

    Tsutomu Namikawa; Kazuhiro Hanazaki

    2009-01-01

    Primary anaplastic carcinoma is a rare variant of small intestinal cancer. Most reports of primary anaplastic carcinoma of the small intestine are isolated case reports, therefore the clinicopathological features, therapeutic management, and surgical outcome of this tumor type remain unclear. This review analyzes the available clinical characteristics of primary anaplastic carcinoma of the small intestine and investigates key differences from differentiated adenocarcinoma of the small intestine. A Medline search was performed using the keywords 'small intestine' and 'anaplastic carcinoma' or 'undifferentiated carcinoma'. Additional articles were obtained from references with in the papers identified by the Medline search. The literature revealed a poor prognosis for patients who underwent surgical resection for anaplastic carcinoma of the small intestine, which gave a 3-year overall survival rate of 10.8% and a median survival time of 5.0 mo. The literature suggests that anaplastic carcinoma is markedly more aggressive than differentiated adenocarcinoma of the small intestine. Surgical resection with the aim of complete tumor removal provides the only beneficial therapeutic option for patients with anaplastic carcinoma of the small intestine, because chemotherapy and radiation therapy have no significant effect on the rate of survival. However, despite complete tumor resection, most patients with anaplastic carcinoma of the small intestine are at great risk of disease recurrence. Multicenter clinical trials are expected to provide additional therapeutic strategies and establish the efficacy of multimodality adjuvant therapy. This report also highlights the importance of a systematic diagnostic approach for anaplastic carcinoma of the small intestine.

  16. Osteoclastoma-like anaplastic carcinoma of the thyroid

    Directory of Open Access Journals (Sweden)

    Joseph Leena

    2008-01-01

    Full Text Available Anaplastic carcinoma is a highly malignant tumor that is partially or totally undifferentiated. The use of fine needle aspiration cytology (FNAC to diagnose anaplastic carcinoma with osteoclast-like giant cells, has been rarely reported. We report here a case of osteoclastoma - anaplastic carcinoma - that was diagnosed on cytology in a 58 year-old female patient, who presented with a progressively increasing swelling over the anterior aspect of the neck. Multinucleated giant cells resembling osteoclasts are rarely seen in the giant cell variant of anaplastic carcinoma.

  17. Evaluation of clinical trial eligibility and prognostic indices in a population-based cohort of systemic peripheral T-cell lymphomas from the Danish Lymphoma Registry

    DEFF Research Database (Denmark)

    Pedersen, Martin Bjerregaard; Hamilton-Dutoit, Stephen Jacques; Bendix, Knud;

    2015-01-01

    patients, approximately half were eligible for multiagent chemotherapy with or without consolidating SCT. Both IPI and PIT are useful prognostic indices in all 'primary nodal' PTCL entities. The prognostic value of ALK protein expression in anaplastic large cell lymphoma is significantly downsized when...

  18. Multi-gene epigenetic silencing of tumor suppressor genes in T-cell lymphoma cells; delayed expression of the p16 protein upon reversal of the silencing

    DEFF Research Database (Denmark)

    Nagasawa, T; Zhang, Q; Raghunath, P N

    2006-01-01

    To understand better T-cell lymphomagenesis, we examined promoter CpG methylation and mRNA expression of closely related genes encoding p16, p15, and p14 tumor suppressor genes in cultured malignant T-cells that were derived from cutaneous, adult type, and anaplastic lymphoma kinase (ALK......)-expressing T-cell lymphomas. p16 gene was epigenetically silenced in all but one of the 10 malignant T-cell lines examined, p15 gene silenced in roughly half of the lines, and p14 was the least frequently affected. Extensive methylation of the p16 promoter was seen in six out of 10 cutaneous T-cell lymphoma...... patient samples and corresponded with lack of p16 protein expression in the cases examined. Treatment of cultured T-cells with the DNA methyltransferase inhibitor, 5-aza-2-deoxy-cytidine, resulted in reversal of the p16 gene silencing. However, expression of p16 protein was delayed in relationship to p16...

  19. Raf-1 kinase inhibitory protein expression in thyroid carcinomas.

    Science.gov (United States)

    Kim, Hyun-Soo; Kim, Gou Young; Lim, Sung-Jig; Kim, Youn Wha

    2010-12-01

    Raf-1 kinase inhibitory protein (RKIP) has been implicated in several fundamental signal transduction pathways that control cellular growth, differentiation, apoptosis and migration. RKIP is reduced in a variety of human carcinomas, but RKIP expression in thyroid carcinomas has not been analyzed at the protein level. In this study, we examined the immunohistochemical expression of RKIP in various subtypes of thyroid carcinoma. Immunostaining for RKIP was performed on 104 cases of primary thyroid carcinoma (40 papillary, 29 follicular, 11 medullary, 11 poorly differentiated, and 13 anaplastic carcinomas) and 26 cases of nodal metastatic tumor (17 papillary, 4 medullary, and 5 anaplastic carcinomas). Normal thyroid tissue and all cases of follicular, papillary, and medullary carcinomas showed uniform, strong cytoplasmic immunoreactivity for RKIP. With the exception of one case, poorly differentiated carcinomas also revealed strong RKIP expression. In contrast, RKIP expression was completely absent in all anaplastic carcinomas. The transition zone from the differentiated carcinoma component (strong RKIP expression) to the anaplastic carcinoma component (no RKIP expression) demonstrated a completely opposite pattern of RKIP immunoreactivity. This reduction of RKIP expression in anaplastic carcinoma was statistically significant (P carcinomas showed uniform, strong cytoplasmic RKIP immunoreactivity, in contrast, in metastatic anaplastic carcinomas, RKIP expression was completely absent. RKIP expression is significantly reduced in anaplastic thyroid carcinoma as compared to other subtypes of thyroid carcinoma. Further studies are necessary to elucidate the precise mechanism of RKIP action in anaplastic thyroid carcinoma.

  20. Protein kinase CK2 inhibition down modulates the NF-κB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells.

    Science.gov (United States)

    Manni, Sabrina; Brancalion, Alessandra; Mandato, Elisa; Tubi, Laura Quotti; Colpo, Anna; Pizzi, Marco; Cappellesso, Rocco; Zaffino, Fortunato; Di Maggio, Speranza Antonia; Cabrelle, Anna; Marino, Filippo; Zambello, Renato; Trentin, Livio; Adami, Fausto; Gurrieri, Carmela; Semenzato, Gianpietro; Piazza, Francesco

    2013-01-01

    CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.

  1. EML4-ALK融合基因阳性肺腺癌合并淋巴瘤1例并文献复习%A Case Report:an EML4-ALK Positive Lung Adenocarcinoma Diagnosed with Lymphoma Previously

    Institute of Scientific and Technical Information of China (English)

    刘丽; 衡伟

    2015-01-01

    近年来随着分子生物学研究的不断深入,靶向治疗成为当前肺癌治疗的趋势。目前肺癌个体化的最佳治疗效果日益受到重视,棘皮动物微管相关蛋白4-间变型淋巴瘤激酶(echinoderm microtubule associated protein like 4 anaplastic lymphoma kinase, EML4-ALK)融合基因作为新兴生物标记物是当前肺癌治疗领域研究热点。与此同时,随着抗肿瘤治疗水平的不断提高,生存期明显延长,发生多原发癌(multiple primary carcinomas, MPC)的机会增多。EML4-ALK融合基因阳性的肺腺癌合并淋巴瘤发生于同一患者文献报道罕见。本文报道1例ALK融合基因阳性的非小细胞肺癌(non-small cell lung cancer, NSCLC)合并淋巴瘤病例,同时对异时性肺癌合并淋巴瘤的文献进行复习。%In recent years, with the deepening of the research of molecular biology, targeted therapy has become one of the trend of lung cancer treatment. hTe individualized treatment of lung cancer is attached great importance at present. Echinoderm microtubule associated protein like 4 anaplastic lymphoma kinase (EML4-ALK) as a new biological marker is a hot topic in the ifeld of lung cancer treatment. Meanwhile, with the improvement of anticancer treatment and survival, the inci-dence of multiple primary carcinomas (MPC) has become increasingly. But the report that malignant lymphoma complicated with lung adenocarcinoma harboring EML4-ALK fusion gene in one individual is rare. Here, we report an EML4-ALK positive non-small cell lung cancer (NSCLC) in a patient previously diagnosed with T cell lymphoma and review literature on meta-chronous lung cancer complicating with lymphoma.

  2. Complete Radiologic Response in an Anaplastic Oligodendroglioma Treated with Temozolomide and Bevacizumab

    Directory of Open Access Journals (Sweden)

    Artur Katz

    2009-03-01

    Full Text Available In this case report, we describe a rare case of a 32-year-old man who presented a highly aggressive, fast growing anaplastic oligodendroglioma five years after being treated with whole brain radiotherapy for a CNS recurrence of a lymphoblastic lymphoma. Initially, the patient was submitted to a surgical intervention and partial tumor resection, which allowed us to establish the pathologic diagnosis and the presence of a 1p deletion. Shortly after the operation the tumor grew back, exerting important mass effect. Since no radiation therapy or surgery could be used and the patient faced a critical condition, chemotherapy was started with a combination of temozolomide and bevacizumab. Immediately after the first cycle a marked clinical and radiological improvement was documented.

  3. Clinical roundtable monograph: CD30 in lymphoma: its role in biology, diagnostic testing, and targeted therapy.

    Science.gov (United States)

    Sotomayor, Eduardo M; Young, Ken H; Younes, Anas

    2014-04-01

    CD30, a member of the tumor necrosis factor receptor superfamily, is a transmembrane glycoprotein receptor consisting of an extracellular domain, a transmembrane domain, and an intracellular domain. CD30 has emerged as an important molecule in the field of targeted therapy because its expression is generally restricted to specific disease types and states. The major cancers with elevated CD30 expression include Hodgkin lymphoma and anaplastic large T-cell lymphoma, and CD30 expression is considered essential to the differential diagnosis of these malignancies. Most commonly, CD30 expression is detected and performed by immunohistochemical staining of biopsy samples. Alternatively, flow cytometry analysis has also been developed for fresh tissue and cell aspiration specimens, including peripheral blood and bone marrow aspirate. Over the past several years, several therapeutic agents were developed to target CD30, with varying success in clinical trials. A major advance in the targeting of CD30 was seen with the development of the antibody-drug conjugate brentuximab vedotin, which consists of the naked anti-CD30 antibody SGN-30 conjugated to the synthetic antitubulin agent monomethyl auristatin E. In 2011, brentuximab vedotin was approved by the US Food and Drug Administration for use in Hodgkin lymphoma and anaplastic large cell lymphoma based on clinical trial data showing high response rates in these indications. Ongoing trials are examining brentuximab vedotin after autologous stem cell transplantation, as part of chemotherapy combination regimens, and in other CD30-expressing malignancies, including primary mediastinal large B-cell lymphomas, diffuse large B-cell lymphoma, lymphoma positive for Epstein-Barr virus, peripheral T-cell lymphoma not otherwise specified, and cutaneous anaplastic large cell lymphoma.

  4. Anaplastic Medullary Ependymoma Presenting as Subarachnoid Hemorrhage

    Directory of Open Access Journals (Sweden)

    Nicolas Nicastro

    2013-01-01

    Full Text Available A-41-year old man presented with violent thunderclap headache and a bilateral proprioceptive sensibility deficit of the upper limbs. Cerebral CT scan and MRI were negative. Lumbar puncture confirmed subarachnoid hemorrhage (SAH, but cerebral angiography was negative. Three months later, the patient presented with paraparesis, and a thorough work-up revealed a diffuse, anaplastic extramedullary C7-D10 ependymoma with meningeal carcinomatosis considered the source of hemorrhage. The patient went through a D5-D8 laminectomy, temozolomide chemotherapy, and radiotherapy. The situation remained stable for a few months. In this paper, we would like to emphasize that spinal masses should be considered in cases of SAH with negative diagnostic findings for aneurysms or arteriovenous malformation.

  5. IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis:contribution of the PI-3' kinase/AKT pathway

    Institute of Scientific and Technical Information of China (English)

    Gregory B Carey; Elena Semenova; Xiulan Qi; Achsah D Keegan

    2007-01-01

    Interleukin-4(IL-4)promotes lymphocyte survival and protects primary lymphomas from apoptosis.Previous studies reported differential requirements for the signal transducer and activator of transcription 6(STAT6)and IRS2/phosphatidylinositol 3 kinase(PI-3K)signaling pathways in mediating the IL-4-induced protection from Fas-mediated apoptosis.In this study,we characterized IL-4-activated signals that suppress anti-IgM-mediated apoptosis and growth arrest of CH31,a model B-cell lymphoma line.In CH31,anti-IgM treatment leads to the loss of mitochondrial membrane potential,phospho-Akt,phospho-CDK2,and c-myc protein.These losses are followed by massive induction ofp27Kip1 protein expression,cell cycle arrest,and apoptosis.Strikingly,IL-4 treatment prevented or reversed these changes.Furthermore,IL-4 suppressed the activation of caspases 9 and 3,and,in contrast to previous reports,induced the phosphorylation(deactivation)of BAD.IL-4 treatment also induced expression of BclxL,a STAT6-dependent gene.Pharmacologic inhibitors and dominant inhibitory forms of PI-3K andAkt abrogated the anti-apoptotic function of IL-4.These results suggest that the IL-4 receptor activates several signaling pathways,with the Akt pathway playing a major role in suppression of the apoptotic program activated by anti-IgM.

  6. Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA.

    Science.gov (United States)

    Marzec, M; Liu, X; Wong, W; Yang, Y; Pasha, T; Kantekure, K; Zhang, P; Woetmann, A; Cheng, M; Odum, N; Wasik, M A

    2011-03-17

    The mechanisms of malignant cell transformation mediated by the oncogenic anaplastic lymphoma kinase (ALK) tyrosine kinase remain only partially understood. In this study, we report that T-cell lymphoma (TCL) cells carrying the nucleophosmin (NPM)/ALK fusion protein (ALK+ TCL) strongly express hypoxia-induced factor 1α (HIF1α) mRNA, even under normoxic conditions, and markedly upregulate HIF1α protein expression under hypoxia. HIF1α expression is strictly dependent on the expression and enzymatic activity of NPM/ALK, as shown in BaF3 cells transfected with wild-type NPM/ALK and kinase-inactive NPM/ALK K210R mutant and by the inhibition of the NPM/ALK function in ALK+ TCL cells by a small-molecule ALK inhibitor. NPM/ALK induces HIF1α expression by upregulating its gene transcription through its key signal transmitter signal transducer and activator of transcription 3 (STAT3), which binds to the HIF1α gene promoter as shown by the chromatin immunoprecipitation assay and is required for HIF1α gene expression as demonstrated by its small interfering RNA-mediated depletion. In turn, depletion of HIF1α increases mammalian target of rapamycin complex 1 activation, cell growth and proliferation and decreases vascular endothelial growth factor synthesis. These results identify a novel cell-transforming property of NPM/ALK, namely its ability to induce the expression of HIF1α, a protein with an important role in carcinogenesis. These results also provide another rationale to therapeutically target NPM/ALK and STAT3 in ALK+ TCL.

  7. Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death

    DEFF Research Database (Denmark)

    Hollmann, C Annette; Owens, Trevor; Nalbantoglu, Josephine;

    2006-01-01

    CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models...... a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines...... and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40....

  8. Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice.

    Science.gov (United States)

    Choudhari, Ramesh; Minero, Valerio Giacomo; Menotti, Matteo; Pulito, Roberta; Brakebusch, Cord; Compagno, Mara; Voena, Claudia; Ambrogio, Chiara; Chiarle, Roberto

    2016-03-10

    Increasing evidence suggests that Rho family GTPases could have a critical role in the biology of T-cell lymphoma. In ALK-rearranged anaplastic large cell lymphoma (ALCL), a specific subtype of T-cell lymphoma, the Rho family GTPases Cdc42 and Rac1 are activated by the ALK oncogenic activity. In vitro studies have shown that Cdc42 and Rac1 control rather similar phenotypes of ALCL biology such as the proliferation, survival, and migration of lymphoma cells. However, their role and possible redundancy in ALK-driven lymphoma development in vivo are still undetermined. We genetically deleted Cdc42 or Rac1 in a mouse model of ALK-rearranged ALCL to show that either Cdc42 or Rac1 deletion impaired lymphoma development, modified lymphoma morphology, actin filament distribution, and migration properties of lymphoma cells. Cdc42 or Rac1 deletion primarily affected survival rather than proliferation of lymphoma cells. Apoptosis of lymphoma cells was equally induced following Cdc42 or Rac1 deletion, was associated with upregulation of the proapoptotic molecule Bid, and was blocked by Bcl2 overexpression. Remarkably, Cdc42/Rac1 double deletion, but not Cdc42 or Rac1 single deletions, completely prevented NPM-ALK lymphoma dissemination in vivo. Thus, Cdc42 and Rac1 have nonredundant roles in controlling ALK-rearranged lymphoma survival and morphology but are redundant for lymphoma dissemination, suggesting that targeting both GTPases could represent a preferable therapeutic option for ALCL treatment.

  9. Gastric lymphoma

    Directory of Open Access Journals (Sweden)

    Sravani Padala

    2016-06-01

    Full Text Available Gastrointestinal lymphomas represent 5-20% of extra nodal lymphomas and mainly occur in the stomach and small intestine. Clinical findings are not specific, thus often determining a delay in the diagnosis. Imaging features at conventional and cross-sectional imaging must be known by the radiologist since he/she plays a pivotal role in the diagnosis and disease assessment, thus assisting in the choice of the optimal treatment to patients. This review focuses on the wide variety of imaging presentation of esophageal, gastric, and small and large bowel lymphoma presenting their main imaging appearances at conventional and cross-sectional imaging, mainly focusing on computed tomography and magnetic resonance, helping in the choice of the best imaging technique for the disease characterization and assessment and the recognition of potential complications. Gastrointestinal tract is the most common extra nodal site involved by lymphoma. Although lymphoma can involve any part of the gastrointestinal tract .The most frequent sites in order of its occurrence are the stomach followed by small intestine and ileocecal region. Gastrointestinal tract lymphoma is usually secondary to the widespread nodal diseases and primary gastrointestinal tract lymphoma is relatively rare. [Int J Res Med Sci 2016; 4(6.000: 2481-2486

  10. Anaplastic Thyroid Carcinoma: Computed Tomographic Differentiation from Other Thyroid Masses

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jun Won; Yoon, Dae Young; Choi, Chul Soon; Chang, Suk Ki; Yun, Eun Joo; Seo, Young Lan; Rho, Young-Soo; Jin Cho, Sung; Kim, Keon Ha (Depts. of Radiology, Otorhinolaryngology, and Pathology, Kangdong Seong-Sim Hospital, Hallym Univ. College of Medicine, Seoul (KR))

    2008-04-15

    Background: Anaplastic thyroid carcinoma is rare but is one of the most aggressive malignancies. Therefore, accurate diagnosis is important in order to provide appropriate therapy. Purpose: To establish useful computed tomographic (CT) criteria for differentiating anaplastic carcinoma from other thyroid masses. Material and Methods: The CT scans of nine patients with anaplastic carcinomas were retrospectively reviewed and compared with those of 32 patients with papillary carcinomas (n = 12) or benign lesions (n = 20) exceeding a maximum diameter of 2.0 cm. Image analysis was performed according to the following CT parameters: size, margin (well defined or ill defined), composition (cystic, mixed, or solid), mean attenuation value, ratio of attenuation of the mass to that of the adjacent muscle (M/m attenuation ratio), necrosis (present or absent), and calcification (stippled, nodular, or absent) of the thyroid mass; and tumor-spreading patterns including the presence of surrounding normal thyroid tissue in the involved lobe, involvement of the contralateral thyroid lobe, extension into the adjacent structures, and cervical lymphadenopathy. Results: Anaplastic carcinomas appeared as large (average 4.6 cm), solid (100%), and ill-defined (88.9%) masses accompanied by necrosis (100%), nodular calcification (44.4%), direct invasion into the adjacent organs (55.6%), and cervical lymph node involvement (77.8%). Tumor necrosis was the most valuable parameter in differentiating anaplastic carcinomas from other thyroid masses. Patient age (>70 years) and low attenuation value on postcontrast scan (attenuation value <100 HU, or M/m attenuation ratio <1.3) are also helpful predictors for anaplastic carcinoma. Conclusion: If a patient is older than 70 years of age and has a large necrotic thyroid mass of low attenuation, anaplastic carcinoma should be included in the differential diagnosis

  11. PRDM1/BLIMP1: a tumor suppressor gene in B and T cell lymphomas.

    Science.gov (United States)

    Boi, Michela; Zucca, Emanuele; Inghirami, Giorgio; Bertoni, Francesco

    2015-05-01

    The gene encoding the human BLIMP1, prdm1, is located on chromosome 6q21, a locus frequently deleted in lymphoid tumors. BLIMP1 is able to silence its target genes in a context-dependent manner through different mechanisms. BLIMP1 is expressed in both B and T cells, in which it plays important functions. In B cells, BLIMP1 acts as the master regulator of plasma cell differentiation, repressed by BCL6 and repressing both BCL6 and PAX5. In T cells, BLIMP1 is a critical factor for most terminal effector cell differentiation in both CD4+ and CD8+ T cells. BLIMP1 is frequently inactivated in a variety of lymphomas, including diffuse large B cell lymphomas, Natural Killer cell lymphoma and anaplastic large T cell lymphoma. In this review, we will summarize the role of BLIMP1 in normal cells, focusing on lymphoid cells, and on its function as tumor suppressor gene in lymphomas.

  12. Hodgkin's Lymphoma

    Science.gov (United States)

    ... for information in your local library and on the Internet. Start your information search with the National Cancer ... www.mayoclinic.org/diseases-conditions/hodgkins-lymphoma/basics/definition/CON-20030667 . Mayo Clinic Footer Legal Conditions and ...

  13. Primary lymphoma of the brain

    Science.gov (United States)

    Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

  14. T-Cell Lymphoma

    Science.gov (United States)

    Getting the Facts T-Cell Lymphoma Overview Lymphoma is the most common blood cancer. The two main forms of lymphoma are Hodgkin lymphoma ... develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). T-cell lymphomas account for ...

  15. Low-grade and anaplastic oligodendroglioma.

    Science.gov (United States)

    Van Den Bent, Martin J; Bromberg, Jacolien E C; Buckner, Jan

    2016-01-01

    Anaplastic oligodendrogliomas have long attracted interest because of their sensitivity to chemotherapy, in particular in the subset of 1p/19q co-deleted tumors. Recent molecular studies have shown that all 1p/19q co-deleted tumors have IDH mutations and most of them also have TERT mutations. Because of the presence of similar typical genetic alterations in astrocytoma and glioblastoma, the current trend is to diagnose these tumors on the basis of their molecular profile. Further long-term follow-up analysis of both EORTC and RTOG randomized studies on (neo)adjuvant procarbazine, lomustine, vincristine (PCV) chemotherapy have shown that adjuvant chemotherapy indeed improves outcome, and this is now standard of care. It is also equally clear that benefit to PCV chemotherapy is not limited to the 1p/19q co-deleted cases; potential other predictive factors are IDH mutations and MGMT promoter methylation. Moreover, a recent RTOG study on low-grade glioma also noted an improved outcome after adjuvant PCV chemotherapy, thus making (PCV) chemotherapy now standard of care for all 1p/19q co-deleted tumors regardless of grade. It remains unclear whether temozolomide provides the same survival benefit, as no data from well-designed clinical trials on adjuvant temozolomide in this tumor type are available. Another question that remains is whether one can safely leave out radiotherapy as part of initial treatment to avoid cognitive side-effects of radiotherapy. The current data suggest that delaying radiotherapy and treatment with chemotherapy only may be detrimental for overall survival.

  16. Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway.

    Science.gov (United States)

    Wu, Qiuling; Lv, Tingting; Chen, Yan; Wen, Lu; Zhang, Junli; Jiang, Xudong; Liu, Fang

    2015-07-01

    The toxicities of conventional chemotherapeutic agents to normal cells restrict their dosage and clinical efficacy in acute leukemia; therefore, it is important to develop novel chemotherapeutics, including natural products, which selectively target cancer-specific pathways. The present study aimed to explore the effect of the chemopreventive agent asiatic acid (AA) on the proliferation and apoptotic rate of the leukemia cell line HL-60 and investigated the mechanisms underlying its anti-tumor activity. The effect of AA on the proliferation of HL-60 cells was evaluated using the MTT assay. Annexin V-fluorescein isothiocyanate/propidium iodide double staining followed by flow cytometric analysis as well as Hoechst 33258 staining were used to analyze the apoptotic rate of the cells. Furthermore, changes of survivin, B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia 1 (Mcl-1), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 expressions were detected by western blot analysis. AA blocked the growth of HL-60 cells in a dose- and time-dependent manner. The IC50-value of AA on HL-60 cells was 46.67 ± 5.08 µmol/l for 24 h. AA induced apoptosis in a dose-dependent manner, which was inhibited in the presence of Z-DEVD-FMK, a specific inhibitor of caspase. The anti-apoptotic proteins Bcl-2, Mcl-1 and survivin were downregulated by AA in a dose-dependent manner. Concurrently, AA inhibited ERK and p38 phosphorylation in a dose-dependent manner, while JNK phosphorylation was not affected. In conclusion, the present study indicated that the p38 and ERK pathways, as well as modulation of Bcl-2 family and survivin proteins were key regulators of apoptosis induced in HL-60 cells in response to AA.

  17. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1).

    Science.gov (United States)

    Marzec, Michal; Zhang, Qian; Goradia, Ami; Raghunath, Puthiyaveettil N; Liu, Xiaobin; Paessler, Michele; Wang, Hong Yi; Wysocka, Maria; Cheng, Mangeng; Ruggeri, Bruce A; Wasik, Mariusz A

    2008-12-30

    The mechanisms of malignant cell transformation caused by the oncogenic, chimeric nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) remain only partially understood, with most of the previous studies focusing mainly on the impact of NPM/ALK on cell survival and proliferation. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells strongly express the immunosuppressive cell-surface protein CD274 (PD-L1, B7-H1), as determined on the mRNA and protein level. The CD274 expression is strictly dependent on the expression and enzymatic activity of NPM/ALK, as demonstrated by inhibition of the NPM/ALK function in ALK+TCL cells by the small molecule ALK inhibitor CEP-14083 and by documenting CD274 expression in IL-3-depleted BaF3 cells transfected with the wild-type NPM/ALK, but not the kinase-inactive NPM/ALK K210R mutant or empty vector alone. NPM/ALK induces CD274 expression by activating its key signal transmitter, transcription factor STAT3. STAT3 binds to the CD274 gene promoter in vitro and in vivo, as shown in the gel electromobility shift and chromatin immunoprecipitation assays, and is required for the PD-L1 gene expression, as demonstrated by siRNA-mediated STAT3 depletion. These findings identify an additional cell-transforming property of NPM/ALK and describe a direct link between an oncoprotein and an immunosuppressive cell-surface protein. These results also provide an additional rationale to therapeutically target NPM/ALK and STAT3 in ALK+TCL. Finally, they suggest that future immunotherapeutic protocols for this type of lymphoma may need to include the inhibition of NPM/ALK and STAT3 to achieve optimal clinical efficacy.

  18. Silicone implants and lymphoma: The role of inflammation.

    Science.gov (United States)

    Bizjak, Mojca; Selmi, Carlo; Praprotnik, Sonja; Bruck, Or; Perricone, Carlo; Ehrenfeld, Michael; Shoenfeld, Yehuda

    2015-12-01

    The risk of hematological malignancies is mainly determined by genetic background, age, sex, race and ethnicity, geographic location, exposure to certain chemicals and radiation; along with the more recently proposed immune factors such as chronic inflammation, immunodeficiencies, autoimmunity, and infections. Paradigmatic examples include the development of lymphoma in Sjögren's syndrome and Hashimoto thyroiditis, gastric MALT lymphoma in Helicobacter pylori infection, or lymphomas associated with infections by Epstein-Barr virus, human herpes virus 8 (HHV 8) and leukemia/lymphoma virus 1 (HTLV-1). A growing number of reports indicates an increased risk of lymphoma, particularly of the anaplastic large cell (ALCL) type. The implants, specifically those used in the past, elicit chronic stimulation of the immune system against the prosthetic material. This is particularly the case in genetically susceptible hosts. We suggest that polyclonal activation may result in monoclonality in those at risk hosts, ultimately leading to lymphoma. We suggest that patients with an inflammatory response against silicone implants be monitored carefully.

  19. Lymphoma cytogenetics.

    Science.gov (United States)

    Dave, Bhavana J; Nelson, Marilu; Sanger, Warren G

    2011-12-01

    Lymphomas are a heterogeneous group of neoplasms with distinct morphologic, immunologic, and cytogenetic characteristics. Overlapping morphologic and immunophenotypic features often makes accurate diagnosis difficult. Cytogenetics helps simplify the diagnostic complexities presented in transforming and progressive lymphoid malignancies. Genetic studies using technical advances such as fluorescence in situ hybridization and the newer approaches of array comparative genomic hybridization and gene expression profiling play a critical and often defining role in the diagnosis, progression, prognosis, and therapeutic stratification. This article reviews characteristic cytogenetic abnormalities in specific subtypes of lymphomas at diagnosis, disease progression, and prognosis.

  20. Anaplastic Thyroid Cancer: A Review of Epidemiology, Pathogenesis, and Treatment

    Directory of Open Access Journals (Sweden)

    Govardhanan Nagaiah

    2011-01-01

    Full Text Available Anaplastic thyroid cancer (ATC is an uncommon malignancy of the thyroid. Only 1-2% of thyroid cancers are anaplastic, but the disease contributes to 14–50% of the mortality with a median survival of 3 to 5 months. Most patients diagnosed with this disease are 65 years of age or older. The incidence of anaplastic thyroid cancer is decreasing worldwide. Most patients present with a rapidly growing neck mass, dysphagia, or voice change. We performed a comprehensive literature search using PubMed focusing on the treatment of anaplastic thyroid cancer including historical review of treatment and outcomes and investigations of new agents and approaches. A total of sixteen chart review and retrospective studies and eleven prospective studies and/or clinical trials were reviewed. The current standard therapeutic approach is to consider the disease as systemic at time of diagnosis and pursue combined modality therapy incorporating cytoreductive surgical resection where feasible and/or chemoradiation either concurrently or sequentially. Doxorubicin is the most commonly used agent, with a response rate of 22%. Several new agents are currently under investigation. Referral of patients for participation in clinical trials is needed.

  1. B-cell and T-cell lymphomas of the breast: clinical--pathological features of 53 cases.

    Science.gov (United States)

    Gualco, Gabriela; Bacchi, Carlos E

    2008-10-01

    Breast involvement by non-Hodgkin lymphomas is rare. We studied the morphological, immunophenotypical, and clinical features of 53 cases of malignant lymphomas involving the breast in a population of Brazilian patients. Most of the cases were of B-cell phenotype. Four of the patients with primary breast lymphomas had T-cell lymphomas, 3 had CD30-positive anaplastic large cell lymphomas, and 1 had panniculitis-like T-cell lymphoma. Most patients presented with an incidental breast mass. Secondary breast lymphoma was seen in 19 patients and most commonly occurred as part of widespread nodal disease. Two patients presented with bilateral breast involvement. The most prevalent histological subtype was also diffuse large B-cell lymphoma, followed by follicular lymphoma. This study shows that the broad morphological and immunophenotypical spectrum of malignant lymphoma of the breast occurring in a large series of Brazilian patients has many similarities with that seen in Western countries, with a higher proportion of high-grade lymphomas in both primary and secondary cases.

  2. Pediatric infratentorial ependymoma: prognostic significance of anaplastic histology.

    Science.gov (United States)

    Phi, Ji Hoon; Wang, Kyu-Chang; Park, Sung-Hye; Kim, Il Han; Kim, In-One; Park, Kyung Duk; Ahn, Hyo Seop; Lee, Ji Yeoun; Son, Young-Je; Kim, Seung-Ki

    2012-02-01

    Pediatric infratentorial ependymomas are difficult to cure. Despite the availability of advanced therapeutic modalities for brain tumors, total surgical resection remains the most important prognostic factor. Recently, histological grade emerged as an independent prognostic factor for intracranial ependymoma. We retrospectively reviewed the treatment outcome of 33 pediatric patients with infratentorial ependymoma. Progression-free survival (PFS) and overall survival (OS) rates were calculated and relevant prognostic factors were analyzed. Fourteen patients (42%) were under the age of 3 at diagnosis. Gross total resection was achieved in 16 patients (49%). Anaplastic histology was found in 13 patients (39%). Adjuvant therapies were delayed until progression in 12 patients (36%). Actuarial PFS rates were 64% in the first year and 29% in the fifth year. Actuarial OS rates were 91% in the first year and 71% in the fifth year. On univariate analysis, brainstem invasion (P = 0.047), anaplastic histology (P = 0.004), higher mitotic count (P = 0.001), and higher Ki-67 index (P = 0.004) were significantly related to a shorter PFS. Gross total resection (P = 0.029) and a greater age at diagnosis (P = 0.033) were significantly related to a longer PFS. On multivariate analysis, anaplastic histology alone was significantly related to a shorter PFS (P = 0.023). Gross total resection (P = 0.039) was significantly related to a longer overall survival (OS) on multivariate analysis. Anaplastic histology and gross total resection were the most important clinical factors affecting PFS and OS, respectively. Anaplastic histology, mitotic count, and Ki-67 index can be used as universal and easily available prognostic parameters in infratentorial ependymomas.

  3. Conjunctival Lymphoma

    DEFF Research Database (Denmark)

    Kirkegaard, Marina M; Rasmussen, Peter Kristian; Coupland, Sarah E;

    2016-01-01

    IMPORTANCE: To date, the clinical features of the various subtypes of conjunctival lymphoma (CL) have not been previously evaluated in a large cohort. OBJECTIVE: To characterize subtype-specific clinical features of CL and their effect on patient outcome. DESIGN, SETTING, AND PARTICIPANTS: A retr...

  4. Brentuximab Vedotin in CD30-Positive Lymphomas: A SIE, SIES, and GITMO Position Paper.

    Science.gov (United States)

    Zinzani, Pier Luigi; Corradini, Paolo; Gianni, Alessandro M; Federico, Massimo; Santoro, Armando; Vitolo, Umberto; Barosi, Giovanni; Tura, Sante

    2015-09-01

    Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology (SIE) and its affiliate societies, Società Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other CD30-positive lymphomas.

  5. Plasma cytokine profiles at diagnosis in pediatric patients with non-hodgkin lymphoma

    DEFF Research Database (Denmark)

    Mellgren, Karin; Hedegaard, Chris Juul; Schmiegelow, Kjeld;

    2012-01-01

    Non-Hodgkin lymphoma (NHL) has been associated with elevated levels of inflammatory and immune-regulating cytokines, and polymorphisms in the genes encoding interleukin (IL)-10 and tumor necrosis factor (TNF)-α have been associated with increased incidence of certain subtypes of NHL. The aim......, between 1995 and 2008. Cytokines and growth factors were measured in serum using the Luminex platform by application of a 30-plex kit. Levels of IL-6, IL-2R, IL-10, TNF-RI, and macrophage inflammatory protein-1α were significantly higher in patients with anaplastic large-cell lymphoma compared...... with patients diagnosed with B-cell lymphomas and lymphoblastic lymphomas. High levels of IL-4, IL-13, TNF-RI, and epidermal growth factor were associated with a poorer general condition at diagnosis. The present study suggests that NHL subgrouping and the general condition of pediatric patients at diagnosis...

  6. Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers

    Science.gov (United States)

    2017-01-31

    Adenoid Cystic Carcinoma; Adnexal Carcinoma; Apocrine Carcinoma; Eccrine Porocarcinoma; Extraocular Cutaneous Sebaceous Carcinoma; Hidradenocarcinoma; Keratoacanthoma; Malignant Sweat Gland Neoplasm; Merkel Cell Carcinoma; Microcystic Adnexal Carcinoma; NK-Cell Lymphoma, Unclassifiable; Non-Melanomatous Lesion; Paget Disease; Papillary Adenocarcinoma; Primary Cutaneous Mucinous Carcinoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Refractory Mycosis Fungoides; Refractory T-Cell Non-Hodgkin Lymphoma; Sezary Syndrome; Signet Ring Cell Carcinoma; Skin Basal Cell Carcinoma; Skin Basosquamous Cell Carcinoma; Skin Squamous Cell Carcinoma; Spiradenocarcinoma; Squamous Cell Carcinoma of Unknown Primary Origin; Stage III Skin Cancer; Stage IV Skin Cancer; Sweat Gland Carcinoma; Trichilemmocarcinoma; Vulvar Squamous Cell Carcinoma

  7. Plasma Cell-Free DNA in Paediatric Lymphomas

    Science.gov (United States)

    Mussolin, Lara; Burnelli, Roberta; Pillon, Marta; Carraro, Elisa; Farruggia, Piero; Todesco, Alessandra; Mascarin, Maurizio; Rosolen, Angelo

    2013-01-01

    Background: Extracellular circulating DNA (cfDNA) can be found in small amounts in plasma of healthy individuals. Increased levels of cfDNA have been reported in patients with cancer of breast, cervix, colon, liver and it was shown that cfDNA can originate from both tumour and non-tumour cells. Objectives: Levels of cfDNA of a large series of children with lymphoma were evaluated and analyzed in relation with clinical characteristics. Methods: plasma cfDNA levels obtained at diagnosis in 201 paediatric lymphoma patients [43 Hodgkin lymphomas (HL), 45 anaplastic large cell lymphomas (ALCL), 88 Burkitt lymphomas (BL), 17 lymphoblastic (LBL), 8 diffuse large B cell lymphoma (DLBCL)] and 15 healthy individuals were determined using a quantitative PCR assay for POLR2 gene and, in addition, for NPM-ALK fusion gene in ALCL patients. Wilcoxon rank sum test was used to compare plasma levels among different patient subgroups and controls and to analyze relationship between levels of cfDNA and clinical characteristics. Results: Levels of cfDNA in lymphoma patients were significantly higher compared with controls (p<0.0001). CfDNA was associated with median age (p=0.01) in HL, and with stage in ALCL (p=0.01). In HL patients high cfDNA levels were correlated with poor prognosis (p=0.03). In ALCL we found that most of the cfDNA (77%) was non-tumor DNA. Conclusion: level of plasma cfDNA might constitute an important non-invasive tool at diagnosis in lymphoma patients' management; in particular in patients with HL, cfDNA seems to be a promising prognostic biomarker. PMID:23678368

  8. SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling.

    Science.gov (United States)

    Honorat, Jean-François; Ragab, Ashraf; Lamant, Laurence; Delsol, Georges; Ragab-Thomas, Jeannie

    2006-05-15

    Anaplastic large-cell lymphoma (ALCL) is frequently associated with the 2;5 translocation and expresses the NPM-ALK fusion protein, which possesses a constitutive tyrosine kinase activity. We analyzed SHP1 tyrosine phosphatase expression and activity in 3 ALK-positive ALCL cell lines (Karpas 299, Cost, and SU-DHL1) and in lymph node biopsies (n = 40). We found an inverse correlation between the level of NPM-ALK phosphorylation and SHP1 phosphatase activity. Pull-down and coimmunoprecipitation experiments demonstrated a SHP1/NPM-ALK association. Furthermore, confocal microscopy performed on ALCL cell lines and biopsy specimens showed the colocalization of the 2 proteins in cytoplasmic bodies containing Y664-phosphorylated NPM-ALK. Dephosphorylation of NPM-ALK by SHP1 demonstrated that NPM-ALK was a SHP1 substrate. Downregulation of SHP1 expression by RNAi in Karpas cells led to hyperphosphorylation of NPM-ALK, STAT3 activation, and increase in cell proliferation. Furthermore, SHP1 overexpression in 3T3 fibroblasts stably expressing NPM-ALK led to the decrease of NPM-ALK phosphorylation, lower cell proliferation, and tumor progression in nude mice. These findings show that SHP1 is a negative regulator of NPM-ALK signaling. The use of tissue microarrays revealed that 50% of ALK-positive ALCLs were positive for SHP1. Our results suggest that SHP1 could be a critical enzyme in ALCL biology and a potential therapeutic target.

  9. Renal Clear Cell Sarcoma - Anaplastic Variant: A Rare Entity.

    Science.gov (United States)

    Walke, Vaishali Atmaram; Shende, Nitin Y; Kumbhalkar, D T

    2017-01-01

    Clear Cell Sarcoma of Kidney (CCSK) is known for its morphologic diversity, aggressive behaviour, tendency to recur and metastasis to bone. Amongst the various morphologic subtypes, anaplastic CCSK is associated with worse prognosis. Here, we report a case of this rare variant of CCSK. A five-year-old boy presented with history of lump and pain in abdomen since one week. The Computed Tomography (CT) scan revealed a large mass occupying the middle and inferior pole of right kidney. The clinical impression was Wilms tumour. Nephrectomy specimen was received and the diagnosis of CCSK anaplastic variant was offered only after excluding the differentials and after performing ancillary tests such as Immunohistochemistry (IHC). Thus, this case emphasizes the diagnostic challenges on morphology and the essential role of IHC in arriving at a definitive diagnosis, because failure to do so may deprive the child from optimal treatment.

  10. Lymphoma of the eyelid

    DEFF Research Database (Denmark)

    Svendsen, Frederik H; Heegaard, Steffen

    2017-01-01

    Lymphoma of the eyelid constitutes 5% of ocular adnexal lymphoma. In previously published cases, 56% of lymphomas of the eyelid are of B-cell origin and 44% are of T-cell origin. The most frequent B-cell lymphomas are extranodal marginal zone lymphoma (27 cases-14%) and diffuse large B-cell lymph......Lymphoma of the eyelid constitutes 5% of ocular adnexal lymphoma. In previously published cases, 56% of lymphomas of the eyelid are of B-cell origin and 44% are of T-cell origin. The most frequent B-cell lymphomas are extranodal marginal zone lymphoma (27 cases-14%) and diffuse large B...... chemotherapy with or without adjuvant treatment is the treatment of choice for high-grade or disseminated lymphomas. The majority of subtypes, especially low-grade subtypes, have a good prognosis with few recurrences or progression. Some subtypes, including mycosis fungoides, have a poorer prognosis...

  11. SGN-35 in CD30-positive Lymphoproliferative Disorders (ALCL), Mycosis Fungoides (MF), and Extensive Lymphomatoid Papulosis (LyP)

    Science.gov (United States)

    2016-08-11

    CD-30 Positive Anaplastic Large T-cell Cutaneous Lymphoma; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Lymphomatoid Papulosis; Mycosis Fungoides; Skin Lymphoma; Cutaneous Lymphomas; Lymphoma; Hematologic Disorder

  12. Non-Invasive Methods to Monitor Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer: Where Do We Stand?

    Science.gov (United States)

    Ulivi, Paola

    2016-07-22

    The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR-TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment. A better understanding of these acquired resistance mechanisms is essential in clinical practice as patients could be treated with specific drugs that are active against the induced alterations. The use of free circulating tumor nucleic acids or circulating tumor cells (CTCs) enables resistance mechanisms to be characterized in a non-invasive manner and reduces the need for tumor re-biopsy. This review discusses the main resistance mechanisms to TKIs and provides a comprehensive overview of innovative strategies to evaluate known resistance mechanisms in free circulating nucleic acids or CTCs and potential future orientations for these non-invasive approaches.

  13. Testicular lymphoma

    DEFF Research Database (Denmark)

    Møller, Michael Boe; d'Amore, F; Christensen, Bjarne Egelund

    1994-01-01

    In a Danish population-based non-Hodgkin's lymphoma registry, 2687 newly diagnosed patients were registered from 1983 to 1992. 39 had testicular involvement (TL) (incidence 0.26/10(5)/year). Median age was 71 years. 24 cases had localised and 15 had disseminated disease. Histologically, all cases...... were diffuse (65% diffuse centroblastic type). Of the 27 tested, 11% were of T- and 89% of B-immunophenotype. In localised cases, where surgery was supplemented by combination chemotherapy (CCT), the relapse rate was 15.4%. The relapse rate for cases with localised disease treated with other regimens...

  14. High-Dose Busulfan and High-Dose Cyclophosphamide Followed By Donor Bone Marrow Transplant in Treating Patients With Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, or Recurrent Hodgkin or Non-Hodgkin Lymphoma

    Science.gov (United States)

    2010-08-05

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With T(15;17)(q22;q12); Adult Acute Myeloid Leukemia With T(16;16)(p13;q22); Adult Acute Myeloid Leukemia With T(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Burkitt Lymphoma; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myelomonocytic Leukemia (M4); Childhood Acute Promyelocytic Leukemia (M3); Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; De Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-Cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent

  15. Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

    Science.gov (United States)

    2013-07-01

    Childhood Burkitt Lymphoma; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Medulloepithelioma; Childhood Meningioma; Childhood Mixed Glioma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Oligodendroglioma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  16. Breast Implant–associated Anaplastic Large Cell Lymphoma: Updated Results from a Structured Expert Consultation Process

    Directory of Open Access Journals (Sweden)

    Benjamin Kim, MD, MPhil

    2015-01-01

    Conclusions: Our assessment yielded consistent results on a number of key, incompletely addressed issues regarding BIA-ALCL, but additional research is needed to support these statement ratings and enhance our understanding of the biology, treatment, and outcomes associated with this disease.

  17. Small cell variant of anaplastic large cell lymphoma with positive immunoreactivity for CD99.

    Science.gov (United States)

    Shiran, M S; Tan, G C; Sabariah, A R; Chye, P C; Pathmanathan, R

    2008-06-01

    A 13 year old boy presented with a huge mass on his right arm of 6 months duration. Histopathological examination revealed sheets of malignant small round blue cells with immunopositivity for LCA, CD43, CD45Ro, CD30, EMA, ALK-1 and CD99, and negativity for CD20, TdT, myogenin, myoD1, NSE, bcl-6, bcl-2 and CD10. Fluorescent In-Situ Hybridization (FISH) testing excluded the diagnosis of Ewing's sarcoma/PNET. Pathologists need to be aware of the diagnosis of a small cell variant of ALCL, as well as of the fact that CD99 expression commonly occurs in cases of ALK-positive ALCL, in order to distinguish this entity from Ewing's sarcoma/PNET.

  18. Stages of Adult Hodgkin Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  19. Stages of Childhood Hodgkin Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  20. Anaplastic thyroid carcinoma with rhabdomyoblastic differentiation : A case report with a good clinical outcome

    NARCIS (Netherlands)

    Olthof, Marijke; Persoon, Adrienne C. M.; Plukker, John T. M.; van der Wal, Jacqueline E.; Links, Thera P.

    2008-01-01

    Anaplastic thyroid carcinoma is a rare and highly malignant disease. Usually, this type of tumor is irresectable, and almost all patients die within 1 year after diagnosis. We present a case of anaplastic thyroid carcinoma with rhabdomyoblastic differentiation and good therapeutic outcome. A 76-year

  1. The effect of low level laser on anaplastic thyroid cancer

    Science.gov (United States)

    Rhee, Yun-Hee; Moon, Jeon-Hwan; Ahn, Jin-Chul; Chung, Phil-Sang

    2015-02-01

    Low-level laser therapy (LLLT) is a non-thermal phototherapy used in several medical applications, including wound healing, reduction of pain and amelioration of oral mucositis. Nevertheless, the effects of LLLT upon cancer or dysplastic cells have been so far poorly studied. Here we report that the effects of laser irradiation on anaplastic thyroid cancer cells leads to hyperplasia. 650nm of laser diode was performed with a different time interval (0, 15, 30, 60J/cm2 , 25mW) on anaplastic thyroid cancer cell line FRO in vivo. FRO was orthotopically injected into the thyroid gland of nude mice and the irradiation was performed with the same method described previously. After irradiation, the xenograft evaluation was followed for one month. The thyroid tissues from sacrificed mice were undergone to H&E staining and immunohistochemical staining with HIF-1α, Akt, TGF-β1. We found the aggressive proliferation of FRO on thyroid gland with dose dependent. In case of 60 J/ cm2 of energy density, the necrotic bodies were found in a center of the thyroid. The phosphorylation of HIF-1α and Akt was detected in the thyroid gland, which explained the survival signaling of anaplastic cancer cell was turned on the thyroid gland. Furthermore, TGF-β1 expression was decreased after irradiation. In this study, we demonstrated that insufficient energy density irradiation occurred the decreasing of TGF-β1 which corresponding to the phosphorylation of Akt/ HIF-1α. This aggressive proliferation resulted to the hypoxic condition of tissue for angiogenesis. We suggest that LLLT may influence to cancer aggressiveness associated with a decrease in TGF-β1 and increase in Akt/HIF-1α.

  2. Myelopathy following hyperfractionated accelerated radiotherapy for anaplastic thyroid carcinoma.

    Science.gov (United States)

    Wong, C S; Van Dyk, J; Simpson, W J

    1991-01-01

    From 1975 to 1982, 32 patients with a diagnosis of anaplastic carcinoma of the thyroid were entered into a protocol of hyperfractionated accelerated radiotherapy. The tumor dose was 30-45 Gy at 1 Gy per fraction given 4 times a day at 3-h intervals. The results were disappointing with a median survival of less than 6 months. Two patients developed radiation myelopathy at 8 and 13 months, total spinal cord dose being 39.9 and 48.3 Gy, respectively. The risk of spinal cord damage was much higher than expected. The possible radiobiological causes and clinical implications are discussed.

  3. Arteriovenous malformation within an isocitrate dehydrogenase 1 mutated anaplastic oligodendroglioma

    Directory of Open Access Journals (Sweden)

    Grace Lai

    2015-01-01

    Full Text Available Background: The co-occurrence of intracranial arteriovenous malformations (AVMs and cerebral neoplasms is exceedingly rare but may harbor implications pertaining to the molecular medicine of brain cancer pathogenesis. Case Description: Here, we present a case of de novo AVM within an isocitrate dehydrogenase 1 mutated anaplastic oligodendroglioma (WHO Grade III and review the potential contribution of this mutation to aberrant angiogenesis as an interesting case study in molecular medicine. Conclusion: The co-occurrence of an IDH1 mutated neoplasm and AVM supports the hypothesis that IDH1 mutations may contribute to aberrant angiogenesis and vascular malformation.

  4. Intravntricular anaplastic hemangiopericytoma: CT and MR imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Bo Hwa; Moon, Jin Il; Baek, Hye Jin; Cho, Soo Buem; Bae, Kyung Soo; Jeon, Kyung Nyeo [Dept. of Radiology, Gyeongsang National University School of Medicine, Gyeongsang National University Changwon Hospital, Changwon (Korea, Republic of)

    2016-09-15

    Intracranial hemangiopericytomas (HPC) are uncommon tumors, and their intraventricular occurrence is even rarer. Although the histopathologic findings in HPC are distinct, the diagnosis of intraventricular HPC can be difficult owing to its rarity and nonspecific clinicoradiologic manifestations. Here we present a case of intraventricular anaplastic HPC in a 20-year-old female patient, confirmed on histopathologic examination. We suggest that HPC should be considered in the differential diagnosis of space-occupying lesions of the ventricles. This article also highlights a situation in which clinical suspicion led to a meticulous radiologic review.

  5. Peripheral T-Cell Lymphoma

    Science.gov (United States)

    Getting the Facts Peripheral T-Cell Lymphoma Overview Lymphoma is the most common blood cancer. The two main forms of lymphoma are Hodgkin lymphoma and ... develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). Peripheral T-cell lymphoma (PTCL) ...

  6. Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

    Science.gov (United States)

    Economopoulou, Panagiota

    2016-01-01

    Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with BM comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. However, in the majority of patients, the occurrence of CNS metastases is usually accompanied by severe morbidity and substantial deterioration in quality of life. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, either alone or as part of a multimodality treatment are available treatment strategies for BM and the choice of therapy varies depending on patient group and prognosis. Meanwhile, introduction of tyrosine kinase inhibitors (TKIs) in clinical practice has led to individualization of therapy based upon the presence of the exact abnormality, resulting in a major therapeutic improvement in patients with NSCLC who harbor epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, respectively. Based on their clinical activity in systemic disease, such molecular agents could offer the promise of improved BM control without substantial toxicity; however, their role in combination with radiotherapy is controversial. In this review, we discuss the controversy regarding the use of TKIs in combination with radiotherapy and illustrate future perspectives in the treatment of BM in NSCLC. PMID:28149754

  7. International Lymphoma Epidemiology Consortium

    Science.gov (United States)

    The InterLymph Consortium, or formally the International Consortium of Investigators Working on Non-Hodgkin's Lymphoma Epidemiologic Studies, is an open scientific forum for epidemiologic research in non-Hodgkin's lymphoma.

  8. Non-Hodgkin's Lymphoma

    Science.gov (United States)

    ... These include the lymphatic vessels, tonsils, adenoids, spleen, thymus and bone marrow. Occasionally, non-Hodgkin's lymphoma involves ... understand the possible link between pesticides and the development of non-Hodgkin's lymphoma. Older age. Non-Hodgkin's ...

  9. Plasmablastic lymphoma

    Science.gov (United States)

    Han, Xiao; Duan, Minghui; Hu, Lixing; Zhou, Daobin; Zhang, Wei

    2017-01-01

    Abstract Background: Plasmablastic lymphoma (PBL) is a B-cell malignancy associated with human immunodeficiency virus (HIV). PBL could also influence the HIV-negative patients. The study aimed to identify prognostic factors for survival among Chinese PBL patients. Materials and methods: Eligible patients from literature and Peking Union Medical College Hospital (PUMCH) were included in this study. Clinical characteristics and immunophenotypic data were extracted. Kaplan–Meier curve was used to describe the survival status. Cox regression was used for multivariate analysis. Results: A total of 60 Chinese PBL patients were included, including 54 patients from 36 published articles and 6 new patients that have not been reported. The median overall survival was 7 months (95% confidence interval 3.853–10.147 months). An overwhelming majority (79.31%) of the included cases were Ann Arbor stage IV patients. All the Chinese PBL patients were HIV-negative; 46.81% were Epstein-Barr virus-positive. CD38, CD138, or MUM1 was positively expressed in more than 80% of patients; CD20 expression was also found in 22.03% of cases. Kaplan–Meier curve revealed obvious differences in patient survival between patients in primary stages and advanced stages, as well as between patients with kidney involvement and those without kidney involvement. Cox regression analysis indicated that stage and age were 2 prognostic factors for patient survival. Conclusions: Advanced stage might be associated with poor prognosis among PBL HIV-negative patients in Chinese. PMID:28248855

  10. Current and Future Developments in the Treatment of CD30+ Lymphomas

    Directory of Open Access Journals (Sweden)

    Lena Specht

    2015-11-01

    Full Text Available CD30 is a cell membrane protein expressed on the surface of a range of lymphomas, which has important diagnostic, pathogenic, and prognostic roles. The most common CD30+ lymphomas are Hodgkin’s lymphoma (HL and anaplastic large cell lymphoma (ALCL, but other types of lymphoma also express CD30, although less frequently. Attempts to develop a monoclonal antibody therapy that targets CD30 were initially unsuccessful, but recent Phase I and II trials have shown promising results from the use of the immune conjugate brentuximab vedotin in HL and ALCL. Phase III trials are ongoing to evaluate clearly the benefit–risk ratio when compared with standard treatment. The first of these to report preliminary findings, the AETHERA trial, showed improved progression-free survival times in relapsing/refractory HL patients treated with brentuximab vedotin as a consolidation therapy after autologous stem cell transplantation compared with those receiving placebo. Patients with rarer CD30+ lymphomas may also benefit from brentuximab vedotin therapy in the future. Moreover, combination treatment with immunomodulatory and cell cycle checkpoint modulators that are currently under development, as well as conventional chemotherapeutic agents, may yield further benefits. To this end, improved methods of CD30 detection and quantitation will improve the delineation of non-HL subtypes in which CD30-targeted therapy may be clinically indicated.

  11. Critical role of SHP2 (PTPN11) signaling in germinal center-derived lymphoma.

    Science.gov (United States)

    Jiang, Xin; Guo, Honggang; Wu, Jianguo; He, Qiang; Li, Yiqiao; Wang, Miao; Pan, Hongyang; Li, Wande; Wang, Jinjie; Wang, Qingqing; Shen, Jing; Ke, Yuehai; Zhou, Ren

    2014-12-01

    Germinal center lymphoma is a heterogeneous human lymphoma entity. Here we report that constitutive activity of SHP2 (PTPN11) and its downstream kinase ERK is essential for the viability of germinal center lymphoma cells and disease progression. Mechanistically, SHP2/ERK inhibition impedes c-Myc transcriptional activity, which results in the repression of proliferative phenotype signatures of germinal center lymphoma. Furthermore, SHP2/ERK signaling is required to maintain the CD19/c-Myc loop, which preferentially promotes survival of a distinct subtype of germinal center lymphoma cells carrying the MYC/IGH translocation. These findings demonstrate a critical function for SHP2/ERK signaling upstream of c-Myc in germinal center lymphoma cells and provide a rationale for targeting SHP2 in the therapy of germinal center lymphoma.

  12. Temozolomide Treatment for Pediatric Refractory Anaplastic Ependymoma with Low MGMT Protein Expression.

    Science.gov (United States)

    Komori, Kazutoshi; Yanagisawa, Ryu; Miyairi, Yosuke; Sakashita, Kazuo; Shiohara, Masaaki; Fujihara, Ikuko; Morita, Daisuke; Nakamura, Tomohiko; Ogiso, Yoshifumi; Sano, Kenji; Shirahata, Mitsuaki; Fukuoka, Kohei; Ichimura, Koichi; Shigeta, Hiroaki

    2016-01-01

    The benefit of postoperative chemotherapy for anaplastic ependymoma remains unknown. We report two pediatric patients with refractory anaplastic ependymoma treated with temozolomide (TMZ). We did not detect O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation in tumor samples; however, MGMT protein expression was low. With TMZ treatment, one patient had a 7-month complete remission; the other, stable disease for 15 months. Three other patients did not respond to TMZ; two had high and one low MGMT expression, and two showed no MGMT promoter methylation. These findings suggest that TMZ may be effective for pediatric refractory anaplastic ependymoma with low MGMT protein expression.

  13. Anaplastic myeloma presenting as mandibular swelling: Diagnosis by cytology

    Directory of Open Access Journals (Sweden)

    K Subitha

    2014-01-01

    Full Text Available Multiple myeloma is a disease resulting from clonal proliferation of plasma cells. A disease of the elderly, jaw lesions are seen in 14% of patients affected with myeloma. Rarely the oral and maxillofacial lesions can be the first manifestation of the disease. We report the case of a 75-year-old man who presented with mandibular swelling. Fine-needle aspiration cytology was done from the swelling and smears were suggestive of anaplastic myeloma, which is a rare and aggressive variant of myeloma. The diagnosis of a plasmacytoma was confirmed by biopsy. Further workup of the patient revealed osteolytic lesions in skull, M band in electrophoresis and evidence of renal failure. Peripheral smear and bone marrow findings were also consistent with myeloma.

  14. Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming

    DEFF Research Database (Denmark)

    Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin;

    2013-01-01

    Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity of nucleophosmin (NPM)/ALK chimeric protein, the dominant form of ALK...... with the cytokine revealed a very similar, albeit inverse, gene-regulation pattern. Depending on the analysis method, up to 67% of the affected genes were modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT- and IL-2-signaling pathways topped the list of pathways identified...... as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes-CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4-was confirmed at the protein level. In both ALK(+) TCL and IL-2-stimulated ALK(-) TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly...

  15. Fusion tyrosine kinase NPM-ALK Deregulates MSH2 and suppresses DNA mismatch repair function novel insights into a potent oncoprotein.

    Science.gov (United States)

    Young, Leah C; Bone, Kathleen M; Wang, Peng; Wu, Fang; Adam, Benjamin A; Hegazy, Samar; Gelebart, Pascal; Holovati, Jelena; Li, Liang; Andrew, Susan E; Lai, Raymond

    2011-07-01

    The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK(+)ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P = 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.

  16. Malignant lymphoma of the conjunctiva

    DEFF Research Database (Denmark)

    Kirkegaard, Marina M; Coupland, Sarah E; Prause, Jan U;

    2015-01-01

    Conjunctival lymphomas constitute 25% of all ocular adnexal lymphomas. The majority are B-cell non-Hodgkin lymphomas (NHLs) (98%), whereas conjunctival T-cell NHLs are rare (2%). The most frequent subtype of conjunctival B-cell lymphoma is extranodal marginal zone lymphoma (EMZL; 81%), followed b...

  17. Racial disparities in anaplastic oligodendroglioma: An analysis on 1643 patients.

    Science.gov (United States)

    Shin, Jacob Y; Yoon, Ja Kyoung; Diaz, Aidnag Z

    2017-03-01

    The objective of our study is to determine the influence of race on overall survival (OS) for anaplastic oligodendroglioma (AO). Data were extracted from the National Cancer Data Base (NCDB). Chi-square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 1643 patients with AO were identified. 1386 (84.3%) were White, 83 (5.0%) Black, 133 (8.1%) Hispanic, and 41 (2.5%) were Asian. White and Black patients were significantly older than Hispanic and Asian patients (49.3% vs. 49.4% vs. 33.1% vs. 39.0%, p=0.003). Black patients were significantly less likely to be insured than White patients (12.8 vs. 7.2%, p<0.001) and significantly more likely to have lower income than other races (p<0.001). A trend towards higher comorbidity burden and lower rate of gross total resection was seen in Black patients. Black patients had significantly worse five-year OS compared to White, Hispanic, and Asian patients (40.3% vs. 52.3% vs. 67.8% vs. 67.7%, p=0.028). Of those who received adjuvant chemoRT, Black patients still had significantly worse OS compared to White patients (p=0.021). On multivariate analysis, Black race, older age at diagnosis, and not receiving adjuvant chemoradiotherapy were independent prognostic factors for worse OS in anaplastic oligodendroglioma. Future studies are warranted to help determine predictors for unfavorable molecular status, ways to optimize management of comorbidities, and interventions to help ensure adequate access to medical care for all patients to better care for those who may be at more risk for poorer outcome.

  18. A case of composite classical and nodular lymphocyte predominant Hodgkin lymphoma with progression to diffuse large B-cell non-Hodgkin lymphoma: Diagnostic difficulty in fine-needle aspiration cytology.

    Science.gov (United States)

    Das, Dilip K; Sheikh, Zafar A; Al-Shama'a, Mariam H; John, Bency; Alawi, Abdulla M S; Junaid, Thamradeen A

    2017-03-01

    A small percentage of nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) progresses to diffuse large B-cell lymphoma (DLBCL). There have also been rare reports of gray zone lymphoma with features intermediate between classical Hodgkin lymphoma (CHL) and DLBCL. We report a very rare case of composite lymphoma (CHL and NLPHL) progressing to DLBCL, and highlight the diagnostic difficulty faced during its fine-needle aspiration (FNA) cytology diagnosis. A 65-year-old woman presented with a right axillary swelling which was subjected to FNA cytology. The routine FNA cytology diagnosis was anaplastic large cell lymphoma (ALCL) but immunocytochemistry did not support this diagnosis completely. The histopathological diagnosis of the excised lymph node was NLPHL with progression to DLBCL in our hospital but in a hospital abroad where the patient was treated, the reviewed diagnosis was CHL. The patient had a rapid downhill course with development of terminal pleural effusion and died approximately one year from initial diagnosis.The review of the cyto-histologic material along with additional immunocyto/histochemical studies and the clinical course of the disease support the diagnosis of a composite lymphoma (CHL and NLPHL) with progression to DLBCL. It is suggested that all the three lesions were clonally related. Diagn. Cytopathol. 2017;45:262-266. © 2016 Wiley Periodicals, Inc.

  19. Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming.

    Science.gov (United States)

    Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin; Wang, Hong Y; Cheng, Mangeng; Baldwin, Donald; Tobias, John W; Schuster, Stephen J; Woetmann, Anders; Zhang, Qian; Turner, Suzanne D; Ødum, Niels; Wasik, Mariusz A

    2013-12-15

    Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity of nucleophosmin (NPM)/ALK chimeric protein, the dominant form of ALK expressed in T cell lymphomas (TCLs), closely resembles cell activation induced by IL-2, the key cytokine supporting growth and survival of normal CD4(+) T lymphocytes. Direct comparison of gene expression by ALK(+) TCL cells treated with an ALK inhibitor and IL-2-dependent ALK(-) TCL cells stimulated with the cytokine revealed a very similar, albeit inverse, gene-regulation pattern. Depending on the analysis method, up to 67% of the affected genes were modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT- and IL-2-signaling pathways topped the list of pathways identified as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes-CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4-was confirmed at the protein level. In both ALK(+) TCL and IL-2-stimulated ALK(-) TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly by the STAT5 and STAT3 transcription factors, whereas transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms the target CD4(+) T lymphocytes, at least in part, by using the pre-existing, IL-2-dependent signaling pathways.

  20. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus.

    Science.gov (United States)

    Nador, R G; Cesarman, E; Chadburn, A; Dawson, D B; Ansari, M Q; Sald, J; Knowles, D M

    1996-07-15

    We recently discovered the Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) in an uncommon and unusual subset of AIDS-related lymphomas that grow mainly in the body cavities as lymphomatous effusions without an identifiable contiguous tumor mass. The consistent presence of KSHV and certain other distinctive features of these body cavity-based lymphomas suggest that they represent a distinct entity. We tested this hypothesis by investigating 19 malignant lymphomatous effusions occurring in the absence of a contiguous tumor mass for their clinical, morphologic, immunophenotypic, viral, and molecular characteristics, KSHV was present in 15 of 19 lymphomas. All four KSHV-negative lymphomatous effusions exhibited Burkitt or Burkitt-like morphology and c-myc gene rearrangements and, therefore, appeared to be Burkitt-type lymphomas occurring in the body cavities. In contrast, all 15 KSHV-positive lymphomatous effusions exhibited a distinctive morphology bridging large-cell immunoblastic lymphoma and anaplastic large-cell lymphoma, and all 12 cases studied lacked c-myc gene rearrangements. In addition, these lymphomas occurred in men (15/15), frequently but not exclusively in association with HIV infection (13/15), in which homosexuality was a risk factor (13/13), presented initially as a lymphomatous effusion (14/15), remained localized to the body cavity of origin (13/15), expressed CD45 (15/15) and one or more activation-associated antigens (9/10) in the frequent absence of B-cell-associated antigens (11/15), exhibited clonal immunoglobulin gene rearrangements (13/13), contained Epstein-Barr virus (14/15), and lacked bcl-2, bcl-6, ras and p53 gene alterations (13/15). These findings strongly suggest that the KSHV-positive malignant lymphomatous effusions represent a distinct clinicopathologic and biologic entity and should be distinguished from other malignant lymphomas occurring in the body cavities. Therefore, we recommend that these malignant lymphomas be

  1. Intracellular TCR-signaling pathway: novel markers for lymphoma diagnosis and potential therapeutic targets.

    Science.gov (United States)

    Agostinelli, Claudio; Rizvi, Hasan; Paterson, Jennifer; Shende, Vishvesh; Akarca, Ayse U; Agostini, Elena; Fuligni, Fabio; Righi, Simona; Spagnolo, Sebastiano; Piccaluga, Pier Paolo; Clark, Edward A; Pileri, Stefano A; Marafioti, Teresa

    2014-10-01

    Despite the immunologic functions of T-cell receptor signaling molecules being extensively investigated, their potential as immunohistochemical markers has been poorly explored. With this background, we evaluated the expression of 5 intracellular proteins-GADS, DOK2, SKAP55, ITK, and PKCα-involved in T-cell receptor signaling in normal and neoplastic hematologic tissue samples, using antibodies raised against fixation-resistant epitopes of the 5 molecules. All 5 antibodies were associated with normal T-cell differentiation. GADS, DOK2, SKAP55, and ITK turned out to be T-cell lineage-specific markers in the setting of lymphoid and myeloid precursor neoplasms but showed differential expression in peripheral T-cell lymphoma (PTCL) subtypes, being detected in PTCL/not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma but negative in anaplastic large cell lymphoma (ALCL). Peripheral B-cell lymphomas were consistently negative for ITK, with occasional cases showing expression of DOK2 and SKAP55, and a proportion (47%) of hairy cell leukemias were GADS. Notably, PKCα highlighted a defective antigen in both PTCL/NOS (6%) and angioimmunoblastic T-cell lymphoma (10%), mostly negative in ALCL, and was aberrantly expressed in classical Hodgkin lymphoma (65%), Burkitt lymphoma (48%), and plasma cell myeloma (48%). In conclusion, all five molecules evaluated play a role in T-cell differentiation in normal and neoplastic tissues. They can be applied confidently to routine sections contributing primarily to assignment of T-lineage differentiation in the setting of hematopoietic precursor neoplasms (GADS/DOK2/SKAP55/ITK) and for the differential diagnosis between ALCL and PTCL/NOS (GADS/DOK2/SKAP55/ITK) or classical Hodgkin lymphoma (PKCα). Finally, association with specific tumor subtypes may have therapeutic potential.

  2. Lymphomas of large cells.

    Science.gov (United States)

    Staples, W G; Gétaz, E P

    1977-09-03

    Historial aspects of the classification of large-cell lymphomas are described. Immunological characterization of the lymphomas has been made possible by identification of T and B lymphocytes according to their cell membrane surface characteristics. The pathogenesis of lymphomas has been clarified by the germinal (follicular) centre cell concepts of Lennert and Lukes and Collins. The various classifications are presented and compared. Whether these subdivisions will have any relevance in the clinical context remains to be seen.

  3. Bilateral primary breast lymphoma

    Institute of Scientific and Technical Information of China (English)

    Jung Im Yi; Byung Joo Chae; Ja Seong Bae; Bong Joo Kang; Ahwon Lee; Byung Joo Song; Sang Seol Jung

    2010-01-01

    @@ Primary breast lymphoma (PBL) is rare, accounting for 0.04%-0.50% of breast malignancies and 1.7% of extranodal lymphoma.1,2 The originally described diagnostic criteria for PBL2 remains the standard definition for this disease. These criteria are breast location as the clinical site of presentation, absence of history of previous lymphoma or evidence of widespread disease at diagnosis, close association of lymphoma with breast tissue in pathologic specimens, and involvement of ipsilateral lymph nodes if they develop simultaneously with PBL.

  4. Primary gastrointestinal lymphoma

    Institute of Scientific and Technical Information of China (English)

    Prasanna Ghimire; Guang-Yao Wu; Ling Zhu

    2011-01-01

    Gastrointestinal tract is the most common extranodal site involved by lymphoma with the majority being non-Hodgkin type. Although lymphoma can involve any part of the gastrointestinal tract, the most frequent sites in order of its occurrence are the stomach followed by small intestine and ileocecal region. Gastrointestinal tract lymphoma is usually secondary to the widespread nodal diseases and primary gastrointestinal tract lymphoma is relatively rare. Gastrointestinal lymphomas are usually not clinically specific and indistinguishable from other benign and malignant conditions. Diffuse large B-cell lymphoma is the most common pathological type of gastrointestinal lymphoma in essentially all sites of the gastrointestinal tract, although recently the frequency of other forms has also increased in certain regions of the world. Although some radiological features such as bulky lymph nodes and maintenance of fat plane are more suggestive of lymphoma, they are not specific,thus mandating histopathological analysis for its definitive diagnosis. There has been a tremendous leap in the diagnosis, staging and management of gastrointestinal lymphoma in the last two decades attributed to a better insight into its etiology and molecular aspect as well as the knowledge about its critical signaling pathways.

  5. Bilateral Primary Intraocular Lymphoma

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    Mehrdad Karimi

    2011-01-01

    Full Text Available Purpose: To report a case of bilateral primary intraocular lymphoma. Case report: A 33-year-old man presented with bilateral blurred vision since two years ago. Examination revealed large keratic precipitates, anterior chamber reaction, posterior subcapsular cataracts, and vitreous infiltration. After a short trial of topical and periocular steroids, diagnostic 25-gauge pars plana vitrectomy was performed and cytologic evaluation of the aspirate confirmed a diagnosis of intraocular lymphoma. The patient was subsequently managed with intravitreal methotrexate in both eyes and responded favorably. Central nervous system workup for lymphoma was negative. Conclusion: Primary intraocular lymphoma should be considered in young adults suffering from chronic recalcitrant panuveitis.

  6. Anaplastic meningioma: progression from atypical and chordoid morphotype with morphologic spectral variation at recurrence.

    Science.gov (United States)

    Bollag, Roni J; Vender, John R; Sharma, Suash

    2010-06-01

    The current WHO 2007 classification divides meningiomas into a 3-grade prognostic hierarchy. Recent literature evokes two pathways to disease progression in meningiomas akin to a comparable paradigm in gliomas, but without similar prognostic connotation: de novo anaplastic meningioma (better prognosis), and transformed meningioma (worse prognosis). We present two adult cases of transformed meningiomas that display a spectrum of morphologic progression. Case 1 at presentation showed a random admixture of meningothelial, atypical and anaplastic meningioma. The tumor recurred as anaplastic meningioma. Case 2 presented as a chordoid meningioma, but recurred as anaplastic meningioma mainly at the invasive front in transition with residual chordoid pattern. Of interest, portions of tumor also showed papillary configuration. In accordance with the dire prognosis for anaplastic meningioma, both patients succumbed to their disease within 2 months of recurrence. The present study highlights two main points: First, that proper recognition of focal high-grade areas in a heterogeneous low-grade meningioma (case 1) provides critical morphologic clues to spatial histologic progression and predicts aggressive biologic behavior, as evidenced by progression to frankly anaplastic meningioma at recurrence. Second, the presence of papillary in addition to anaplastic areas, in the recurrence of a previously diagnosed chordoid meningioma supports the ostensibly heightened transforming potential of grade II meningiomas, but also reflects on the morphologic heterogeneity of high-grade meningiomas, and their potentially diverse pathways of progression. We propose that grading of meningiomas as outlined by WHO is of more critical prognostic import than histologic sub-typing, and must include a thorough survey of the tumor-brain interface. Future molecular genetic correlates, akin to those characterized in gliomas, could help stratify prognostic subcategories to refine meningioma grading, and

  7. Peripheral T-cell lymphoma: Frequency and distribution in a tertiary referral center in South India

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    Deepak K Burad

    2012-01-01

    Full Text Available Background and Aim: Peripheral T/NK-cell lymphomas are uncommon types of non-Hodgkin′s lymphoma (NHL with a higher frequency in Far East countries as compared to the West. This study was undertaken to ascertain the frequency and distribution pattern of peripheral T-cell lymphomas (PTCLs diagnosed in a tertiary care center in South India. Materials and Methods: This retrospective study was carried out in Department of General Pathology, Christian Medical College, Vellore. The time period was for 2 years from 1 st January 2008 till 31st December 2009. All PTCLs were reviewed and classified according to the World Health Organization (WHO 2008 classification. Results: Of a total of 1032 cases of NHL, 180 cases were PTCL, which accounted for 17.4% cases of all the NHLs. Of these, PTCL, not otherwise specified (PTCL, NOS was the most common subtype (48 cases, 26.1%, followed by anaplastic large cell lymphoma (41 cases, 22.8%, mycosis fungoides (21 cases, 11.7%, angioimmunoblastic T-cell lymphoma (16 cases, 8.9%, subcutaneous panniculitis like T-cell lymphoma (15 cases, 8.4%, extranodal NK/T-cell lymphoma, nasal type (12 cases, 6.7%, and hepatosplenic T-cell lymphoma (10 cases, 5.6%. The most common primary site of presentation was nodal accounting for 42% followed by cutaneous (34%, upper aerodigestive sites (8.9%, spleen (6.7%, and gastrointestinal tract (GIT; 3.3%. Conclusions: This is the largest single study on PTCLs in India and we document that its frequency is higher than that reported in Western literature and previous Indian studies and almost similar to that reported in some Far East studies. The frequency of mycosis fungoides, subcutaneous panniculitis like T-cell lymphoma, and hepatosplenic T-cell lymphoma was higher than that reported in the World literature and previous Indian studies. The frequency of extranodal NK/T-cell lymphoma and angioimmunoblastic T-cell lymphoma was much lower than that reported in the Far East literature.

  8. Anaplastic astrocytoma 14 years after radiotherapy for pituitary adenoma

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Masaru; Misumi, Syuuzou; Kurosaki, Syuuhei; Shibasaki, Takashi; Ohye, Chihiro (Gunma Univ., Maebashi (Japan). School of Medicine)

    1992-04-01

    A case of anaplastic astrocytoma following radiotherapy for growth hormone secreting pituitary adenoma is presented with a review of the literature. A 43 year old female was admitted with signs of acromegaly and hypertension. An eosinophilic pituitary adenoma was subtotally removed by transsphenoidal approach, followed by 60 Gy irradiation using a 2x2 cm lateral field. Fourteen years later at the age of 57, she suffered from headache, recent-memory disturbance and uncinate fits. CT scan and MRI disclosed ring-like enhanced mass lesion in the left temporal lobe, corresponding to the previous irradiated field. {sup 18}F-FDG PET showed hypermetabolism at the lesion. Left frontotemporal craniotomy was performed, and a reddish gray gelatinous tumor containing necrotic center and cyst was partially removed. Histologically, the tumor consisted of hypercellular astrocytic cells with perivascular pseudorosette. Coagulation necrosis at the center of the tumor, and hyalinosis and fibrosis of the blood vessels in and around the tumor, which might have been caused by the antecedent radiotherapy, were recognized. Postoperative radiotherapy and chemotherapy, were given, however, she expired 13 months after the operation. Seven cases, including ours, of malignant glioma following radiotherapy for pituitary adenoma were reported in the literature. A total dose of irradiation varies from 45 to 95 Gy with a mean of 50 Gy. The period of latency before tumor occurrence ranges from 5 to 22 years with a mean of 10 years. The differentiation of radiation-induced gliomas from radionecrosis of the brain is also discussed. (author).

  9. O-GlcNAcylation enhances anaplastic thyroid carcinoma malignancy.

    Science.gov (United States)

    Cheng, Y U; Li, Honglun; Li, Jianlin; Li, Jisheng; Gao, Yan; Liu, Baodong

    2016-07-01

    O-linked N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation), a dynamic post-translational modification of nuclear and cytoplasmic proteins, may have a critical role in the regulation of biological cell processes and human cancer. O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Accumulating evidence suggests that O-GlcNAcylation is involved in a variety of types of human cancer. However, the exact role of O-GlcNAcylation in tumor pathogenesis or progression remains to be established. Computed tomography scans of patients with anaplastic thyroid carcinoma (ATC) reveal a rapid growth rate and invasion. The present study demonstrated that O-GlcNAcylation accelerates the progression of ATC. The global O-GlcNAc level of intracellular proteins was increased by overexpression of OGT or downregulation of OGA activity with the specific inhibitor Thiamet-G. By contrast, the global O-GlcNAc level was decreased by silencing of OGT. MTT assay indicated that O-GlcNAcylation significantly promotes cell proliferation. Furthermore, O-GlcNAcylation enhanced cellular biological functions, such as colony formation ability, migration and invasion, of ATC cells in vitro. The findings of the present study suggest that O-GlcNAcylation is associated with malignant properties of thyroid cancer, and may be a potential target for the diagnosis and treatment of thyroid cancer.

  10. Large B-cell lymphoma arising in cardiac myxoma or intracardiac fibrinous mass: a localized lymphoma usually associated with Epstein-Barr virus?

    Science.gov (United States)

    Aguilar, Cristian; Beltran, Brady; Quiñones, Pilar; Carbajal, Tomas; Vilcapaza, Jorge; Yabar, Alejandro; Segura, Pedro; Quintanilla-Martinez, Leticia; Miranda, Roberto N; Castillo, Jorge J

    2015-01-01

    Primary cardiac neoplasms are rare. However, among them, cardiac myxoma is the most common tumor. In contrast, primary cardiac lymphoma within a cardiac myxoma is extremely rare and might be difficult to diagnose because of non-specific clinical manifestations. We report the case of a previously healthy 52-year-old man who presented with acute onset of transient dysarthria and left hemiplegia. A transthoracic echocardiography showed a 6×2.5-cm solid mass in the left atrium, which was subsequently resected. Histological, immunohistochemical, and molecular analyses revealed an EBV-associated CD30-positive large B-cell lymphoma with anaplastic morphology within a cardiac myxoma and fibrinous material. Staging studies showed no evidence of lymphoma elsewhere. The patient achieved complete remission and is alive 42 months after diagnosis, and did not receive chemotherapy. We discuss the clinical and pathologic features of lymphoma arising in cardiac myxoma or in intra-atrial fibrinoid mass and the potential role of IL-6 in its pathogenesis.

  11. Value of CT-guided core-needle biopsy in diagnosis and classification of malignant lymphomas using automated biopsy gun

    Institute of Scientific and Technical Information of China (English)

    Li Li; Qiu-Liang Wu; Li-Zhi Liu; Yun-Xian Mo; Chuan-Miao Xie; Lie Zheng; Lin Chen; Pei-Hong Wu

    2005-01-01

    AIM: To evaluate the value of CT-guided core-needle biopsy in diagnosis and classification of malignant lymphomas.METHODS: From January 1999 to October 2004, CT-guided core-needle biopsies were performed in 80 patients with suspected malignant lymphoma. Biopsies were performed with an 18-20 G biopsy-cut (CR Bard, Inc., Covington, GA,USA) needle driven by a spring-loaded Bard biopsy gun.RESULTS: A definite diagnosis and accurate histological subtype were obtained in 61 patients with a success rate of 76.25% (61/80). Surgical sampling was performed in 19 patients (23.75%) with non-diagnostic core-needle biopsies. The success rate of CT-guided core-needle biopsy varied with the histopathologic subtypes in our group.The relatively high success rates of core-needle biopsy were noted in diffuse large B-cell non-Hodgkin's lymphoma (NHL, 88.89%) and peripheral T-cell NHL (90%). However,the success rates were relatively low in anaplastic large cell (T/null cell) lymphoma (ALCL, 44.44%) and Hodgkin's disease (HD, 28.57%) in our group.CONCLUSION: CT-guided core-needle biopsy is a reliable means of diagnosing and classifying malignant lymphomas,and can be widely applied in the management of patients with suspected malignant lymphoma.

  12. Biomarkers for lymphoma

    Science.gov (United States)

    Zangar, Richard C.; Varnum, Susan M.

    2014-09-02

    A biomarker, method, test kit, and diagnostic system for detecting the presence of lymphoma in a person are disclosed. The lymphoma may be Hodgkin's lymphoma or non-Hodgkin's lymphoma. The person may be a high-risk subject. In one embodiment, a plasma sample from a person is obtained. The level of at least one protein listed in Table S3 in the plasma sample is measured. The level of at least one protein in the plasma sample is compared with the level in a normal or healthy subject. The lymphoma is diagnosed based upon the level of the at least one protein in the plasma sample in comparison to the normal or healthy level.

  13. Angioimmunoblastic T-Cell Lymphoma

    Science.gov (United States)

    Angioimmunoblastic T-Cell Lymphoma Overview Lymphoma is the most common blood cancer. The two main forms of lymphoma are ... develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). Cancerous lymphocytes can travel to ...

  14. Paucicellular variant of anaplastic thyroid carcinoma: A diagnostic pitfall in thyroid pathology

    Directory of Open Access Journals (Sweden)

    Reetika Sharma

    2016-01-01

    Full Text Available Paucicellular variant is a rare variant of anaplastic carcinoma. Anaplastic thyroid carcinomas usually creates no problems in histologic diagnosis because of the obvious invasive growth, high cellularity, and marked degree of anaplasia, but paucicellular variant of anaplastic carcinoma is problematic in diagnosis because of its histologic mimicry to benign lesions, e.g. Riedel disease and fibrous variant of Hashimoto thyroiditis, i.e. prominent fibrosis and low cellularity. It is important to distinguish it from these two lesions because both are reactive conditions with favorable prognosis while anaplastic carcinoma is a malignant condition with poor prognosis. We present a case of 45-year-old female presented with a history of thyroid swelling for 10 years. The cytological diagnosis was given as colloid goiter while histopathological examination turned out to be paucicellular variant of anaplastic carcinoma thyroid. To conclude paucicellular variant is the entity to which all pathologists should be familiar and should know differential diagnosis while dealing with any fibrosed lesion of the thyroid.

  15. Nonconventional papillary thyroid carcinomas with pleomorphic tumor giant cells: a diagnostic pitfall with anaplastic carcinoma.

    Science.gov (United States)

    Hommell-Fontaine, Juliette; Borda, Angela; Ragage, Florence; Berger, Nicole; Decaussin-Petrucci, Myriam

    2010-06-01

    The presence of pleomorphic tumor giant cells in thyroid carcinomas of follicular cell origin is always worrisome for the pathologist as they first of all refer to anaplastic carcinoma, one of the most aggressive human malignancies. However, non-anaplastic pleomorphic giant cells are well described in other thyroid diseases, most often benign. In this paper, we describe four cases of papillary thyroid carcinoma displaying pleomorphic tumor giant cells with features that differ from those of anaplastic carcinoma. Pleomorphic giant cells were admixed with the underlying thyroid carcinoma and constituted from 5% to 25% of the tumor. Cytologically, they had an abundant eosinophilic cytoplasm with large and irregular nuclei. Compared to pleomorphic giant cells of anaplastic carcinoma, they reproduced the growth pattern of the underlying carcinoma, had a low mitotic index without necrosis or inflammation, and were reactive with thyroglobulin and thyroid-specific transcription factor-1 and strongly and diffusely positive for cytokeratin AE1/AE3. After 16-84 months of follow-up, patients are relapse-free and still alive. These cases show that pleomorphic tumor giant cells arising in papillary thyroid carcinomas do not always represent dedifferentiation and progression to anaplastic carcinoma. Distinction among these processes is critical as their treatment and prognosis are very different.

  16. TrkAIII Promotes Microtubule Nucleation and Assembly at the Centrosome in SH-SY5Y Neuroblastoma Cells, Contributing to an Undifferentiated Anaplastic Phenotype

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    Antonietta R. Farina

    2013-01-01

    Full Text Available The alternative TrkAIII splice variant is expressed by advanced stage human neuroblastomas (NBs and exhibits oncogenic activity in NB models. In the present study, employing stable transfected cell lines and assays of indirect immunofluorescence, immunoprecipitation, Western blotting, microtubule regrowth, tubulin kinase, and tubulin polymerisation, we report that TrkAIII binds α-tubulin and promotes MT nucleation and assembly at the centrosome. This effect depends upon spontaneous TrkAIII activity, TrkAIII localisation to the centrosome and pericentrosomal area, and the capacity of TrkAIII to bind, phosphorylate, and polymerise tubulin. We propose that this novel role for TrkAIII contributes to MT involvement in the promotion and maintenance of an undifferentiated anaplastic NB cell morphology by restricting and augmenting MT nucleation and assembly at the centrosomal MTOC.

  17. Primary pediatric gastrointestinal lymphoma

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    Ranjana Bandyopadhyay

    2011-01-01

    Full Text Available Background: Primary non-Hodgkin′s lymphoma (NHL of the gastrointestinal (GI tract is the most common extranodal lymphoma in pediatric age group. Yet, the overall incidence is very low. The rarity of the disease as well as variable clinical presentation prevents early detection when the possibility of cure exists. Materials and Methods: We studied six cases of primary GI NHL in pediatric age group with reference to their clinical presentation, anatomic distribution and histopathologic characteristics. Results: All were males except one. Intestinal obstruction was the presenting feature in 50%. Half the cases showed ileocaecal involvement, while large bowel was involved in 16%. Histology showed four cases of diffuse large B-cell lymphoma (DLBCL, one case of Burkitt lymphoma, and one Burkitt-like lymphoma. Immunohistochemistry for Tdt, CD20, CD3, CD30, bcl2, bcl6 confirmed the morphological diagnosis. Conclusion: Pediatric GI lymphoma commonly involves the ileocaecal region and presents with intestinal obstruction. A higher prevalence of DLBCL is found compared to other series. A high proliferative index is useful in differentiating Burkitt-like lymphoma from DLBCL.

  18. Incidentally Detected Kaposi Sarcoma of Adrenal Gland with Anaplastic Features in an HIV Negative Patient

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    Zeliha Esin Celik

    2016-01-01

    Full Text Available Kaposi sarcoma (KS, a vascular tumor caused by infection with human herpesvirus 8 (HHV8, is a systemic disease that can present with cutaneous lesions with or without visceral involvement. Very few cases of KS, most of which were associated with AIDS, have been reported in the adrenal gland. Anaplastic transformation of KS is a rare clinical presentation known as an aggressive disease with local recurrence and metastatic potential. We report here a 47-year-old HIV negative male presented with extra-adrenal symptoms and had an incidentally detected anaplastic adrenal KS exhibited aggressive clinical course. To the best of our knowledge, this is the first case of anaplastic primary adrenal KS without mucocutaneous involvement but subsequently developed other side adrenal metastases in an HIV negative patient.

  19. Incidentally Detected Kaposi Sarcoma of Adrenal Gland with Anaplastic Features in an HIV Negative Patient

    Science.gov (United States)

    Celik, Murat; Sen, Erdem; Cebeci, Hakan; Ata, Ozlem; Yavas, Cagdas

    2016-01-01

    Kaposi sarcoma (KS), a vascular tumor caused by infection with human herpesvirus 8 (HHV8), is a systemic disease that can present with cutaneous lesions with or without visceral involvement. Very few cases of KS, most of which were associated with AIDS, have been reported in the adrenal gland. Anaplastic transformation of KS is a rare clinical presentation known as an aggressive disease with local recurrence and metastatic potential. We report here a 47-year-old HIV negative male presented with extra-adrenal symptoms and had an incidentally detected anaplastic adrenal KS exhibited aggressive clinical course. To the best of our knowledge, this is the first case of anaplastic primary adrenal KS without mucocutaneous involvement but subsequently developed other side adrenal metastases in an HIV negative patient.

  20. Radiotherapy for Hodgkin lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Specht, Lena [Rigshospitalet Copenhagen Univ. (Denmark). Depts. of Oncology and Haematology; Yahalom, Joachim (eds.) [Memorial Sloan-Kettering Cancer, New York, NY (United States). Dept. of Radiation Oncology

    2011-07-01

    This book deals in detail with all aspects of the best practice in modern radiotherapy for Hodgkin lymphoma. It provides the background and rationale for the inclusion of radiotherapy in today's combined-modality approach, including special clinical situations such as Hodgkin lymphoma in children, in the pregnant patient, and in the elderly. Radiotherapy planning using state-of-the-art imaging, target definition, planning software, and treatment equipment is expounded in detail. Acute and long-term side effects of radiotherapy are analyzed, and the implications for modern radiotherapy approaches in Hodgkin lymphomas are explained. (orig.)

  1. The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met.

    Science.gov (United States)

    Williamson, Ashley J; Doscas, Michelle E; Ye, Jin; Heiden, Katherine B; Xing, Mingzhao; Li, Yi; Prinz, Richard A; Xu, Xiulong

    2016-03-01

    The sonic hedgehog (Shh) pathway is highly activated in thyroid neoplasms and promotes thyroid cancer stem-like cell phenotype, but whether the Shh pathway regulates thyroid tumor cell motility and invasiveness remains unknown. Here, we report that the motility and invasiveness of two anaplastic thyroid tumor cell lines, KAT-18 and SW1736, were inhibited by two inhibitors of the Shh pathway (cyclopamine and GANT61). Consistently, the cell motility and invasiveness was decreased by Shh and Gli1 knockdown, and was increased by Gli1 overexpression in KAT-18 cells. Mechanistic studies revealed that Akt and c-Met phosphorylation was decreased by a Gli1 inhibitor and by Shh and Gli1 knockdown, but was increased by Gli1 overexpression. LY294002, a PI-3 kinase inhibitor, and a c-Met inhibitor inhibited the motility and invasiveness of Gli1-transfected KAT-18 cells more effectively than the vector-transfected cells. Knockdown of Snail, a transcription factor regulated by the Shh pathway, led to decreased cell motility and invasiveness in KAT-18 and SW1736 cells. However, key epithelial-to-mesenchymal transition (EMT) markers including E-cadherin and vimentin as well as Slug were not affected by cyclopamine and GANT61 in either SW1736 or WRO82, a well differentiated follicular thyroid carcinoma cell line. Our data suggest that the Shh pathway-stimulated thyroid tumor cell motility and invasiveness is largely mediated by AKT and c-Met activation with little involvement of EMT.

  2. Treatment Options for Adult Hodgkin Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  3. General Information about AIDS-Related Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  4. General Information about Adult Hodgkin Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  5. Treatment Options for AIDS-Related Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  6. Treatment Option Overview (Childhood Hodgkin Lymphoma)

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  7. Treatment Option Overview (Adult Hodgkin Lymphoma)

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  8. Stages of Childhood Non-Hodgkin Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  9. Treatment Options for Hodgkin Lymphoma during Pregnancy

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  10. Anaplastic pleomorphic xanthoastrocytoma with spinal leptomeningeal spread at the time of diagnosis in an adult.

    Science.gov (United States)

    Benjamin, Carolina; Faustin, Arline; Snuderl, Matija; Pacione, Donato

    2015-08-01

    We describe the first patient, to our knowledge, with anaplastic pleomorphic xanthoastrocytoma (PXA) with spinal leptomeningeal spread at the time of diagnosis and present a review of the literature. PXA is a tumor that typically has an indolent course but occasionally, when anaplastic features are present, behaves in a more aggressive manner. We found that PXA with spinal leptomeningeal spread at the time of diagnosis confers a worse prognosis. Craniospinal imaging should be obtained at time of diagnosis of PXA and the presence of leptomeningeal spread may be indicative of a more aggressive disease process.

  11. CD44 variant expression in cutaneous T-cell lymphoma.

    Science.gov (United States)

    Orteu, C H; Li, W; Allen, M H; Smith, N P; Barker, J N; Whittaker, S J

    1997-07-01

    Expression of the lymphocyte homing receptor CD44 and its splice variants have been linked to tumour dissemination and poor prognosis in non-Hodgkin's lymphoma. Specifically, the in vitro expression of variant exon V6 confers metastatic potential in rat pancreatic carcinoma cell lines. In this study, we investigated the expression of CD44 splice variants in cutaneous T-cell lymphomas, including patients with mycosis fungoides (MF), Sezary syndrome (SS), large-cell anaplastic lymphoma (LCAL) and HTLV1-associated cutaneous lymphoma. In addition, 4 involved lymph nodes from 2 patients with MF and 1 patient with SS were examined. Inflammatory dermatoses, lichen planus and psoriasis, and normal skin were also studied. Immunohistochemistry was performed using a panel of monoclonal antibodies, including those with specificity for CD44H (standard isoform) and variant exons V3, V6 and V8-9. Normal epidermal keratinocytes were consistently CD44H and CD44 V3, V6 and V8-9 positive. In all the different clinicopathological subtypes and stages of cutaneous T-cell lymphomas, including involved lymph nodes, tumour cells consistently expressed CD44H, but were CD44 V3 and V6 negative. CD44 V8-9 was expressed on a majority of tumour cells in 2/5 LCAL and on occasional tumour cells in 2/5 LCAL. Occasional V8-9 positive tumour cells were also identified in 6/13 MF, 1/4 SS and 3/4 HTLV1. In 2/3 lymph node samples from 2 patients with tumour-stage MF, CD44 V8-9 expression was found on a small percentage of atypical mononuclear cells. Scattered V8-9 positive dermal mononuclear cells were present in sections of lichen planus and psoriasis. We have found no evidence to suggest that the metastasis-associated CD44 variant exon (V6) is expressed in cutaneous T-cell lymphoma, or that CD44H expression is associated with an adverse prognostic group. It is not clear whether the strong expression of CD44 V8-9 in 2 patients with CD30 positive LCAL reflects activation status or metastatic potential.

  12. Lymphoma Research Foundation

    Science.gov (United States)

    ... the stem cell transplantation process. Read More LYMPHOMA RESEARCH Featured Researcher – David Scott, MBChB, PhD Dr. Scott ... and Advocacy News Action Center Advocacy Tool Kit Research LRF Research Portfolio Disease-Specific Focus Areas Grants ...

  13. Central nervous system involvement in T-cell lymphoma: A single center experience.

    Science.gov (United States)

    Gurion, Ronit; Mehta, Neha; Migliacci, Jocelyn C; Zelenetz, Andrew; Moskowitz, Alison; Lunning, Matthew; Moskowitz, Craig; Hamlin, Paul; Horwitz, Steven

    2016-05-01

    Background We characterized the incidence of central nervous system (CNS) involvement, risk factors and outcome in a large single institution dataset of peripheral T-cell lymphoma (PTCL). Methods Retrospective review of the PTCL database at Memorial Sloan Kettering Cancer Center. We identified 231 patients with any subtype of PTCL between 1994-2011 with a minimum six months of follow-up or an event defined as relapse or death. Results Histologies included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) (31.6%), angioimmunoblastic (16.9%), anaplastic large cell lymphoma (ALCL), ALK- (12.1%), ALCL, ALK + (6.1%), extranodal NK/T-cell lymphoma (7.4%), adult T-cell leukemia/lymphoma (ATLL) (7.4%), and transformed mycosis fungoides (8.7%). Seventeen patients had CNS disease (7%). Fifteen had CNS involvement with PTCL and two had diffuse large B-cell lymphoma and glioblastoma. Median time to CNS involvement was 3.44 months (0.16-103.1). CNS prophylaxis was given to 24 patients (primarily intrathecal methotrexate). Rates of CNS involvement were not different in patients who received prophylaxis. Univariate analysis identified stage III-IV, bone marrow involvement, >1 extranodal site and ATLL as risk factors for CNS disease. On multivariate analysis, >1 extranodal site and international prognostic index (IPI) ≥ 3 were predictive for CNS involvement. The median survival of patients with CNS involvement was 2.63 months (0.10-75). Conclusions Despite high relapse rates, PTCL, except ATLL, carries a low risk of CNS involvement. Prognosis with CNS involvement is poor and risk factors include: >1 extra nodal site and IPI ≥3.

  14. {sup 123}I-IMP SPET in the diagnosis of primary central nervous system lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikai, Tomonori; Fukahori, Tetsuhiro; Ishimaru, Junichiro; Kato, Akira; Uchino, Akira; Kudo, Sho [Dept. of Radiology, Saga Medical School, Nabeshima (Japan); Tabuchi, Kazuo [Dept. of Neurosurgery, Saga Medical School (Japan)

    2001-01-01

    We reviewed N-isopropyl-p-[{sup 123}I]iodoamphetamine ({sup 123}I-IMP) single-photon emission tomography (SPET) images of brain tumours and assessed the usefulness of {sup 123}I-IMP SPET for the diagnosis of primary central nervous system (CNS) lymphoma. We analysed 52 tumours that showed enhancement on magnetic resonance imaging: 11 malignant lymphomas, 3 anaplastic astrocytomas, 17 glioblastomas, 12 meningiomas, 4 metastatic brain tumours and 5 other brain tumours. {sup 123}I-IMP uptake in the tumours on early (15-min) and delayed (4-h) scans was visually classified as high, moderate or low as compared with the contralateral brain cortex. Early and delayed {sup 123}I-IMP uptake ratios comparing tumours with contralateral brain cortex (T/N ratio) were also calculated. In malignant lymphomas, the visual uptake of {sup 123}I-IMP was moderate to high on the delayed scans. The delayed T/N ratios were significantly higher than the early ratios (P<0.05) and all lymphomas, with the exception of one small one, had delayed ratios greater than 0.9. In non-lymphomatous tumours, the visual uptake of {sup 123}I-IMP was low on the delayed scans. The delayed T/N ratios were significantly lower than the early ratios (P<0.01) and all non-lymphomatous tumours had delayed ratios of less than 0.8. The T/N ratios of lymphomas were significantly higher than those of non-lymphomatous tumours on both early and delayed scans (P<0.0001). These results suggest that {sup 123}I-IMP SPET may be a useful tool in the differential diagnosis of primary CNS lymphoma. (orig.)

  15. Anaplastic carcinoma of pancreas:report of 6 cases and literature review

    Institute of Scientific and Technical Information of China (English)

    SHAO Cheng-hao; HU Xian-gui; GAO Li; TANG Yan; LIU Rui; ZHANG Yi-jie; ZHOU Ying-qi

    2005-01-01

    Objective:To investigate clinicopathological features,diagnosis and treatment of anaplastic carcinoma of the pancreas and to review relevant literature on this entity. Methods :A retrospective clinical analysis was made in 6 cases of anaplastic pancreatic carcinomas admitted from 1989 to 2001. Results:Anaplastic pancreatic carcinoma was found in 5 men and 1 woman with a mean age of 61.5 years. Tumor location was in the head of the pancreas in 3 patients,body and tail in 3 cases. Tumors were surgically resected in all patients, by pancreaticoduodenectomy in 1, by pancreaticoduodenectomy combined resection and reconstruction of superior mesenteric vein(SMV) in 1 ,by pancreaticoduodenectomy combined resection and reconstruction of SMV and superior mesenteric artery(SMA) in 1,by distal pancreatectomy in 2,by distal pancreatectomy combined total gastrotectomy in 1. Liver metastasis was found in one patient. Follow-up suggested the prognosis was poor with a mean survival of 5.5 months after operation. All patients were dead with tumor recurrence and liver metastasis. Conclusion:Histologically,anaplastic pancreatic carcinoma is characterized by pleomorphic cell carcinoma consisting of pleomorphic giant/small cells and spindle cells ,or osteoclast-like giant cell tumor composed of pleomorphic small cells,or pleomorphic giant cell carcinoma with osteoclastoid giant cells,and demonstrates aggressive biological behavior. Invasions to adjoined organ and metastasis are usual. The prognosis of this tumor appears to be very poor.

  16. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

    Science.gov (United States)

    Kim, S-M; Kim, H; Yun, M R; Kang, H N; Pyo, K-H; Park, H J; Lee, J M; Choi, H M; Ellinghaus, P; Ocker, M; Paik, S; Kim, H R; Cho, B C

    2016-07-18

    Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met

  17. 506U78 in Treating Patients With Recurrent or Refractory Non-Hodgkin's Lymphoma or T-cell Lymphoma

    Science.gov (United States)

    2013-01-22

    Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  18. Intravascular large B cell lymphoma

    Directory of Open Access Journals (Sweden)

    Ricardo García-Muñoz

    2014-01-01

    Full Text Available Intravascular large B cell lymphoma (IVBCL is a rare type of extranodal large B cell lymphoma characterized by selective growth of lymphoma cells within the microvasculature. We present an illustrative case of intravascular B cell lymphoma suspected by the presence of a very small monoclonal B cell population identified by immunophenotype and polymerase chain reaction in bone marrow. The diagnosis was confirmed by skin biopsy.

  19. Danish National Lymphoma Registry

    DEFF Research Database (Denmark)

    Arboe, Bente; Josefsson, Pär; Jørgensen, Judit;

    2016-01-01

    AIM OF DATABASE: The Danish National Lymphoma Registry (LYFO) was established in order to monitor and improve the diagnostic evaluation and the quality of treatment of all lymphoma patients in Denmark. STUDY POPULATION: The LYFO database was established in 1982 as a seminational database including...... all lymphoma patients referred to the departments of hematology. The database became nationwide on January 1, 2000. MAIN VARIABLES: The main variables include both clinical and paraclinical variables as well as details of treatment and treatment evaluation. Up to four forms are completed for each...... patient: a primary registration form, a treatment form, a relapse form, and a follow-up form. Variables are used to calculate six result quality indicators (mortality 30 and 180 days after diagnosis, response to first-line treatment, and survival estimates 1, 3, and 5 years after the time of diagnosis...

  20. Ophthalmic lymphoma: epidemiology and pathogenesis.

    Science.gov (United States)

    Sjö, Lene Dissing

    2009-02-01

    With a lifetime risk of 1% and 700 new cases per year, Non-Hodgkin lymphoma (NHL) is the seventh most frequent type of cancer in Denmark. The incidence of NHL has increased considerably in Western countries over the last decades; consequently, NHL is an increasing clinical problem. Ophthalmic lymphoma, (lymphoma localized in the ocular region, i.e. eyelid, conjunctiva, lacrimal sac, lacrimal gland, orbit, or intraocularly) is relatively uncommon, accounting for 5%-10% of all extranodal lymphomas. It is, however, the most common orbital malignancy. The purpose of this thesis was to review specimens from all Danish patients with a diagnosis of ophthalmic lymphoma during the period 1980-2005, in order to determine the distribution of lymphoma subtypes, and the incidence- and time trends in incidence for ophthalmic lymphoma. Furthermore, an extended analysis of the most frequent subtype, extranodal marginal zone lymphoma (MALT lymphoma), was done to analyse clinical factors and cytogenetic changes with influence on prognosis. A total of 228 Danish patients with a biopsy-reviewed verified diagnosis of ocular adnexal-, orbital-, or intraocular lymphoma were identified. We found that more than 50% of orbital- and ocular adnexal lymphomas were of the MALT lymphoma subtype, whereas diffuse large B-cell lymphoma (DLBCL) predominated intraocularly (Sjo et al. 2008a). Furthermore, lymphoma arising in the lacrimal sac was surprisingly predominantly DLBCL (Sjo et al. 2006). Incidence rates were highly dependent on patient age. There was an increase in incidence rates for the whole population from 1980 to 2005, corresponding to an annual average increase of 3.4% (Sjo et al. 2008a). MALT lymphoma arising in the ocular region was found in 116 patients (Sjo et al. 2008b). One third of patients had a relapse or progression of disease after initial therapy and relapses were frequently found at extra-ocular sites. Overall survival, however, was not significantly poorer for patients

  1. Lymphoma of the Cervix

    Directory of Open Access Journals (Sweden)

    Juanita Parnis

    2012-01-01

    Full Text Available Primary non-Hodgkins lymphoma of the uterine cervix is a very rare diagnosis. A 54-year-old woman presented with a 3-month history of postmenopausal bleeding per vaginum. On examination, a friable, fungating lesion was seen on the cervix. Histology revealed a CD 20 positive high-grade non-Hodgkin’s diffuse large B cell lymphoma from cervical biopsies and endometrial curettage. She was diagnosed as stage IE after workup and subsequently treated with six cycles of R-CHOP chemotherapy followed by radiotherapy of the involved field.

  2. Primary Pancreatic Lymphomas

    Directory of Open Access Journals (Sweden)

    Muhammad Wasif Saif

    2006-05-01

    Full Text Available Extranodal non-Hodgkin’s lymphomas (NHLs represent up to 30-40% of all NHL cases. The gastrointestinal tract is the most commonly involved extranodal site; accounting for about half of such cases [1]. Stomach and the small intestine constitute the most common gastrointestinal sites. Secondary invasion of the pancreas from contiguous, retroperitoneal lymph node disease is the prevalent mode of involvement. Secondary involvement of the pancreas from the duodenum or adjacent peripancreatic lymphadenopathy is well-known. Primary pancreatic lymphoma (PPL is an extremely rare disease [2]. PPL can present as an isolated mass mimicking pancreatic carcinoma. However, unlike carcinomas, PPL are potentially treatable [3].

  3. New drugs for aggressive B-cell and T-cell lymphomas.

    Science.gov (United States)

    Murawski, Niels; Pfreundschuh, Michael

    2010-11-01

    Over the past decade an unprecedented number of new drugs for lymphomas have been developed. Most of these new drugs target molecules or pathways that are important for the growth and proliferation of lymphomas. The introduction of the B-lymphoma specific monoclonal anti-CD20 antibody, rituximab, has improved the prognosis of patients with B-cell lymphomas more than any other drug in the past 50 years; today less than half of the patients with aggressive B-cell lymphomas die of their disease than in the pre-rituximab era. Many new drugs are now available for clinical testing in addition to new CD20 antibodies and antibodies directed against other surface molecules specifically or preferentially expressed on the lymphoma-cell surface. A prerequisite for the development of these drugs was the recognition of aberrant cell-signal transduction involved in lymphoma pathogenesis and progression. New therapeutic targets include receptor tyrosine and cyclin-dependent kinases, histone deacetylases, and molecules involved in the regulation of apoptosis. The definition of the role of these new drugs alone or in combination with established chemotherapy regimens in adequately designed prospective trials represents one of the major challenges in clinical lymphoma research.

  4. Centrofacial angiocentric lymphoma.

    Science.gov (United States)

    Peral-Cagigal, Beatriz; Galdeano-Arenas, María; Crespo-Pinilla, Juan Ignacio; García-Cantera, José Miguel; Sánchez-Cuéllar, Luis Antonio; Verrier-Hernández, Alberto

    2005-01-01

    The centrofacial angiocentric lymphoma is a rare lymphoid neoplasm, with an often-difficult diagnosis due to the non-specific clinical picture. On many occasions it is necessary to perform various biopsies to reach the correct diagnosis. This lymphoma is an aggressive Non-Hodgkin's (NHL) type, which is normally found in the upper respiratory tract (predominantly in the nasal cavity), and has an ominous prognosis, as the average survival rate is between 12 and 18 months (1). It is predominantly found in subjects of oriental and South American extraction, who are between the ages of 50 and 60 years and with a slight tendency towards males (2:1). This is the case study of a female Ecuadorian patient who was referred to our department with a hemifacial edema, chocolate- like rhinorrhea and nasal respiratory obstruction, which had been treated with antibiotics and anti-inflammatories for a month without success. After performing a number of diagnostic tests, it was found histologically that the patient had an extranodal T-cell lymphoma of the nasal type (also known as T-cell angiocentric lymphoma).

  5. Lymphatic system and lymphoma

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970385 The changes of cell immune function in ap-tients with non-Hodgkin’s lymphoma by flow cytome-try analysis. LU Ming(吕鸣), et al. Clin ImmunolCenter, Changzheng Hosp, 2nd Milit Med Univ, Shang-hai, 200003. Shanghai Med J 1997; 20(2): 73-75.

  6. Ocular Adnexal Follicular Lymphoma

    DEFF Research Database (Denmark)

    Rasmussen, Peter K; Coupland, Sarah E; Finger, Paul T

    2014-01-01

    IMPORTANCE The clinical features of the follicular subtype of ocular adnexal lymphoma (OAL) have not been previously evaluated in a large cohort. OBJECTIVE To characterize the clinical features of follicular OAL. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective multicenter study tha...

  7. Primary Pulmonary Hodgkin Lymphoma

    OpenAIRE

    Shumaila Tanveer; Ahmed El Damati; Ayman El Baz; Ahmed Alsayyah; Tarek ElSharkawy; Mohamed Regal

    2015-01-01

    Primary pulmonary Hodgkin lymphoma (PPHL) is a rare disease. Herein, we report a case of PPHL with diagnostic concerns encountered during initial evaluation which is of paramount importance to keep the differential diagnosis in cases with high index of sus- picion for this rare entity.

  8. Lymphoma: Immune Evasion Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Upadhyay, Ranjan; Hammerich, Linda; Peng, Paul [Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States); Brown, Brian [Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States); Merad, Miriam [Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States); Brody, Joshua D., E-mail: joshua.brody@mssm.edu [Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (United States)

    2015-04-30

    While the cellular origin of lymphoma is often characterized by chromosomal translocations and other genetic aberrations, its growth and development into a malignant neoplasm is highly dependent upon its ability to escape natural host defenses. Neoplastic cells interact with a variety of non-malignant cells in the tumor milieu to create an immunosuppressive microenvironment. The resulting functional impairment and dysregulation of tumor-associated immune cells not only allows for passive growth of the malignancy but may even provide active growth signals upon which the tumor subsequently becomes dependent. In the past decade, the success of immune checkpoint blockade and adoptive cell transfer for relapsed or refractory lymphomas has validated immunotherapy as a possible treatment cornerstone. Here, we review the mechanisms by which lymphomas have been found to evade and even reprogram the immune system, including alterations in surface molecules, recruitment of immunosuppressive subpopulations, and secretion of anti-inflammatory factors. A fundamental understanding of the immune evasion strategies utilized by lymphomas may lead to better prognostic markers and guide the development of targeted interventions that are both safer and more effective than current standards of care.

  9. Lymphatic system and lymphoma

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009236 Clinical significance in detection of immunoglobulin heavy chain clonal rearrangement in bone marrow of patients with B cell lymphoma.CHEN Zhiyu(陈治宇),et al.Dept Med Oncol,Cancer Hosp,Fudan Univ;Dept Oncel,Shanghai Med Coll,Fudan Univ,Shanghai 200032,Chin J Oncol,2009;3193):183-188.

  10. Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma

    Science.gov (United States)

    2017-03-24

    Anemia; B-Cell Prolymphocytic Leukemia; Fatigue; Fever; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma; Hairy Cell Leukemia; Lymphadenopathy; Lymphocytosis; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Night Sweats; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Richter Syndrome; Splenomegaly; Thrombocytopenia; Weight Loss

  11. Development of autoimmunity in lymphoma.

    Science.gov (United States)

    Jardin, Fabrice

    2008-03-01

    Development of lymphoproliferative diseases during the course of autoimmune and chronic inflammatory conditions is well established. Conversely, development of clinical or biological signs of autoimmunity at the time of the diagnosis of lymphoma or during its course indicates that lymphoma and autoimmune manifestations may constitute two faces of the same process. The aim of this review is to describe autoimmune manifestations related to non-Hodgkin's lymphoma and Hodgkin's lymphoma, their specificity according to the lymphoma subtype and their physiopathological signification. Lymphoma-related autoimmune manifestations include mainly skin diseases, hematological manifestations, rheumatic diseases and renal lesions. Despite the lack of studies providing a systematic prospective assessment, autoimmune manifestations are observed in all lymphoma subtypes and seem particularly prevalent in marginal-zone lymphoma and T-cell lymphoma. Autoimmune manifestation's physiopathology may implicate production of autoantibodies by CD5-positive autoreactive B cells, a loss of immune tolerance, an alteration of the Fas/Fas-ligand pathway and/or a chronic antigenic stimulation. Monoclonal antibodies (including rituximab, Campath-1H or epratuzumab) constitute the most promising approach to treat lymphoma-related immune disorders.

  12. Update on Anaplastic Thyroid Carcinoma: Morphological, Molecular, and Genetic Features of the Most Aggressive Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    Moira Ragazzi

    2014-01-01

    Full Text Available Anaplastic thyroid carcinoma (ATC is the most aggressive form of thyroid cancer. It shows a wide spectrum of morphological presentations and the diagnosis could be challenging due to its high degree of dedifferentiation. Molecular and genetic features of ATC are widely heterogeneous as well and many efforts have been made to find a common profile in order to clarify its cancerogenetic process. A comprehensive review of the current literature is here performed, focusing on histopathological and genetic features.

  13. Anaplastic transformation of metastatic papillary thyroid carcinoma at shoulder mimicking soft tissue sarcoma

    Directory of Open Access Journals (Sweden)

    Seema Kaushal

    2011-01-01

    Full Text Available A 52-year-old woman presented with fracture upper end of the left humerus after trivial trauma and aspiration cytology from the lytic lesion in the upper humerus seen on X-ray revealed a metastatic papillary carcinoma from the thyroid. Total thyroidectomy confirmed the papillary carcinoma thyroid. Post-operatively, she was given radioactive iodine (I-131 ablation therapy for 8 years and was asymptomatic during this period; however, for the last 1 year, she has been complaining of swelling in the shoulder, which did not respond to palliative radiotherapy and rapidly increased in size. Disarticulation of the shoulder joint was performed, which showed anaplastic carcinoma on histopathological examination. Anaplastic transformation of papillary carcinoma at the metastatic sites is well documented in the literature and is rare. However, the same has not been reported at the shoulder and from India before. Although soft tissue sarcomas are most common at this site, however, the possibility of anaplastic transformation should be kept in the differential diagnosis of rapidly enlarging painful mass in a known case of metastatic thyroid carcinoma to prevent misdiagnosis.

  14. Stages of AIDS-Related Lymphoma

    Science.gov (United States)

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  15. Distribution and ZAP-70 expression of WHO lymphoma categories in Shanxi, China: a review of 447 cases using a tissue microarray technique.

    Science.gov (United States)

    Wang, Jinfen; Young, Lillian; Win, William; Taylor, Clive R

    2005-12-01

    This study aims to assess the distribution of lymphoma subtypes in Shanxi, China, according to the World Health Organization (WHO) classification, and to compare the relative distribution with other areas of the world. H&E-stained tissue sections from the archives of the Shanxi Tumor Hospital, China, were reviewed and 447 cases with sufficient materials were selected for detailed study. A panel of antibodies and probes was assembled, including antibodies to ALK1, bcl-6, CDs 1alpha, 3, 4, 5, 7, 8, 10, 15, 20, 23, 30, 43, 56, 68, 79alpha, and 99, cyclin D1, EMA, kappa, lambda, LMP1, PAX5, TdT, Vs38C and ZAP70, plus EBER RNA probe by in situ hybridization. The 447 lymphoma cases, subtyped according to the WHO classification, were assembled in triplicate into 11 tissue microarrays and examined with the panel of markers described. Among the 447 cases, 385 (82.6%) were confirmed to be non-Hodgkin lymphomas (NHL) and 62 (13.9%) were Hodgkin lymphomas of classic type (CHL). Of the NHL cases, 68.6% were B-cell lymphomas and 30.6% T/NK-cell lymphomas. Histiocytic neoplasms accounted for only three cases (0.8%). Diffuse large B-cell lymphomas (DLBCL) were the most common subtype (35.1%), followed by peripheral T-cell lymphomas unspecified (PTun, 12.0%), extranodal marginal zone B-cell lymphomas (MALT lymphomas, 11.7%), follicular lymphomas (FL, 8.6%), T-lymphoblastic lymphomas (T-LBL, 7.0%), anaplastic large cell lymphomas (ALCL, 4.2%), B small lymphocytic lymphomas (B SLL, 3.6%), and mantle cell lymphomas (MCL, 2.6%). Of 263 B-cell neoplasms, 105 (39.9%) expressed immunoglobulin light chain, including 52 kappa and 53 lambda, detectable in paraffin sections. The incidence of DLBCL was similar to many Western countries and Asia. The frequency of FL was, however, much lower than the usual pattern in Western countries, although NK/T-cell lymphomas were more common (30.6%), similar to other countries in Asia, including Japan and Korea. With regard to markers of EBV infection, 8

  16. Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression.

    Science.gov (United States)

    Kotani, H; Ebi, H; Kitai, H; Nanjo, S; Kita, K; Huynh, T G; Ooi, A; Faber, A C; Mino-Kenudson, M; Yano, S

    2016-07-07

    Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR

  17. Hypothermia & Hodgkin lymphoma in children

    OpenAIRE

    Köse, Doğan; Köksal, Yavuz; Çalışkan, Ümran

    2016-01-01

    Hypothermia associated with Hodgkin lymphoma is defined rarely. This may be caused by a dysfunction that shall occur in hypothalamus, central and peripheral vascular system, skin and muscles. In this study, two Hodgkin lymphoma cases with developed hypothermia are presented. Case 1: An “Hodgkin lymphoma, mixed cellular type” was diagnosed by a biopsy conducted due to lesions found in her spleen on a girl in 7 ages, who applied to the hospital with complaints such as fever, weight loss and nig...

  18. Multimodality imaging of cardiothoracic lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Carter, Brett W., E-mail: bcarter2@mdanderson.org [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Section of Thoracic Imaging, 1515 Holcombe Blvd., Unit 1478, Houston, TX 77030 (United States); Wu, Carol C. [Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, FND-202, Boston, MA 02114 (United States); Khorashadi, Leila [Department of Radiology, Mount Auburn Hospital, Cambridge, MA 02138 (United States); Godoy, Myrna C.B.; Groot, Patricia M. de [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Section of Thoracic Imaging, 1515 Holcombe Blvd., Unit 1478, Houston, TX 77030 (United States); Abbott, Gerald F. [Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, FND-202, Boston, MA 02114 (United States); Lichtenberger III, John P. [Department of Radiology, David Grant Medical Center, Travis AFB, CA 94535 (United States)

    2014-08-15

    Lymphoma is the most common hematologic malignancy and represents approximately 5.3% of all cancers. The World Health Organization published a revised classification scheme in 2008 that groups lymphomas by cell type and molecular, cytogenetic, and phenotypic characteristics. Most lymphomas affect the thorax at some stage during the course of the disease. Affected structures within the chest may include the lungs, mediastinum, pleura, and chest wall, and lymphomas may originate from these sites as primary malignancies or secondarily involve these structures after arising from other intrathoracic or extrathoracic sources. Pulmonary lymphomas are classified into one of four types: primary pulmonary lymphoma, secondary pulmonary lymphoma, acquired immunodeficiency syndrome-related lymphoma, and post-transplantation lymphoproliferative disorders. Although pulmonary lymphomas may produce a myriad of diverse findings within the lungs, specific individual features or combinations of features can be used, in combination with secondary manifestations of the disease such as involvement of the mediastinum, pleura, and chest wall, to narrow the differential diagnosis. While findings of thoracic lymphoma may be evident on chest radiography, computed tomography has traditionally been the imaging modality used to evaluate the disease and effectively demonstrates the extent of intrathoracic involvement and the presence and extent of extrathoracic spread. However, additional modalities such as magnetic resonance imaging of the thorax and {sup 18}F-FDG PET/CT have emerged in recent years and are complementary to CT in the evaluation of patients with lymphoma. Thoracic MRI is useful in assessing vascular, cardiac, and chest wall involvement, and PET/CT is more accurate in the overall staging of lymphoma than CT and can be used to evaluate treatment response.

  19. Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation.

    Science.gov (United States)

    Pittaluga, S; Bijnens, L; Teodorovic, I; Hagenbeek, A; Meerwaldt, J H; Somers, R; Thomas, J; Noordijk, E M; De Wolf-Peeters, C

    1996-05-15

    In the Working Formulation (WF), non-Hodgkin's lymphomas (NHL) are grouped according to their clinical behavior. These disorders are listed as entities defined by morphology, phenotype, and cytogenetics in the proposed Revised European-American Classification of Lymphoid Neoplasms (REAL), the clinical relevance of which is still debated. We analyzed 670 NHL cases included in two randomized clinical trials (EORTC 20855 WF-intermediate/high-grade and 20856 WF-low-grade malignancy) with histologic material available for review. Based on hematoxylin-eosin-stained sections, 77% of cases could be subtyped. Immunophenotyping was considered to be mandatory only in diagnosing T-cell lymphoma and anaplastic large-cell lymphoma. Of 522 cases subtyped, 11% were mantle cell lymphoma (MCL), 5% were marginal zone B-cell lymphoma (MZBCL), 46% were follicle center lymphoma, and 32% were diffuse large B-cell lymphoma. Statistical analysis and comparisons between classifications were made only within each trial and treatment group. MCL and MZBCL were characterized by a shorter median survival (3.4 and 4.1 years, respectively) in comparison with low- and intermediate-grade WF groups (> 9.3 and 5.8 years, respectively). In terms of progression-free survival, MCL showed a behavior similar to the low-grade group, with frequent relapses. Follicle center cell lymphomas behaved as low-grade lymphomas as defined by the WF and diffuse large B-cell lymphomas as the WF-intermediate grade group. Because several NHL entities have a clinical behavior of their own, their recognition by the REAL classification offers clinicians additional information that is not obtained when the WF is used.

  20. 肺癌中棘皮动物微管相关蛋白4-间变型淋巴瘤激酶融合基因及表皮生长因子受体基因突变分析%Gene mutation of echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene and epidermal growth factor receptor in lung cancer

    Institute of Scientific and Technical Information of China (English)

    徐恩伟

    2015-01-01

    目的 检测非小细胞肺癌(NSCLC)中棘皮动物微管相关蛋白4-间变型淋巴瘤激酶(EML4-ALK)融合基因和表皮生长因子受体(EGFR)基因突变情况,从而指导有效的个体化靶向治疗.方法 采用扩增阻滞突变系统(ARMS)-聚合酶链反应(PCR),检测200例NSCLC患者EML4-ALK融合基因和EGFR基因表达情况.结果 200例NSCLC患者中,EML4-ALK融合基因扩增阳性为16例(8%),EGFR基因突变为64例(32%),18外显子(G719X)突变1例,19外显子突变32例,20外显子突变4例,21外显子突变25例,19外显子和20外显子联合突变1例,20外显子和21外显子联合突变1例.本组EML4-ALK融合基因阳性患者中均无EGFR基因突变发生.结论 NSCLC患者中,EML4-ALK融合基因和EGFR基因突变检测对有效的个体化靶向治疗至关重要.

  1. Lymphoma-associated dysimmune polyneuropathies.

    Science.gov (United States)

    Stübgen, Joerg-Patrick

    2015-08-15

    Lymphoma consists of a variety of malignancies of lymphocyte origin. A spectrum of clinical peripheral neuropathy syndromes with different disease mechanisms occurs in about 5% of lymphoma patients. There exists a complex inter-relationship between lymphoproliferative malignancies and autoimmunity. An imbalance in the regulation of the immune system presumably underlies various immune-mediated neuropathies in patients with lymphoma. This article reviews lymphoma and more-or-less well-defined dysimmune neuropathy subgroups that are caused by humoral and/or cell-mediated immune disease mechanisms directed against known or undetermined peripheral nerve antigens.

  2. Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

    Science.gov (United States)

    2014-11-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Gonadotroph Adenoma; Pituitary Basophilic Adenoma; Pituitary Chromophobe Adenoma; Pituitary Eosinophilic Adenoma; Prolactin Secreting Adenoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Pituitary Tumor; Recurrent/Refractory Childhood Hodgkin Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; TSH Secreting Adenoma; Unspecified Childhood Solid Tumor, Protocol Specific

  3. Classification of distinct subtypes of peripheral T-cell lymphoma unspecified, identified by chemokine and chemokine receptor expression: Analysis of prognosis.

    Science.gov (United States)

    Ohshima, Koichi; Karube, Kennosuke; Kawano, Riko; Tsuchiya, Takeshi; Suefuji, Hiroaki; Yamaguchi, Takahiro; Suzumiya, Junji; Kikuchii, Masahiro

    2004-09-01

    WHO classification for malignant lymphoma was recently proposed. However, PTCL is heterogeneous. Chemokines and its receptors are closely associated with the T-cell subtypes. To clarify the T-cell subtype in PTCL, we conducted DNA chips of chemokine, its receptor (R) and cytokines. Angioimmunoblastic T-cell lymphoma (AILD, n=4), anaplastic large cell lymphoma (ALCL, n=4), adult T-cell leukemia lymphoma (ATLL, n=7), NK-cell lymphoma (NKL, n=2) and PTCL, unspecified (PTCL-U, n=6) were analyzed using DNA chips. In addition, immunological stainings were performed in 280 cases. In DNA chip, AILD, ALCL, NKL and ATLL showed a tendency for respective clusters, otherwise, PTCL-U clustered with AILD, ALCL and ATLL. From the gene expression profiling, CCR4, CCR3, MIG, CXCR3 and BLC were selected for immunohistochemistry. ATLL (n=48) expressed CCR4. ALCL (n=26) expressed CCR3, NKL (n=20) expressed MIG, and AILD (n=29) expressed CXCR3 and/or BLC. From the expression patterns, PTCL-U (n=134) were classified into three groups; CCR4 type (CCR4(+), n=42), CCR3 type (CCR3(+), n=31) and CXCR3 type (CXCR3(+) BLC(+/-), n=54). The prognosis was poor for ATLL, intermediate for AILD and favorable for ALCL (P=0.0014). Among PTCL-U, CCR4 type, CXCR3 type and CCR3 type had prognoses equivalent to ATLL, AILD and ALCL, respectively (P<0.0001).

  4. Emerging therapeutic options for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.

    Science.gov (United States)

    Chakraborty, Rajshekhar; Kapoor, Prashant; Ansell, Stephen M; Gertz, Morie A

    2015-01-01

    Lymphoplasmacytic lymphoma is an indolent B-cell, non-Hodgkin lymphoma (NHL), the majority of which are characterized by production of a monoclonal immunoglobulin M (IgM) protein and are known as Waldenström macroglobulinemia. Identification of highly recurrent activating somatic mutation in MYD88 has improved our understanding of the pathogenesis of Waldenström macroglobulinemia and has therapeutic implications. Here, we review novel therapeutic agents in Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, which have emerged in the past decade and discuss their comparative efficacy and safety, with emphasis on a Bruton's tyrosine kinase (BTK) inhibitor, which has been recently approved by the US FDA, specifically for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. Future research should focus on identifying targeted agents against activating mutations and long-term data for currently available novel agents should be critically evaluated, both in treatment-naïve and in relapsed/refractory settings.

  5. Danish National Lymphoma Registry

    Directory of Open Access Journals (Sweden)

    Arboe B

    2016-10-01

    Full Text Available Bente Arboe,1 Pär Josefsson,2 Judit Jørgensen,3 Jacob Haaber,4 Paw Jensen,5 Christian Poulsen,6 Dorthe Rønnov-Jessen,7 Robert S Pedersen,8 Per Pedersen,9 Mikael Frederiksen,10 Michael Pedersen,1 Peter de Nully Brown1 1Department of Hematology, Copenhagen University Hospital, Rigshospitalet, 2Department of Hematology, Copenhagen University Hospital, Herlev Hospital, Copenhagen, 3Department of Hematology, Aarhus University Hospital, Aarhus, 4Department of Hematology, Odense University Hospital, Odense, 5Department of Hematology, Aalborg University Hospital, Aalborg, 6Department of Hematology, Roskilde Hospital, Roskilde, 7Department of Hematology, Vejle Hospital, Vejle, 8Department of Hematology, Holstebro Hospital, Holstebro, 9Department of Hematology, Esbjerg Hospital, Esbjerg, 10Department of Hematology, Haderslev Hospital, Haderslev, Denmark Aim of database: The Danish National Lymphoma Registry (LYFO was established in order to monitor and improve the diagnostic evaluation and the quality of treatment of all lymphoma patients in Denmark. Study population: The LYFO database was established in 1982 as a seminational database including all lymphoma patients referred to the departments of hematology. The database became nationwide on January 1, 2000. Main variables: The main variables include both clinical and paraclinical variables as well as details of treatment and treatment evaluation. Up to four forms are completed for each patient: a primary registration form, a treatment form, a relapse form, and a follow-up form. Variables are used to calculate six result quality indicators (mortality 30 and 180 days after diagnosis, response to first-line treatment, and survival estimates 1, 3, and 5 years after the time of diagnosis, and three process quality indicators (time from diagnosis until the start of treatment, the presence of relevant diagnostic markers, and inclusion rate in clinical protocols. Descriptive data: Approximately 23

  6. Low-grade and anaplastic oligodendrogliomas: differences in tumour microvascular permeability evaluated with dynamic contrast-enhanced magnetic resonance imaging.

    Science.gov (United States)

    Jia, Zhongzheng; Geng, Daoying; Liu, Ying; Chen, Xingrong; Zhang, Jun

    2013-08-01

    This study was designed to quantitatively assess the microvascular permeability of oligodendroglioma using the volume transfer constant (K(trans)) and the volume of the extravascular extracellular space per unit volume of tissue (V(e)) with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). We aimed to evaluate the effectiveness of K(trans) and V(e) in distinguishing between low-grade and anaplastic oligodendroglioma. The maximal values of K(trans) and V(e) for 65 patients with oligodendroglioma (27 grade II, 38 grade III) were obtained. Differences in K(trans) and V(e) between the two groups were analysed using the Mann-Whitney rank-sum test. Receiver operating characteristic (ROC) curve analyses were performed to determine the cut-off values for the K(trans) and Ve that could differentiate between low-grade and anaplastic oligodendrogliomas. Values for K(trans) and Ve in low-grade oligodendrogliomas were significantly lower than those in anaplastic oligodendrogliomas (p low-grade and anaplastic oligodendrogliomas in a statistically significant manner. Our results suggest that DCE-MRI can distinguish the differences in microvascular permeability between low-grade and anaplastic oligodendrogliomas.

  7. Lymphoma risk in systemic lupus

    DEFF Research Database (Denmark)

    Bernatsky, Sasha; Ramsey-Goldman, Rosalind; Joseph, Lawrence

    2014-01-01

    OBJECTIVE: To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE). METHODS: We performed case-cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated...

  8. Lymphoma of the Urinary Bladder

    Directory of Open Access Journals (Sweden)

    Anthony Kodzo-Grey Venyo

    2014-01-01

    Full Text Available Background. Lymphoma of the urinary bladder (LUB is rare. Aims. To review the literature on LUB. Methods. Various internet databases were used. Results. LUB can be either primary or secondary. The tumour has female predominance; most cases occur in middle-age women. Secondary LUB occurs in 10% to 25% of leukemias/lymphomas and in advanced-stage systemic lymphoma. Less than 100 cases have been reported. MALT typically affects adults older than 60 years; 75% are female. Diffuse large B-cell lymphoma is also common and may arise from transformation of MALT. LUB presents with haematuria, dysuria, urinary frequency, nocturia, and abdominal or back pain. Macroscopic examination of LUBs show large discrete tumours centred in the dome or lateral walls of the bladder. Positive staining of LUB varies by the subtype of lymphoma; B-cell lymphomas are CD20 positive. MALT lymphoma is positively stained for CD20, CD19, and FMC7 and negatively stained for CD5, CD10, and CD11c. LUB stains negatively with Pan-keratin, vimentin, CK20, and CK7. MALT lymphoma exhibits t(11; 18(q21: 21. Radiotherapy is an effective treatment for the MALT type of LUB with no recurrence. Conclusions. LUB is diagnosed by its characteristic morphology and immunohistochemical characteristics. Radiotherapy is a useful treatment.

  9. Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: long term results of RTOG BR0131.

    Science.gov (United States)

    Vogelbaum, Michael A; Hu, Chen; Peereboom, David M; Macdonald, David R; Giannini, Caterina; Suh, John H; Jenkins, Robert B; Laack, Nadia N; Brachman, David G; Shrieve, Dennis C; Souhami, Luis; Mehta, Minesh P

    2015-09-01

    We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma. Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range 1.1-10.1), median progression-free survival (PFS) is 5.8 years (95 % CI 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78 % (95 % CI 61-95 %) and 83 % (95 % CI 67-98 %), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67 %, 95 % CI 55-79 %). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs.

  10. Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas.

    Science.gov (United States)

    Mao, Xin; Orchard, Guy; Lillington, Debra M; Russell-Jones, Robin; Young, Bryan D; Whittaker, Sean J

    2003-02-15

    Primary cutaneous lymphomas (PCLs) represent a heterogeneous group of extranodal T- and B-cell malignancies. The underlying molecular pathogenesis of this malignancy remains unclear. This study aimed to characterize oncogene abnormalities in PCLs. Using genomic microarray, we detected oncogene copy number gains of RAF1 (3p25), CTSB (8p22), PAK1 (11q13), and JUNB (19p13) in 5 of 7 cases of mycosis fungoides (MF)/Sezary syndrome (SS) (71%), gains of FGFR1 (8p11), PTPN (20q13), and BCR (22q11) in 4 cases (57%), and gains of MYCL1 (1p34), PIK3CA (3q26), HRAS (11p15), MYBL2 (20q13), and ZNF217 (20q13) in 3 cases (43%). Amplification of JUNB was studied in 104 DNA samples from 78 PCL cases using real-time polymerase chain reaction. Twenty-four percent of cases, including 7 of 10 cases of primary cutaneous CD30(+) anaplastic large-cell lymphoma (C-ALCL), 4 of 14 MF, 4 of 22 SS, and 2 of 23 primary cutaneous B-cell lymphoma (PCBCL) showed amplification of JUNB, and high-level amplification of this oncogene was present in 3 C-ALCL and 2 MF cases. JUNB protein expression was analyzed in tissue sections from 69 PCL cases, and 44% of cases, consisting of 21 of 23 SS, 6 of 8 C-ALCL, 5 of 10 MF, and 9 of 21 PCBCL, demonstrated nuclear expression of JUNB by tumor cells. Overexpression of JUNB also was detected in 5 C-ALCL and 2 SS cases. These results have revealed, for the first time, amplification and expression patterns of JUNB in PCL, suggesting that JUNB may be critical in the pathogenesis of primary cutaneous T-cell lymphomas.

  11. [Malignant non-Hodgkin's lymphoma].

    Science.gov (United States)

    Bourrier, P; Grodner, F; Ruf, R; Texier, J; Cottencin, R; Cousteau, C; Deslandre, A; Gounant, C; Szpirglas, H; Laufer, J

    1983-01-01

    Rapid regression of all symptoms was obtained after moderate chemotherapy in two women aged 69 and 77 years respectively with malignant non-Hodgkin's lymphomas. Cervico-facial locations of these tumors are discussed in relation to definition, etiology, geographic factors, genetic markers, and associated immunologic disorders. Diagnosis requires a series of explorations including, obviously as a last resort, exploratory cervicotomy. Other regions may be involved and must be investigated, but lesions not affecting lymph nodes occur in only approximately 2 p. cent of patients with cervico-facial malignant non-Hodgkin's lymphoma (approximately 10 p. cent of all malignant non-Hodgkin's lymphomas). Other localizations include the hard palate, gums, sinuses, and salivary glands. Burkitt's lymphoma represents, on the contrary, 30 p. cent of malignant non-Hodgkin's lymphoma seen in European children. The different therapeutic modalities available are discussed.

  12. THE ASSOCIATION OF WELL-DIFFERENTIATED THYROID-CARCINOMA WITH INSULAR OR ANAPLASTIC THYROID-CARCINOMA - EVIDENCE FOR DEDIFFERENTIATION IN TUMOR PROGRESSION

    NARCIS (Netherlands)

    van der Laan, Bernard F.A.M.; FREEMAN, JL; TSANG, RW; ASA, SL

    1993-01-01

    The sequence of tumorigenesis in the thyroid is unclear. It has been proposed that anaplastic carcinomas of the thyroid develop by dedifferentiation in pre-existing differentiated carcinomas. We reviewed all anaplastic and insular (poorly differentiated) thyroid carcinomas in a consultation practice

  13. Iodine I 131 Monoclonal Antibody BC8 Before Autologous Stem Cell Transplant in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma or Non-Hodgkin Lymphoma

    Science.gov (United States)

    2016-06-10

    Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent T-Cell Non-Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Hodgkin Lymphoma; Refractory T-Cell Non-Hodgkin Lymphoma

  14. Abnormal number cell division of human thyroid anaplastic carcinoma cell line, SW 1736

    Directory of Open Access Journals (Sweden)

    Keiichi Ikeda

    2015-12-01

    Full Text Available Cell division, during which a mother cell usually divides into two daughter cells during one cell cycle, is the most important physiological event of cell biology. We observed one-to-four cell division during imaging of live SW1736 human thyroid anaplastic carcinoma cells transfected with a plasmid expressing the hybrid protein of green fluorescent protein and histone 2B (plasmid eGFP-H2B. Analysis of the images revealed a mother cell divided into four daughter cells. And one of the abnormally divided daughter cells subsequently formed a dinucleate cell.

  15. [Incidence of anaplastic tumor in structure of other histologic forms of the thyroid gland cancer].

    Science.gov (United States)

    Vinnik, Iu A; Gorbenko, V N; Vas'ko, A R; Kikhtenko, E V; Gargin, V V

    2014-01-01

    The degrees of invasiveness, proliferative activity, morphofunctional activity of nuclei in the thyroidal gland tumors were studied, while analyzing material, obtained in 1343 patients, suffering thyroidal gland cancer (THGC) and operated on in 2000-2013 yrs. Morphological point quantity of malignancy (as a criterion of the tumor progression grade) and mitotic activity in cellular population were determined in various kinds of THGC. Undifferentiated (anaplastic carcinoma) type of THGC is the most malignant one. There were determined a spindle-like, giant-cell and squamous-cell forms of undifferentiated THGC. The presence of sites of differentiated cancer in 33% of histological preparations witnesses the interrelationship with the earlier existed pathological process.

  16. Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report.

    Science.gov (United States)

    Kessler, Brice A; Bookhout, Christine; Jaikumar, Sivakumar; Hipps, John; Lee, Yueh Z

    2015-01-01

    We report the neuroimaging and histopathologic findings of a 12-year-old female patient with a disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural metastatic disease. These tumors may represent distinct pathology primarily seen in pediatric patients. Neuroimaging demonstrates diffuse, progressive enhancement of the leptomeninges often with interval development of intraparenchymal lesions on follow-up. Disease is typically confined to the central nervous system, though diffuse peritoneal disease was seen in our case, possibly through metastatic seeding of the abdomen via ventriculoperitoneal shunt.

  17. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis.

    Science.gov (United States)

    Wiestler, Benedikt; Capper, David; Holland-Letz, Tim; Korshunov, Andrey; von Deimling, Andreas; Pfister, Stefan Michael; Platten, Michael; Weller, Michael; Wick, Wolfgang

    2013-09-01

    Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients (n = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, histology, isocitrate dehydrogenase (IDH), 1p/19q, alternative lengthening of telomeres (ALT) and O6-methylguanine-DNA methyltransferase (MGMT) status, and the trial efficacy endpoints. Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas (AA), 27 % of anaplastic oligoastrocytomas (AOA) and 10 % of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. The ALT phenotype was significantly correlated with ATRX loss. ATRX and 1p/19q status were used to re-classify AOA: AOA harboring ATRX loss shared a similar clinical course with AA, whereas AOA carrying 1p/19q co-deletion shared a similar course with AO. Accordingly, in a Cox regression model including ATRX and 1p/19q status, histology was no longer significantly associated with time to treatment failure. Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status: tumors with ATRX loss had a significantly better prognosis (median time to treatment failure 55.6 vs. 31.8 months, p = 0.0168, log rank test). ATRX status helps better define the clinically and morphologically mixed group of AOA, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of astrocytic tumors with a favorable prognosis.

  18. Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation.

    Science.gov (United States)

    Kiss, Izabella; Unger, Christine; Huu, Chi Nguyen; Atanasov, Atanas Georgiev; Kramer, Nina; Chatruphonprasert, Waranya; Brenner, Stefan; McKinnon, Ruxandra; Peschel, Andrea; Vasas, Andrea; Lajter, Ildiko; Kain, Renate; Saiko, Philipp; Szekeres, Thomas; Kenner, Lukas; Hassler, Melanie R; Diaz, Rene; Frisch, Richard; Dirsch, Verena M; Jäger, Walter; de Martin, Rainer; Bochkov, Valery N; Passreiter, Claus M; Peter-Vörösmarty, Barbara; Mader, Robert M; Grusch, Michael; Dolznig, Helmut; Kopp, Brigitte; Zupko, Istvan; Hohmann, Judit; Krupitza, Georg

    2015-01-28

    An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this

  19. Lymphatic system and lymphoma

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930583 Analysis of therapeutic efficacy of com- bination chemotherapy and adjuvant radiothera-py in 207 cases of diffuse non—Hodgkin’s lym-phoma.YONG Weiben(勇威本),et al.BeijingCancer Res Instit,Beijing,100000. Chin J Hema-tol 1992;13(12):638—640.Two hundred and seven cases of diffuse non—Hodgkin’s lymphoma(D—NHL)were treatedwith combination chemotherapy(cyclophospha-mide,vincristine,procarbazine,prednisone andpingyingmycin or adriamycin)and adjuvant ra-diotherapy.Complete remission(CR)wasachieved in 94 of 207 patients(45.4%),partial

  20. FISH analysis of MALT lymphoma-specific translocations and aneuploidy in primary cutaneous marginal zone lymphoma.

    NARCIS (Netherlands)

    Schreuder, M.I.; Hoefnagel, J.J.; Jansen, P.A.M.; Krieken, J.H.J.M. van; Willemze, R.; Hebeda, K.M.

    2005-01-01

    Primary cutaneous marginal zone lymphomas (PCMZL) share histological and clinical characteristics with mucosa-associated lymphoid tissue (MALT) lymphomas suggesting a common pathogenesis. A number of recurrent structural and numerical chromosomal aberrations have been described in MALT lymphoma, but

  1. Involvement of cysteine-rich protein 61 in the epidermal growth factor-induced migration of human anaplastic thyroid cancer cells.

    Science.gov (United States)

    Chin, Li-Han; Hsu, Sung-Po; Zhong, Wen-Bin; Liang, Yu-Chih

    2016-05-01

    Anaplastic thyroid cancer (ATC) is among the most aggressive types of malignant cancer. Epidermal growth factor (EGF) plays a crucial role in the pathogenesis of ATC, and patients with thyroid carcinoma typically exhibit increased cysteine-rich protein 61 (Cyr61). In this study, we found that EGF treatment induced cell migration, stress fiber formation, Cyr61 mRNA and protein expressions, and Cyr61 protein secretion in ATC cells. The recombinant Cyr61 protein significantly induced cell migration; however, inhibition of Cyr61 activity by a Cyr61-specific antibody abrogated EGF-induced cell migration. EGF treatment also affected epithelial-to-mesenchymal transition (EMT)-related marker protein expression, as evidenced by an increase in vimentin and a decrease in E-cadherin expression. Inhibition of Cyr61 expression by Cyr61 siRNA decreased cell migration and reversed the EMT-related marker protein expression. EGF treatment increased the phosphorylation of the extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), and finally activated Cyr61 promoter plasmid activity. Our results suggest that Cyr61 is induced by EGF through the ERK/CREB signal pathway and that it plays a crucial role in the migration and invasion of ATC cells; moreover, Cyr61 might be a therapeutic target for metastatic ATC.

  2. Gene Therapy in Treating Patients With Human Immunodeficiency Virus-Related Lymphoma Receiving Stem Cell Transplant

    Science.gov (United States)

    2016-12-15

    HIV Infection; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Plasmablastic Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Recurrent Follicular Lymphoma; Stage III Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  3. Dendritic Cell Therapy, Cryosurgery, and Pembrolizumab in Treating Patients With Non-Hodgkin Lymphoma

    Science.gov (United States)

    2017-01-26

    Aggressive Non-Hodgkin Lymphoma; Indolent Non-Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Recurrent T-Cell Non-Hodgkin Lymphoma; Small Lymphocytic Lymphoma

  4. Lymphoma caused by intestinal microbiota.

    Science.gov (United States)

    Yamamoto, Mitsuko L; Schiestl, Robert H

    2014-09-01

    The intestinal microbiota and gut immune system must constantly communicate to maintain a balance between tolerance and activation: on the one hand, our immune system should protect us from pathogenic microbes and on the other hand, most of the millions of microbes in and on our body are innocuous symbionts and some can even be beneficial. Since there is such a close interaction between the immune system and the intestinal microbiota, it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue (MALT) lymphoma have been shown to be caused by the presence of certain bacteria. Animal models played an important role in establishing causation and mechanism of bacteria-induced MALT lymphoma. In this review we discuss different ways that animal models have been applied to establish a link between the gut microbiota and lymphoma and how animal models have helped to elucidate mechanisms of microbiota-induced lymphoma. While there are not a plethora of studies demonstrating a connection between microbiota and lymphoma development, we believe that animal models are a system which can be exploited in the future to enhance our understanding of causation and improve prognosis and treatment of lymphoma.

  5. Obinutuzumab in follicular lymphoma.

    Science.gov (United States)

    Martinez-Calle, N; Figueroa-Mora, R; Villar-Fernandez, S; Marcos-Jubilar, M; Panizo, C

    2016-12-01

    The CD20 marker continues to be exploited as a therapeutic target for non-Hodgkin's lymphoma. Obinutuzumab is part of a new generation of anti-CD20 monoclonal antibodies, which are synthesized using molecular engineering technology, resulting in novel target epitopes and unprecedented optimization of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Rituximab is the current gold standard for anti-CD20 therapy, yet despite outstanding results published over the past decade, many patients continue to relapse after anti-CD20 regimens. Obinutuzumab is slowly positioning itself in the treatment of CD20+ B-cell neoplasms. On the basis of favorable results from the phase III GADOLIN trial, obinutuzumab was recently approved by the U.S. Food and Drug Administration in combination with bendamustine followed by obinutuzumab maintenance, for the treatment of follicular lymphoma (FL) patients who relapsed or are refractory to a rituximab-containing regimen. Additional phase III trials are underway to test obinutuzumab as a first-line anti-CD20 agent in FL with good preliminary results (GALLIUM trial); thus, it is likely that obinutuzumab will soon achieve a first-line indication. It is plausible that obinutuzumab will replace rituximab as the gold standard for chemoimmunotherapy in FL, although some safety concerns still need to be resolved. This review will address the preclinical pharmacology and the main aspects of the clinical development of obinutuzumab for the treatment of FL.

  6. Haemorrhage and intestinal lymphoma

    Directory of Open Access Journals (Sweden)

    Attilia M. Pizzini

    2013-04-01

    Full Text Available Background: The prevalence of coeliac disease is around 1% in general population but this is often unrecognised. The classical presentation of adult coeliac disease is characterized by diarrhoea and malabsorption syndrome, but atypical presentations are probably more common and are characterized by iron deficiency anaemia, weight loss, fatigue, infertility, arthralgia, peripheral neuropathy and osteoporosis. Unusual are the coagulation disorders (prevalence 20% and these are due to vitamin K malabsorption (prolonged prothrombin time. Clinical case: A 64-year-old man was admitted to our Department for an extensive spontaneous haematoma of the right leg. He had a history of a small bowel resection for T-cell lymphoma, with a negative follow-up and he didn’t report any personal or familiar history of bleeding. Laboratory tests showed markedly prolonged prothrombin (PT and partial-thromboplastin time (PTT, corrected by mixing studies, and whereas platelet count and liver tests was normal. A single dose (10 mg of intravenous vitamin K normalized the PT. Several days before the patient had been exposed to a superwarfarin pesticide, but diagnostic tests for brodifacoum, bromadiolone or difenacoum were negative. Diagnosis of multiple vitamin K-dependent coagulationfactor deficiencies (II, VII, IX, X due to intestinal malabsorption was made and coeliac disease was detected. Therefore the previous lymphoma diagnosis might be closely related to coeliac disease. Conclusions: A gluten free diet improves quality of life and restores normal nutritional and biochemical status and protects against these complications.

  7. PATHOBIOLOGY OF HODGKIN LYMPHOMA

    Directory of Open Access Journals (Sweden)

    Claudio Agostinelli

    2014-06-01

    Full Text Available Hodgkin’s lymphoma is a lymphoid tumour that represents about 1% of all de novo neoplasms occurring every year worldwide. Its diagnosis is based on the identification of characteristic neoplastic cells within an inflammatory milieu. Molecular studies have shown that most, if not all cases, belong to the same clonal population, which is derived from peripheral B-cells. The relevance of Epstein-Barr virus infection at least in a proportion of patients was also demonstrated. The REAL/WHO classification recognizes a basic distinction between nodular lymphocyte predominance  HL (NLPHL and classic HL (CHL, reflecting the differences in clinical presentation, behavior, morphology, phenotype, molecular features as well as in the composition of their cellular background. CHL has been classified into four subtypes: lymphocyte rich, nodular sclerosing, mixed cellularity and lymphocyte depleted. Despite its well known histological and clinical features, Hodgkin's lymphoma (HL has recently been the object of intense research activity, leading to a better understanding of its phenotype, molecular characteristics and possible mechanisms of lymphomagenesis.

  8. Hodgkin Lymphoma: Diagnosis and Treatment.

    Science.gov (United States)

    Ansell, Stephen M

    2015-11-01

    Hodgkin lymphoma is a rare B-cell malignant neoplasm affecting approximately 9000 new patients annually. This disease represents approximately 11% of all lymphomas seen in the United States and comprises 2 discrete disease entities--classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Within the subcategorization of classical Hodgkin lymphoma are defined subgroups: nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich Hodgkin lymphoma. Staging of this disease is essential for the choice of optimal therapy. Prognostic models to identify patients at high or low risk for recurrence have been developed, and these models, along with positron emission tomography, are used to provide optimal therapy. The initial treatment for patients with Hodgkin lymphoma is based on the histologic characteristics of the disease, the stage at presentation, and the presence or absence of prognostic factors associated with poor outcome. Patients with early-stage Hodgkin lymphoma commonly receive combined-modality therapies that include abbreviated courses of chemotherapy followed by involved-field radiation treatment. In contrast, patients with advanced-stage Hodgkin lymphoma commonly receive a more prolonged course of combination chemotherapy, with radiation therapy used only in selected cases. For patients with relapse or refractory disease, salvage chemotherapy followed by high-dose treatment and an autologous stem cell transplant is the standard of care. For patients who are ineligible for this therapy or those in whom high-dose therapy and autologous stem cell transplant have failed, treatment with brentuximab vedotin is a standard approach. Additional options include palliative chemotherapy, immune checkpoint inhibitors, nonmyeloablative allogeneic stem cell transplant, or participation in a clinical trial testing novel agents.

  9. A comparative evaluation of supervised and unsupervised representation learning approaches for anaplastic medulloblastoma differentiation

    Science.gov (United States)

    Cruz-Roa, Angel; Arevalo, John; Basavanhally, Ajay; Madabhushi, Anant; González, Fabio

    2015-01-01

    Learning data representations directly from the data itself is an approach that has shown great success in different pattern recognition problems, outperforming state-of-the-art feature extraction schemes for different tasks in computer vision, speech recognition and natural language processing. Representation learning applies unsupervised and supervised machine learning methods to large amounts of data to find building-blocks that better represent the information in it. Digitized histopathology images represents a very good testbed for representation learning since it involves large amounts of high complex, visual data. This paper presents a comparative evaluation of different supervised and unsupervised representation learning architectures to specifically address open questions on what type of learning architectures (deep or shallow), type of learning (unsupervised or supervised) is optimal. In this paper we limit ourselves to addressing these questions in the context of distinguishing between anaplastic and non-anaplastic medulloblastomas from routine haematoxylin and eosin stained images. The unsupervised approaches evaluated were sparse autoencoders and topographic reconstruct independent component analysis, and the supervised approach was convolutional neural networks. Experimental results show that shallow architectures with more neurons are better than deeper architectures without taking into account local space invariances and that topographic constraints provide useful invariant features in scale and rotations for efficient tumor differentiation.

  10. General Information about Childhood Non-Hodgkin Lymphoma

    Science.gov (United States)

    ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ... Treatment Adult NHL Treatment AIDS-Related Lymphoma Treatment Mycosis Fungoides & Sézary Syndrome Treatment Primary CNS Lymphoma Treatment ...

  11. Casein kinases

    DEFF Research Database (Denmark)

    Issinger, O G

    1993-01-01

    subunits are highly conserved during evolution. The relationship between CK-2 alpha from humans and plants is still 73%. Similar relationships are reported for the beta-subunit. Chromosomal assignment of CK-2 alpha shows two gene loci, one of which is a pseudogene. They are located on different chromosomes......, no genetic changes are necessarily involved; the observed changes may be entirely due to a signal transduction pathway where CK-2 could be phosphorylated by another kinase(s). CK-2 cDNAs from various organisms have been isolated and characterized. From the deduced amino acid sequence it turns out that CK-2......-subunit affecting: (i) stability, (ii) enzyme specificity and (iii) enzyme activity. The question where CK-2 and its subunits are located throughout the cell cycle has also been addressed, mainly because of the large discrepancies that still exist between results obtained by different investigators. Tissue...

  12. Non-Hodgkin’s lymphoma with bone involvement: a single center experience with 18 patients

    Directory of Open Access Journals (Sweden)

    Filiz Vural

    2010-03-01

    Full Text Available Objective: Non-Hodgkin’s lymphoma (NHL of bone is a rare entity. The most common histological subtype is diffuse large B cell lymphoma (DLBCL. The major presenting symptoms are soft tissue swelling, bone pain and pathological fracture. Treatment options are chemotherapy, radiotherapy, surgery, or a combination of these modalities. Materials and Methods: We retrospectively analyzed the 18 patients (11 females, 7 males with NHL of bone who were diagnosed and treated between 1995-2005. The median age was 56.5 years. The median duration of symptoms was 4.5 months. The bone pain was the first symptom in all patients. Tru-cut biopsy was performed for diagnosis in most of the cases. Diagnosis in five patients (27.8% required open biopsy. Results: DLBCL (77.8% was the most common histological type among all patients. Other histological subtypes were anaplastic large cell lymphoma (11.1%, Burkitt-like lymphoma (5.6% and marginal zone lymphoma (5.6%. According to Ann Arbor staging system, 44.4% of patients were Stage I, 11.1% were Stage II and 44.4% were Stage IV. Bone marrow involvement was determined in four patients (22.2%. All patients except one were treated with anthracycline-containing regimens and eight patients (44.4% received rituximab combination with chemotherapy. Radiation therapy was performed as the first-line therapy in 9 (50% patients. The median follow-up was 37 months (range, 2-124 months. Among the 17 patients who achieved complete remission, five (27.8% relapsed. All patients were still alive. The five-year relapse-free survival was 73.5%.Conclusion: The treatment of bone lymphoma can be planned according to the stage and location of the disease. Although we had a relatively low number of patients, it could be concluded that whether or not radiation therapy is performed, rituximab in combination with systemic chemotherapy has been proven beneficial on survival.

  13. Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma.

    Science.gov (United States)

    Chevret, Edith; Andrique, Laetitia; Prochazkova-Carlotti, Martina; Ferrer, Jacky; Cappellen, David; Laharanne, Elodie; Idrissi, Yamina; Boettiger, Anna; Sahraoui, Wafa; Ruiz, Florian; Pham-Ledard, Anne; Vergier, Beatrice; Belloc, Francis; Dubus, Pierre; Beylot-Barry, Marie; Merlio, Jean-Philippe

    2014-03-20

    Telomere erosion may be counteracted by telomerase. Here we explored telomere length (TL) and telomerase activity (TA) in primary cutaneous T-cell lymphoma (CTCL) by using quantitative polymerase chain reaction and interphase quantitative fluorescence in situ hybridization assays. Samples from patients with Sézary syndrome (SS), transformed mycosis fungoides (T-MF), and cutaneous anaplastic large cell lymphoma were studied in parallel with corresponding cell lines to evaluate the relevance of TL and TA as target candidates for diagnostic and therapeutic purposes. Compared with controls, short telomeres were observed in aggressive CTCL subtypes such as SS and T-MF and were restricted to neoplastic cells in SS. While no genomic alteration of the hTERT (human telomerase catalytic subunit) locus was observed in patients' tumor cells, TA was detected. To understand the role of telomerase in CTCL, we manipulated its expression in CTCL cell lines. Telomerase inhibition rapidly impeded in vitro cell proliferation and led to cell death, while telomerase overexpression stimulated in vitro proliferation and clonogenicity properties and favored tumor development in immunodeficient mice. Our data indicate that, besides maintenance of TL, telomerase exerts additional functions in CTCL. Therefore, targeting these functions might represent an attractive therapeutic strategy, especially in aggressive CTCL.

  14. Heterogeneous abnormalities of CCND1 and RB1 in primary cutaneous T-Cell lymphomas suggesting impaired cell cycle control in disease pathogenesis.

    Science.gov (United States)

    Mao, Xin; Orchard, Guy; Vonderheid, Eric C; Nowell, Peter C; Bagot, Martine; Bensussan, Armand; Russell-Jones, Robin; Young, Bryan D; Whittaker, Sean J

    2006-06-01

    Upregulation of cyclin D1/B-cell leukemia/lymphoma 1 (CCND1/BCL1) is present in most mantle cell lymphomas with the t(11;14)(q13;q32) translocation. However, little is known about the abnormalities of CCND1 and its regulator RB1 in primary cutaneous T-cell lymphomas (CTCL). We analyzed CCND and RB status in CTCL using fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and Affymetrix expression microarray. FISH revealed loss of CCND1/BCL1 in five of nine Sézary syndrome (SS) cases but gain in two cases, and RB1 loss in four of seven SS cases. IHC showed absent CCND1/BCL1 expression in 18 of 30 SS, 10 of 23 mycosis fungoides (MF), and three of 10 primary cutaneous CD30+ anaplastic large-cell lymphoma (C-ALCL). Increased CCND1/BCL1 expression was seen in nine MF, seven C-ALCL, and six SS cases. Absent RB1 expression was detected in 8 of 12 MF and 7 of 9 SS cases, and raised RB1 expression in 7 of 8 C-ALCL. Affymetrix revealed increased gene expression of CCND2 in four of eight CTCL cases, CCND3 in three cases, and CDKN2C in two cases with a normal expression of CCND1 and RB1. These findings suggest heterogeneous abnormalities of CCND and RB in CTCL, in which dysregulated CCND and RB1 may lead to impaired cell cycle control.

  15. Radiographically Negative, Asymptomatic, Sentinel Lymph Node Positive Cutaneous T-Cell Lymphoma in a 3-Year-Old Male: A Case Report

    Directory of Open Access Journals (Sweden)

    Jeffrey Carson

    2012-01-01

    Full Text Available We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

  16. Intracranial manifestations of malignant lymphomas

    Energy Technology Data Exchange (ETDEWEB)

    Galanski, M.; Fahrendorf, G.; Urbanitz, D.; Beckmann, A.; Elger, C.

    1985-06-01

    Approximately 10% of patients with malignant lymphoma will show neurological symptoms at some time during the course of their illness. In non-Hodgkin lymphoma, CNS involvement is more frequent than in Hodgkin's disease. Diffuse histiocytic and poorly differentiated lymphomas, bone marrow involvement, advanced tumor stage and hematogenous spread are particular risk factors. Invasion of the spinal canal is the most common type of CNS involvement. Intracranial lesions, which are comparatively rare, may present as intracerebral metastases, epi- or subdural masses or focal or diffuse leptomeningeal disease. Lymphomatous leptomeningitis usually cannot be demonstrated by CT. On the other hand, dural and cerebral parenchymal lesions are sometimes highly characteristic of lymphoma as a result of their features and location.

  17. Proton therapy for Hodgkin lymphoma.

    Science.gov (United States)

    Rutenberg, Michael S; Flampouri, Stella; Hoppe, Bradford S

    2014-09-01

    Hodgkin lymphoma has gone from an incurable disease to one for which the majority of patients will be cured. Combined chemotherapy and radiotherapy achieves the best disease control rates and results in many long-term survivors. As a result, a majority of long-term Hodgkin lymphoma survivors live to experience severe late treatment-related complications, especially cardiovascular disease and second malignancies. The focus of research and treatment for Hodgkin lymphoma is to maintain the current high rates of disease control while reducing treatment-related morbidity and mortality. Efforts to reduce late treatment complications focus on improvements in both systemic therapies and radiotherapy. Herein we review the basis for the benefits of proton therapy over conventional X-ray therapy. We review outcomes of Hodgkin lymphoma treated with proton therapy, and discuss the ability of protons to reduce radiation dose to organs at risk and the impact on the most significant late complications related to the treatment.

  18. Primary intracerebral lymphoma: Case report

    Directory of Open Access Journals (Sweden)

    Olcay Eser

    2012-09-01

    Full Text Available We describe a case of primary central nervous lymphoma (PCNSL that may be confused with magnetic resonance imaging (MRI findings of high grade glioma. Primary central nervous lymphoma is a rare tumour and it account for 0.3-3% of intracranial tumours. A 61 year’s old woman was admitted to our clinic with a severe headache, vomiting, left hemiparesia and transient loss of consciousness. Primary central nervous lymphoma may show various biological and radiological characteristics. We herein emphasized being confused with MRI findings of PCNSL and high grade glioma. J Clin Exp Invest 2012; 3 (3: 409-411Key words: Primary central nervous lymphoma, high grade glioma, B-cell, diagnosis

  19. Ovarian mucinous cystic tumor with sarcoma-like mural nodules and multifocal anaplastic carcinoma: a case report.

    Science.gov (United States)

    Zheng, Jinfeng; Geng, Ming; Li, Peifeng; Li, Yi; Cao, Yongcheng

    2013-01-01

    A 48-year-old woman presented with left abdominal pain and fullness. Computed tomography scan revealed a multicystic mass with multifocal mural nodules. Histologic examination showed a mucinous cystic tumor with cystadenoma, borderline malignant cystadenoma and cystadenocarcinoma, which were associated with sarcoma-like mural nodules (SLMNs) and multifocal anaplastic carcinoma. Mural nodules showed a positive reaction for CD56 and vimentin, but were negative for cytokeratin 7 and SMA. She underwent postoperative chemotherapy and is currently under follow-up; no recurrence or metastases were found in the first year of follow-up. Ovarian mucinous cystic tumor with SLMNs and foci of anaplastic carcinoma is extremely rare. To our knowledge, this case reports the most complex neoplastic and reactive components. Our findings shed some light on the pathogenesis of this rather rare carcinoma. We think that the formation of SLMNs may be the result of the reactive proliferation of undifferentiated mesenchymal cells, while the anaplastic carcinoma may be derived from mucinous epithelium. Moreover, because of difficulties encountered in their differential diagnosis, we think that the existence of foci of anaplastic carcinoma along with SLMNs necessitates careful histologic and immunohistochemical analysis of mural nodules for the determination of treatment and prognosis.

  20. Clonal heterogeneity of small-cell anaplastic carcinoma of the lung demonstrated by flow-cytometric DNA analysis

    DEFF Research Database (Denmark)

    Vindeløv, L L; Hansen, H H; Christensen, I J

    1980-01-01

    Flow-cytometric DNA analysis yields information on ploidy and proliferative characteristics of a cell population. The analysis was implemented on small-cell anaplastic carcinoma of the lung using a rapid detergent technique for the preparation of fine-needle aspirates for DNA determination...

  1. Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951.

    NARCIS (Netherlands)

    Idbaih, A.; Dalmasso, C.; Kouwenhoven, M.; Jeuken, J.W.M.; Carpentier, C.; Gorlia, T.; Kros, J.M.; French, P.; Teepen, J.; Broet, P.; Delattre, O.; Mokhtari, K.; Sanson, M.; Delattre, J.Y.; Bent, M. van den; Hoang-Xuan, K.

    2011-01-01

    Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify ne

  2. Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951

    NARCIS (Netherlands)

    A. Idbaih (Ahmed); C. Dalmasso (Cyril); M.C.M. Kouwenhoven (Mathilde); J. Jeuken (Judith); C. Carpentier (Catherine); T.S. Gorlia (Thierry); J.M. Kros (Johan); P.J. French (Pim); J.L.J.M. Teepen; P. Broët (Philippe); O. Delattre (Olivier); K. Mokhtari (Karima); M. Sanson (Marc); M.J. van den Bent (Martin); K. Hoang-Xuan (Khe)

    2011-01-01

    textabstractDespite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To

  3. Anti-CD22 CAR-T Therapy for CD19-refractory or Resistant Lymphoma Patients

    Science.gov (United States)

    2016-08-22

    Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Stage III/IV Adult Diffuse Large Cell Lymphoma; Stage III/IV Follicular Lymphoma; Stage III/IV Mantle Cell Lymphoma

  4. A Phase II Trial of Panobinostat and Lenalidomide in Patients With Relapsed or Refractory Hodgkin's Lymphoma

    Science.gov (United States)

    2016-07-15

    Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Recurrent Adult Hodgkin Lymphoma

  5. Targeted immunotherapy in Hodgkin lymphoma

    DEFF Research Database (Denmark)

    Hutchings, Martin

    2015-01-01

    In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13.......In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13....

  6. Prediction of anaplastic transformation in low-grade oligodendrogliomas based on magnetic resonance spectroscopy and 1p/19q codeletion status.

    Science.gov (United States)

    Bourdillon, Pierre; Hlaihel, Chadi; Guyotat, Jacques; Guillotton, Laurent; Honnorat, Jérôme; Ducray, François; Cotton, François

    2015-05-01

    The aim of this study was to assess whether combining multimodal magnetic resonance imaging (MRI) with the determination of the 1p/19q codeletion status could improve the ability to predict anaplastic transformation in low-grade oligodendrogliomas. Twenty patients with grade II oligodendrogliomas were followed-up using multimodal MR [proton MR spectroscopy (MRS), perfusion, and conventional MR imaging]. All patients diagnoses were histologically proven, and 1p/19q codeletion status was analyzed for all patients. Median follow-up was 30.5 ± 11.4 months. Anaplastic transformation was observed in six patients. The only MRI feature that was associated with anaplastic transformation was an elevation of the choline/creatine ratio >2.4 which was observed in 4 out of 6 patients with anaplastic transformation versus 1 out of 14 patients without anaplastic transformation. In patients without 1p/19q codeletion, an elevation of the choline/creatine ratio >2.4 was associated with the occurrence of anaplastic transformation in all cases (4 out of 4 patients), with a mean time of 12 months. In contrast, in patients with a 1p/19q codeletion, no anaplastic transformation was observed in the patient who had an elevation of >2.4 of the choline/creatine ratio and two patients demonstrated an anaplastic transformation without any elevation of this ratio.Prospective validation in a larger series is needed, yet the present study suggests that combining data from in vivo proton MRS and genetic analysis could be a promising strategy to predict time to anaplastic transformation at the individual level in patients with low-grade oligodendrogliomas and may help deciding when chemotherapy and/or radiotherapy should be initiated in these tumors.

  7. Molecular Pathogenesis of MALT Lymphoma

    Directory of Open Access Journals (Sweden)

    Katharina Troppan

    2015-01-01

    Full Text Available Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT, also known as MALT lymphoma, which was first described in 1983 by Isaacson and Wright. MALT lymphomas arise at a wide range of different extranodal sites, with the highest frequency in the stomach, followed by lung, ocular adnexa, and thyroid, and with a low percentage in the small intestine. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations and missense and frameshift mutations, all pathway-related genes affecting the NF-κB signal, have been implicated in the development and progression of MALT lymphoma. However, these genetic abnormalities alone are not sufficient for malignant transformation. There is now increasing evidence suggesting that the oncogenic product of translocation cooperates with immunological stimulation in oncogenesis, that is, the association with chronic bacterial infection or autoaggressive process. This review mainly discusses MALT lymphomas in terms of their genetic aberration and association with chronic infections and summarizes recent advances in their molecular pathogenesis.

  8. Primary lymphoma of the colon

    Directory of Open Access Journals (Sweden)

    Tauro Leo

    2009-01-01

    Full Text Available Primary lymphoma of the colon is a rare tumor of the gastrointestinal (GI tract and comprises only 0.2-1.2% of all colonic malignancies. The most common variety of colonic lymphoma is non-Hodgkin′s lymphoma (NHL. The GI tract is the most frequently involved site, accounting for 30-40% of all extra nodal lymphomas, approximately 4-20% of which are NHL. The stomach is the most common location of GI lymphomas, followed by the small intestine. Early diagnosis may prevent intestinal perforation; however, the diagnosis is often delayed in most cases. Therapeutic approaches described in two subsets include: Radical tumor resection (hemicolectomy plus multi-agent chemotherapy (polychemotherapy in early stage patients, biopsy plus multidrug chemotherapy in advanced stage patients. Radiotherapy is reserved for specific cases; surgery alone can be considered as an adequate treatment for patients with low-grade NHL disease that does not infiltrate beyond the sub mucosa. Although resection plays an important role in the local control of the disease and in preventing bleeding and/or perforation, it rarely eradicates the lymphoma by itself. Those with limited stage disease may enjoy prolonged survival when treated with aggressive chemotherapy.

  9. Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential.

    Science.gov (United States)

    Barrientos, Jacqueline C

    2016-01-01

    Idelalisib is a first-in-class, oral, selective phosphatidylinositol 3-kinase δ inhibitor that offers a chemotherapy-free option for patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Clinical trials in iNHL have evaluated idelalisib as monotherapy and as combination therapy with rituximab, bendamustine, and rituximab + bendamustine. When administered to heavily pretreated patients with R/R iNHL, idelalisib monotherapy or combination therapy showed durable antitumor activity accompanied by sustained or improved quality-of-life outcomes. Idelalisib has an acceptable safety profile; however, serious or fatal diarrhea/colitis, hepatoxicity, pneumonitis, and intestinal perforation have occurred in treated patients. Selective inhibition of phosphatidylinositol 3-kinase δ with idelalisib is a valuable addition to available treatment options for patients with iNHL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. Two Phase III, randomized, placebo-controlled trials of idelalisib as combination therapy with rituximab or bendamustine + rituximab and a Phase I trial of idelalisib in combination with the Bruton's tyrosine kinase inhibitor ONO/GS-4059 in R/R B-cell malignancies are currently ongoing. A Phase III monotherapy trial in previously treated follicular lymphoma or small lymphocytic lymphoma is planned. The development of other kinase inhibitors for the treatment of iNHL raises the potential for new treatment combinations. Additional research is needed to determine optimal therapy (monotherapy vs combination regimens), treatment sequencing, and long-term management.

  10. Impact of 1p/19q Codeletion and Histology on Outcomes of Anaplastic Gliomas Treated With Radiation Therapy and Temozolomide

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    Speirs, Christina K.; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd A. [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Tran, David D.; Linette, Gerry [Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Chicoine, Michael R.; Dacey, Ralph G.; Rich, Keith M.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H. [Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri (United States); Huang, Jiayi, E-mail: jhuang@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States)

    2015-02-01

    Purpose: Anaplastic gliomas represent a heterogeneous group of primary high-grade brain tumors, and the optimal postoperative treatment remains controversial. In this report, we present our institutional data on the clinical outcomes of radiation therapy (RT) plus temozolomide (RT + TMZ) for anaplastic gliomas, stratified by histology and 1p/19q codeletion. Methods and Materials: A single-institution retrospective review was conducted of patients with supratentorial anaplastic oligodendroglioma (AO), mixed anaplastic oligoastrocytoma (AOA), and anaplastic astrocytoma (AA). After surgery, RT was delivered at a median total dose of 60 Gy (range, 31.6-63 Gy) in daily fractions. All patients received standard concurrent TMZ, with or without adjuvant TMZ. Histological/molecular subtypes were defined as codeleted AO/AOA, non-codeleted AO/AOA, and AA. Results: From 2000 to 2012, 111 cases met study criteria and were evaluable. Codeleted AO/AOA had superior overall survival (OS) to non-codeleted AO/AOA (91% vs 68% at 5 years, respectively, P=.02), whereas progression-free survival (PFS) was not significantly different (70% vs 46% at 5 years, respectively, P=.10). AA had inferior OS to non-codeleted AO/AOA (37% vs 68% at 5 years, respectively, P=.007) and inferior PFS (27% vs 46%, respectively, P=.03). On multivariate analysis, age, performance status, and histological or molecular subtype were independent predictors for both PFS and OS. Compared to historical controls, RT + TMZ provided comparable OS to RT with procarbazine, lomustine, and vincristine (RT + PCV) for codeleted AO/AOA, superior OS to RT alone for non-codeleted AO/AOA, and similar OS to RT alone for AA. Conclusions: RT + TMZ may be a promising treatment for both codeleted and non-codeleted AO/AOA, but its role for AA remains unclear.

  11. Developing retroperitoneal anaplastic carcinoma with choriocarcinoma focus after ovarian non-gestastional choriocarcinoma: Case report

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    Nikolić Branka

    2012-01-01

    Full Text Available Introduction. Choriocarcinoma is a malignant form of gestational trophoblastic neoplasm (GTN. It is a rare event but also a curable malignancy. In the majority of instancies it developes after any gestational event. In some cases it developes as non-gestational extrauterine malignancy. Prognosis of choriocarcinoma is poor when invasion and metastases appear early and spread fast. This form of choriocarcinoma can lead to incurable and letal outcome. Case report. We presented a 20-year-old patient with abdominal and retroperitoneal malignancy - anaplastic carcinoma combined with choriocarcinoma metastases in. Tumor developed three months after left adnexectomy which had been done because of adnexal tumor. Choriocarcinoma was immunohistochemicaly confirmed in adnexal masses. Two courses of chemotherapy, metotrexate + folic acid (MTX+FA regimen, were administrated. The initial serum beta human chorionic gonadotropin level stayed unknown as well as the last one after the treatment. The patient came from the other country and was hospitalized because of pelvic and abdominal pain and palpable abdominal masses in hypogastrium with progressive anemia. The human chorionic gonadotropin level was 38 mIU/L. Tumor biopsy was done and choriocarcinoma metastases were immunohistochemicaly confirmed with predominant anaplastic carcinoma. Five day course of MTX + cyclophosphamide regimen was administrated and the patient was prepared for operative treatment. Relaparotomy was perforemed and tumor completely exceeded. Tumor mass mostly developed retroperitonely and partialy in abdominal cavity infiltrating intestinal wall with rupture of sigmoid colon. Anaplastic carcinoma, with large fields of necrosis and bleeding, was confirmed after histological examination. Immunohistochemical examination excluded choriocarcinoma in tumor mass. After 20 blood units transfusion, one course of chemotherapy and tumor excision, the patient left hospital on the 9th postoperative day

  12. Agatolimod Sodium, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Recurrent or Refractory Non-Hodgkin Lymphoma

    Science.gov (United States)

    2016-01-04

    Adult Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Nodal Marginal Zone Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

  13. Utility of interim and end-of-treatment PET/CT in peripheral T-cell lymphomas: A review of 124 patients.

    Science.gov (United States)

    El-Galaly, Tarec Christoffer; Pedersen, Martin Bjerregård; Hutchings, Martin; Mylam, Karen Juul; Madsen, Jakob; Gang, Anne Ortved; Bøgsted, Martin; de Nully Brown, Peter; Loft, Annika; Nielsen, Anne Lerberg; Hendel, Helle Westergreen; Iyer, Victor; Gormsen, Lars Christian

    2015-11-01

    According to the updated guidelines for imaging in lymphoma, 18F-FDG positron emission tomography/computed tomography (PET/CT) is recommended for staging and evaluation of treatment response in FDG-avid lymphomas. The purpose of the study was to evaluate the utility of PET/CT in nodal peripheral T-cell lymphomas (PTCL). Patients with newly diagnosed nodal PTCL (peripheral T-cell lymphoma NOS, anaplastic large-cell lymphoma, or angioimmunoblastic T-cell lymphoma) seen at five Danish hematology centers during the period 2006 to 2012 were included, if they had been pretherapeutically staged with PET/CT. Medical records were reviewed for baseline clinical and follow-up information. Staging, interim (I-PET), and end-of-treatment PET/CT (E-PET) studies were centrally reviewed, and reported using the Deauville 5-point score (DS). A total of 124 patients fulfilled the inclusion criteria. The median age was 58 years, and 88% received CHOP/CHOP-like therapy. Five years PFS and OS of the study population was 36.8% (95% CI 27.3-46.4) and 49.7% (95% CI 38.9-59.6), respectively. The presence of PET/CT-ascertained lung and/or liver involvement was associated with a worse outcome. The sensitivity of PET/CT for detecting biopsy-defined bone marrow involvement was only 18% (95% CI 4-43). An interim DS >3 was not prognostic for worse OS and PFS among CHOP/CHOP-like treated patients in uni- or multivariate analyses. A DS >3 after treatment predicted a worse prognosis. In conclusion, I-PET was not predictive of outcome in CHOP/CHOP-like treated PTCL patients when using the DS. Prospective studies are needed to determine the optimal use of PET/CT in PTCL including the role of quantitative PET/CT analysis.

  14. Memory-enriched CAR-T Cells Immunotherapy for B Cell Lymphoma

    Science.gov (United States)

    2016-04-25

    Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  15. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.

    Directory of Open Access Journals (Sweden)

    Bonnie K Harrington

    Full Text Available Acalabrutinib (ACP-196 is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL. First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR was 25% (5/20 with a median progression free survival (PFS of 22.5 days. Clinical benefit was observed in 30% (6/20 of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL.

  16. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma

    Science.gov (United States)

    Gardner, Heather L.; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R.; Covey, Todd; Kaptein, Allard; Gulrajani, Michael; Van Lith, Bart; Krejsa, Cecile; Coss, Christopher C.; Russell, Duncan S.; Zhang, Xiaoli; Urie, Bridget K.; London, Cheryl A.; Byrd, John C.; Johnson, Amy J.; Kisseberth, William C.

    2016-01-01

    Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL). PMID:27434128

  17. Composite Lymphoma : EBV-positive Classic Hodgkin Lymphoma and Peripheral T-cell Lymphoma A Case Report

    NARCIS (Netherlands)

    Gualco, Gabriela; Chioato, Lucimara; Van Den Berg, Anke; Weiss, Lawrence M.; Bacchi, Carlos E.

    2009-01-01

    Composite lymphomas are rare and defined as hematopoietic neoplasms with more than I malignant lymphomatous clone showing different phenotypic features. Of all possible combinations between non-Hodgkin lymphomas, B cell or T cell, and Hodgkin lymphoma, the least frequent are the ones combining T-cel

  18. Acute exacerbation of Hashimoto thyroiditis mimicking anaplastic carcinoma of the thyroid: A complicated case.

    Science.gov (United States)

    Kanaya, Hiroaki; Konno, Wataru; Fukami, Satoru; Hirabayashi, Hideki; Haruna, Shin-ichi

    2014-12-01

    The fibrous variant of Hashimoto thyroiditis is uncommon, accounting for approximately 10% of all cases of Hashimoto thyroiditis. We report a case of this variant that behaved like a malignant neoplasm. The patient was a 69-year-old man who presented with a right-sided anterior neck mass that had been rapidly growing for 2 weeks. Fine-needle aspiration cytology revealed clusters of large multinucleated cells suggestive of an anaplastic carcinoma. A week after presentation, we ruled out that possibility when the mass had shrunk slightly. Instead, we diagnosed the patient with an acute exacerbation of Hashimoto thyroiditis on the basis of laboratory findings. We performed a right thyroid lobectomy, including removal of the isthmus, to clarify the pathology and alleviate pressure symptoms. The final diagnosis was the fibrous variant of Hashimoto thyroiditis, with no evidence of malignant changes. Physicians should keep in mind that on rare occasions, Hashimoto thyroiditis mimics a malignant neoplasm.

  19. Anaplastic carcinoma of the pancreas: Case report and literature review of reported cases in Japan

    Science.gov (United States)

    Hoshimoto, Sojun; Matsui, Junichi; Miyata, Ryohei; Takigawa, Yutaka; Miyauchi, Jun

    2016-01-01

    We report a case of a 64-year-old woman with anaplastic carcinoma of the pancreas (ACP) with cyst formation and review 60 ACP cases reported in Japan. In 20% of cases, laboratory tests revealed severe anemia (hemoglobin level 12000/mm3), which were likely attributable to rapid tumor growth, intratumoral hemorrhage, and necrosis. Elevated serum CA19-9 levels were observed in 55% of cases. Cyst-like structures were observed on imaging in 47% of cases, and this finding appears to reflect subsequent cystic degeneration in the lesion. Macroscopically, hemorrhagic necrosis was observed in 77% of cases, and cyst formation was observed in 33% of cases. ACP should be considered when diagnosing pancreatic tumors with a cyst-like appearance, especially in the presence of severe anemia, elevated leucocyte counts, or elevated serum CA19-9 levels.

  20. Conduction Aphasia as a Result of Left Parietal-Temporal-Occipital Anaplastic Astrocytoma: A Case Study

    Directory of Open Access Journals (Sweden)

    Oscar Mauricio Aguilar Mejía

    2011-01-01

    Full Text Available Conduction aphasia is a language disorder characterized by an impaired ability to repeat verbal material associated with phonological paraphasias but a relatively fluent spontaneous speech and preserved comprehension. It has been attributed to lesions of the arcuate fasciculus by disconnection between posterior temporal lobe and frontal lobe, however, this idea has been debated, because the integrity and function of the arcuate fasciculus does not seem to be essential in verbal repetition. We report a case of a 23 year old male, with conduction aphasia as a result of a recurrent anaplastic astrocytoma in parietal and temporo-occipital areas. We propose a reconceptualization of the aphasia, analyzing it in terms of clinical neuropsychological and neural networks between ipsilateral and contralateral posterior brain areas

  1. Metronomic chemotherapy in anaplastic thyroid carcinoma: A potentially feasible alternative to therapeutic nihilism

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    Swaroop Revannasiddaiah

    2015-01-01

    Full Text Available Anaplastic thyroid carcinoma (ATC is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT, and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC.

  2. Pomalidomide and Dexamethasone in Treating Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma or Newly Diagnosed or Relapsed or Refractory Intraocular Lymphoma

    Science.gov (United States)

    2016-09-12

    B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; Central Nervous System Lymphoma; Intraocular Lymphoma; Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System; Recurrent Adult Diffuse Large Cell Lymphoma; Retinal Lymphoma

  3. Obinutuzumab, Venetoclax, and Lenalidomide in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

    Science.gov (United States)

    2017-03-01

    B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma; Recurrent Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

  4. Utilization and impact of adjuvant therapy in anaplastic oligodendroglioma: an analysis on 1692 patients.

    Science.gov (United States)

    Shin, Jacob Y; Diaz, Aidnag Z

    2016-09-01

    The aim of this study was to determine the utilization rates and impact of adjuvant therapy on overall survival (OS) for anaplastic oligodendroglioma (AO). Data were extracted from the National Cancer Data Base (NCDB). Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 1692 patients with AO who underwent surgery were identified. 945 (55.9 %) received adjuvant radiotherapy with concomitant chemotherapy (chemoRT), 102 (6.0 %) adjuvant radiotherapy (RT) sequentially followed by chemotherapy, 244 (14.4 %) adjuvant RT alone, and 401 (23.7 %) received no adjuvant therapy. Patients were more likely to receive adjuvant chemoRT if they were diagnosed in 2009-2013 vs. 2004-2008 (p 70 vs. <70 (p = 0.018), had private insurance vs. Medicaid vs. no insurance (p < 0.001), or had median income ≥$63,000 vs. <$63,000 (p = 0.014). Those who received adjuvant chemoRT (concomitant or sequential) had significantly better 5-year OS than those who received adjuvant RT alone or no adjuvant therapy (59.8 % vs. 65.0 % vs. 44.9 % vs. 45.6 %, p < 0.001). This significant 5-year OS benefit was also observed regardless of age. There was no difference in OS when comparing concomitant chemoRT to sequential RT and chemotherapy (p = 0.481). On multivariate analysis, receipt of adjuvant chemoRT (concomitant or sequential) remained an independent prognostic factor for improved OS. Adjuvant chemoRT (concomitant or sequential) is an independent prognostic factor for improved OS in anaplastic oligodendroglioma and should be considered for all clinically suitable patients who have undergone surgery for the disease.

  5. Cutaneous natural killer/T-cell lymphoma.

    Science.gov (United States)

    Radonich, Michael A; Lazova, Rossitza; Bolognia, Jean

    2002-03-01

    Lymphomas are classified as either Hodgkin's or non-Hodgkin's. The 2 subtypes of non-Hodgkin's lymphoma that can present primarily in the skin are cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, both of which tend to be low-grade malignant neoplasms. Recently another distinct subtype of lymphoma was discovered, the natural killer (NK)/T-cell lymphoma, which can involve the skin in a primary or secondary fashion. The NK/T-cell subtype of lymphoma is characterized by the expression of the NK-cell antigen CD56. These CD56(+) lymphomas are further subdivided into nasal NK/T-cell lymphomas that commonly present as midfacial destructive disease and non-nasal NK/T-cell lymphomas that often arise in extranodal locations, including the skin. We report a case of aggressive NK-cell leukemia/lymphoma with numerous secondary cutaneous lesions and review the clinical and histopathologic spectrum of non-nasal CD56(+) lymphomas, with an emphasis on the dermatologic findings.

  6. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: A report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial

    NARCIS (Netherlands)

    H.J. Dubbink (Erik Jan); P.N. Atmodimedjo; J.M. Kros (Johan); P.J. French (Pim); M. Sanson (Marc); A. Idbaih (Ahmed); P. Wesseling (Pieter); R. Enting (Roelien); W.G.M. Spliet (Wim); C.C. Tijssen (Cees); W.N.M. Dinjens (Winand); T.S. Gorlia (Thierry); M.J. van den Bent (Martin)

    2016-01-01

    textabstractBackground Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in

  7. Case presentation – thyroid lymphoma

    Directory of Open Access Journals (Sweden)

    Belkisa Izić

    2011-11-01

    Full Text Available Malignant tumors of the thyroid gland account for about 1% of thenewly diagnosed malignant tumors each year, and their incidence inwomen is twice the incidence in men. According to the WHO classification (2004 thyroid tumors are divided into: carcinoma of the thyroid, adenoma and similar tumors, and other thyroid tumors which include: teratomas, angiosarcomas, paragangliomas and others, as well as primary lymphomas and plasmacytomas. Primary thyroid lymphomasare defined as lymphomas which originate in the thyroid gland. This study presents the case of a 68-year-old patient with a thyroid lymphoma, which caused compression of the airways. In the patientpresented there was reduced activity of the thyroid gland. The dominant symptoms were: breathing difficulties, hoarse voice and the enlargement of the thyroid. An ultrasound examination was performedbefore surgery on the neck, which showed a multinodular thyroid,with compromised and compressed trachea to the right and rear. Anemergency surgical procedure was performed to reduce the tumor.Pathohistological diagnosis confirmed diffuse large B cell lymphoma.The aim of the study was to present a patient with a thyroid lymphoma, who had previously not had any immunological changes to the gland,that is, she had not had any chronic lymphocyte thyroiditis, but due to the compressive syndrome it was necessary to perform an emergencysurgical procedure to reduce the tumor.

  8. Managing Risk in Hodgkin Lymphoma.

    Science.gov (United States)

    Armitage, James O; Chen, Robert W; Moskowitz, Craig H; Sweetenham, John

    2015-02-01

    Approximately 90% of patients with limited-stage Hodgkin lymphoma are cured. The cure rate in advanced-stage Hodgkin lymphoma is dramatically better than it once was, but it is still lower than the rate in patients with limited disease. The choice of treatment is based on several factors, including symptoms, disease stage, extent of tumor burden, and prognosis. Positron emission tomography scanning can be used to assess the patient's stage of disease, which can allow further individualization of therapy. Traditional frontline treatment options include doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and, for high-risk patients, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Autologous stem cell transplantation cures approximately 50% of patients. The antibody-drug conjugate brentuximab vedotin is very active in relapsed/refractory Hodgkin lymphoma. Data presented at the 2014 meeting of the American Society of Hematology (ASH) showed that brentuximab vedotin was beneficial in several settings, including as consolidation therapy posttransplant in patients at high risk for relapse, as first-line salvage therapy in relapsed/refractory Hodgkin lymphoma prior to autologous hematopoietic cell transplantation, and in combination with bendamustine in relapsed/refractory disease. The ASH meeting also offered promising data on novel agents, such as the programmed cell death 1 (PD-1) inhibitors. In this monograph, 4 experts in the management of Hodgkin lymphoma discuss various aspects of the disease and provide their perspectives on the new data presented at the ASH meeting.

  9. Expanding horizons in the treatment of mantle cell lymphoma: Ibrutinib a novel BTK-targeting inhibitor

    Directory of Open Access Journals (Sweden)

    Sameer Dhingra

    2014-02-01

    Full Text Available Mantle cell lymphoma (MCL is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood, and bone marrow with short remission duration to standard therapies and a median overall survival of 4–5 years. Small molecule inhibitors targeting dysregulated pathways (MAPK/ERK, PI3K/PKB/mTOR, JAK/STAT have significantly improved clinical outcomes in cancer patients. Recently Bruton’s tyrosine kinase (BTK, a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK-inhibitor, has demonstrated clinical effectiveness and tolerability in clinical trials, recently been approved by FDA in the treatment of MCL. [Int J Basic Clin Pharmacol 2014; 3(1.000: 249-254

  10. Interleukin-12 in Treating Patients With Previously Treated Non-Hodgkin's Lymphoma or Hodgkin's Disease

    Science.gov (United States)

    2015-04-14

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  11. Primary thyroid lymphoma: CT findings

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyo-Cheol; Han, Moon Hee E-mail: hanmh@radcom.snu.ac.kr; Kim, Keon Ha; Jae, Hwan Jun; Lee, Sang Hyun; Kim, Sam Soo; Kim, Kwang Hyun; Chang, Kee-Hyun

    2003-06-01

    Introduction: To evaluate the computed tomographic (CT) findings of primary thyroid lymphoma. Methods and material: The clinicopathological data and CT images of nine patients with primary thyroid lymphoma were retrospectively reviewed. The CT appearances were classified into three types: type 1, a solitary nodule surrounded by normal thyroid tissue; type 2, multiple nodules in the thyroid, and type 3, a homogeneously enlarged both thyroid glands with a reduced attenuation with or without peripheral thin hyperattenuating thyroid tissue. Results: All patients had a rapidly enlarging thyroid mass and coexistent Hashimoto's thyroiditis. One patient showed type 1 pattern, three type 2, and five type 3. Six patients had homogeneous tumor isoattenuating to surrounding muscles. The tumors had a strong tendency to compress normal remnant thyroid and the surrounding structure without invasion. Conclusion: Primary thyroid lymphoma should be included in the differential diagnosis when old female had a homogeneous thyroidal mass isoattenuating to muscles, which does not invade surrounding structures.

  12. Characterization of the novel indolylmaleimides' PDA-66 and PDA-377 effect on canine lymphoma cells

    Science.gov (United States)

    Schmidt, Laura C.; Roolf, Catrin; Pews-Davtyan, Anahit; Rütgen, Barbara C.; Hammer, Sabine; Willenbrock, Saskia; Sekora, Anett; Rolfs, Arndt; Beller, Matthias; Brenig, Bertram; Nolte, Ingo; Junghanss, Christian

    2016-01-01

    Protein kinase inhibitors are widely used in chemotherapeutic cancer regimens. Maleimide derivatives such as SB-216763 act as GSK-3 inhibitor targeting cell proliferation, cell death and cell cycle progression. Herein, the two arylindolylmaleimide derivatives PDA-66 and PDA-377 were evaluated as potential chemotherapeutic agents on canine B-cell lymphoma cell lines. Canine lymphoma represents a naturally occurring model closely resembling the human high-grade non-Hodgkin's lymphoma (NHL). PDA-66 showed more pronounced effects on both cell lines. Application of 2.5μM PDA-66 resulted in a significant induction of apoptosis (approx. 11 %), decrease of the metabolic activity (approx. 95 %), anti-proliferative effect (approx. 85 %) and cell death within 48h. Agent induced mode of action was characterized by whole transcriptome sequencing, 12 h and 24 h post-agent exposure. Key PDA-66-modulated pathways identified were cell cycle, DNA replication and p53 signaling. Expression analyses indicated that the drug acting mechanism is mediated through DNA replication and cycle arrest involving the spindle assembly checkpoint. In conclusion, both PDA derivatives displayed strong anti-proliferation activity in canine B-cell lymphoma cells. The cell and molecular PDA-induced effect characterization and the molecular characterization of the agent acting mechanism provides the basis for further evaluation of a potential drug for canine lymphoma serving as model for human NHL. PMID:27177088

  13. Inhibition of p21 and Akt potentiates SU6656-induced caspase-independent cell death in FRO anaplastic thyroid carcinoma cells.

    Science.gov (United States)

    Kim, S H; Kang, J G; Kim, C S; Ihm, S-H; Choi, M G; Yoo, H J; Lee, S J

    2013-06-01

    SU6656 is a small-molecule indolinone that selectively inhibits Src family kinase and induces death of cancer cells. The aim of the present study was to investigate the influence of SU6656 on cell survival and to assess the role of p21 and PI3K/Akt signaling in cell survival resulting from SU6656 treatment in anaplastic thyroid carcinoma (ATC) cells. When 8505C, CAL62, and FRO ATC cells were treated with SU6656, the viability of 8505C and CAL62 ATC cells decreased only after treatment with SU6656 at a dosage of 100 μM for 72 h, while the viability of FRO ATC cells decreased after treatment with SU6656 in a concentration- and time-dependent manner. Cell viability was not changed by pretreatment with the broad-spectrum caspase inhibitor z-VAD-fmk. Phospho-Src protein levels were reduced, and p21 protein levels were elevated. Phospho-ERK1/2 protein levels were multiplied without alteration of total ERK1/2, total Akt, and phospho-Akt protein levels. Regarding FRO ATC cells, the decrement of cell viability, the increment of cleaved PARP-1 protein levels, and the decrement of phospho-Src protein levels were shown in p21 siRNA- or LY294002-pretreated cells compared to SU6656-treated control cells. ERK1/2 siRNA transfection did not affect cell viability and protein levels of cleaved PARP-1, p21, and Akt. In conclusion, these results suggest that SU6656 induces caspase-independent death of FRO ATC cells by overcoming the resistance mechanism involving p21 and Akt. Suppression of p21 and Akt enhances the cytotoxic effect of SU6656 in FRO ATC cells.

  14. Radioimmunotherapy for first-line and relapse treatment of aggressive B-cell non-Hodgkin lymphoma: an analysis of 215 patients registered in the international RIT-Network

    Energy Technology Data Exchange (ETDEWEB)

    Hohloch, Karin; Lankeit, H.K.; Truemper, L. [Georg August University, Hematology and Oncology, Goettingen (Germany); Zinzani, P.L. [University of Bologna, Institute of Hematology and Medical Oncology ' ' L. e A. Seragnoli' ' , Bologna (Italy); Scholz, C.W. [Charite, University Berlin, Hematology, Oncology and Tumor Immunology, Berlin (Germany); Lorsbach, M.; Windemuth-Kieselbach, C. [Alcedis GmbH, Giessen (Germany)

    2014-08-15

    Very few reliable clinical data about the use of radioimmunotherapy in aggressive B-cell lymphoma exist. Patients with aggressive B-cell lymphoma registered in the international RIT-Network were analysed with regard to prior treatment, response and side effects. The RIT-Network is a web-based registry that collects observational data from radioimmunotherapy-treated patients with malignant lymphoma across 13 countries. This analysis included 215 with aggressive B-cell lymphoma out of 232 patients registered in the RIT-Network. Histological subtypes were as follows: 190 diffuse large B-cell, 15 primary mediastinal, 9 anaplastic large cell, and 1 intravascular lymphoma. The median age of the patients was 62 years (range 17 - 88), with 27 % above the age of 70 years. Radioimmunotherapy was mainly used as consolidation after first-line or second-line chemotherapy (56.1 %), as part of third-line to eighth-line therapy for relapse (16.4 %), and in refractory disease (12.2 %). Grade IV neutropenia and thrombopenia and grade III anaemia were observed. The median time to recovery of blood count was 81 days (range 0 - 600 days). The overall response rate was 63.3 %. The complete response rate was 76.4 % in patients treated as part of first-line therapy, and 44.3 % in patients with relapse. Mean overall survival in first-line therapy patients was 32.7 months and 14.0 months in patients with relapse or refractory disease, respectively. Most patients with aggressive B-cell lymphoma in the RIT-Network received radioimmunotherapy as consolidation after first-line therapy with excellent complete remission and overall survival rates compared to published data. In relapsed aggressive B-cell lymphoma, radioimmunotherapy is a safe and feasible treatment leading to satisfactory response rates with acceptable toxicity. (orig.)

  15. Microfocus of Anaplastic Carcinoma Arising in Mural Nodule of Ovarian Mucinous Borderline Tumor With Very Rapid and Fatal Outcome.

    Science.gov (United States)

    Mhawech-Fauceglia, Paulette; Ramzan, Amin; Walia, Saloni; Pham, Huyen Q; Yessaian, Annie

    2016-07-01

    A 36-yr-old woman presented with abdominal discomfort. A computed tomography scan revealed a large left cystic and solid pelvic mass without evidence of metastatic disease. Total hysterectomy with bilateral salpingo-oophorectomy and tumor staging was performed. Grossly, the ovarian mass measured 20×18 cm and the cut surface was multiloculated with 1 single mural nodule measuring 2×1.5 cm. The histologic diagnosis of ovarian mucinous borderline tumor with a microfocus of anaplastic carcinoma arising in sarcoma-like mural nodule, FIGO Stage IA was rendered. After 3 mo, the patient returned with symptomatic anemia. A computed tomography scan showed enlarged retroperitoneal and pelvic lymph nodes. Image-guided biopsy of the pelvic lymph node showed a metastatic anaplastic carcinoma from her primary ovarian carcinoma. Chemotherapy was initiated, but the patient developed fulminant disseminated intravascular coagulation within <1 wk of her presentation which was fatal.

  16. Differential effects of interleukin-2 and interleukin-15 versus interleukin-21 on CD4+ cutaneous T-cell lymphoma cells

    DEFF Research Database (Denmark)

    Marzec, Michal; Halasa, Krzysztof; Kasprzycka, Monika

    2008-01-01

    In this study, we compared the effects of interleukin-2 (IL-2), IL-15, and IL-21 on gene expression, activation of cell signaling pathways, and functional properties of cells derived from CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 modulated, in a CTCL cell line, the expres......In this study, we compared the effects of interleukin-2 (IL-2), IL-15, and IL-21 on gene expression, activation of cell signaling pathways, and functional properties of cells derived from CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 modulated, in a CTCL cell line...... of transcription 5, phosphoinositide 3-kinase/Akt, and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK signaling pathways in the cell lines and mitogen-primed native cells. In contrast, IL-21 selectively activated signal transducers and activators of transcription 3. Whereas all...

  17. Imaging of non-hodgkin lymphomas

    DEFF Research Database (Denmark)

    El-Galaly, Tarec Christoffer; Hutchings, Martin

    2015-01-01

    Optimal lymphoma management requires accurate pretreatment staging and reliable assessment of response, both during and after therapy. Positron emission tomography with computerized tomography (PET/CT) combines functional and anatomical imaging and provides the most sensitive and accurate methods...... for lymphoma imaging. New guidelines for lymphoma imaging and recently revised criteria for lymphoma staging and response assessment recommend PET/CT staging, treatment monitoring, and response evaluation in all FDG-avid lymphomas, while CT remains the method of choice for non-FDG-avid histologies. Since...... interim PET imaging has high prognostic value in lymphoma, a number of trials investigate PET-based, response-adapted therapy for non-Hodgkin lymphomas (NHL). PET response is the main determinant of response according to the new response criteria, but PET/CT has little or no role in routine surveillance...

  18. Treatment options for ocular adnexal lymphoma (OAL

    Directory of Open Access Journals (Sweden)

    Victoria Mary Lendrum Cohen

    2009-11-01

    Full Text Available Victoria Mary Lendrum CohenSt. Bartholomew’s and Moorfields Eye Hospital, London UKAbstract: Most lymphomas that involve the ocular adnexal structure are low grade, B cell, non-Hodgkin’s lymphomas. The treatment depends upon the grade and stage of the disease. High grade lymhoma requires treatment with systemic chemotherapy whereas the localized low grade (extranodal marginal zone lymphoma can be successfully managed with local radiotherapy. Chlamydia psittaci infection is associated with low grade ocular lymphoma; however there is wide geographic variation in the strength of this association. Blanket antibiotic therapy is not advised unless there is proof of an infective agent. The monoclonal antibody, rituximab, may be successful for CD20 positive lymphoma, although it is likely that rituximab will have better long-term results when used in combination with systemic chemotherapy.Keywords: ocular adnexal lymphoma, mucosa associated lymphoid tissue, extranodal marginal zone lymphoma, Chlamydia psittaci, rituximab, radiotherapy, chemotherapy

  19. Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation.

    Science.gov (United States)

    Ji, Meng-Meng; Wang, Li; Zhan, Qin; Xue, Wen; Zhao, Yan; Zhao, Xia; Xu, Peng-Peng; Shen, Yang; Liu, Han; Janin, Anne; Cheng, Shu; Zhao, Wei-Li

    2015-01-01

    Autophagy is closely related to tumor cell sensitivity to anticancer drugs. The HDAC (histone deacetylase) inhibitor valproic acid (VPA) interacted synergistically with chemotherapeutic agents to trigger lymphoma cell autophagy, which resulted from activation of AMPK (AMP-activated protein kinase) and inhibition of downstream MTOR (mechanistic target of rapamycin [serine/threonine kinase]) signaling. In an HDAC-independent manner, VPA potentiated the effect of doxorubicin on lymphoma cell autophagy via reduction of cellular inositol 1,4,5 trisphosphate (IP3), blockade of calcium into mitochondria and modulation of PRKAA1/2-MTOR cascade. In murine xenograft models established with subcutaneous injection of lymphoma cells, dual treatment of VPA and doxorubicin initiated IP3-mediated calcium depletion and PRKAA1/2 activation, induced in situ autophagy and efficiently retarded tumor growth. Aberrant genes involving mitochondrial calcium transfer were frequently observed in primary tumors of lymphoma patients. Collectively, these findings suggested an HDAC-independent chemosensitizing activity of VPA and provided an insight into the clinical application of targeting autophagy in the treatment of lymphoma.

  20. Ovarian mucinous cystic tumor of borderline malignancy with a mural nodule of anaplastic spindle cell carcinoma: a case report.

    Science.gov (United States)

    Yamazaki, Hitoshi; Matsuzawa, Akiyo; Shoda, Takashi; Iguchi, Hiroyoshi; Kyushima, Noriyuki

    2013-12-05

    Ovarian cystic tumors with a mural nodule are a rare entity. We report a case of a mural nodule of anaplastic spindle cell carcinoma in an ovarian mucinous cystic tumor of borderline malignancy. The patient was a 45-years-old Japanese woman who presented with an ovarian cyst. She suffered from mature cystic teratoma of both ovaries 9 years before the present history. Image analysis and laboratory data showing a high serum CA19-9 level suggested ovarian malignancy. She underwent bilateral salpingo-oophorectomy with hysterectomy and omentectomy. There was a mural nodule in the ovarian mucinous cystic lesion. Microscopically, the nodule was composed of spindle-shaped cells with severe nuclear atypia. Immunohistochemical analysis allowed the cells to be categorized as anaplastic spindle cell carcinoma. Fifteen months after the operation the patient is alive without any clinical findings of tumor recurrence. To the best of our knowledge in the English literature, this is the first report of a mural nodule of an anaplastic spindle cell carcinoma within an ovarian mucinous cystic borderline tumor harboring previously confirmed cystic teratoma.

  1. Malignant Trigeminal Nerve Sheath Tumor and Anaplastic Astrocytoma Collision Tumor with High Proliferative Activity and Tumor Suppressor P53 Expression

    Directory of Open Access Journals (Sweden)

    Maher Kurdi

    2014-01-01

    Full Text Available Background. The synchronous development of two primary brain tumors of distinct cell of origin in close proximity or in contact with each other is extremely rare. We present the first case of collision tumor with two histological distinct tumors. Case Presentation. A 54-year-old woman presented with progressive atypical left facial pain and numbness for 8 months. MRI of the brain showed left middle cranial fossa heterogeneous mass extending into the infratemporal fossa. At surgery, a distinct but intermingled intra- and extradural tumor was demonstrated which was completely removed through left orbitozygomatic-temporal craniotomy. Histopathological examination showed that the tumor had two distinct components: malignant nerve sheath tumor of the trigeminal nerve and temporal lobe anaplastic astrocytoma. Proliferative activity and expressed tumor protein 53 (TP53 gene mutations were demonstrated in both tumors. Conclusions. We describe the first case of malignant trigeminal nerve sheath tumor (MTNST and anaplastic astrocytoma in collision and discuss the possible hypothesis of this rare occurrence. We propose that MTNST, with TP53 mutation, have participated in the formation of anaplastic astrocytoma, or vice versa.

  2. Arsenic Trioxide in Treating Patients With Relapsed or Refractory Lymphoma or Leukemia

    Science.gov (United States)

    2013-01-31

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  3. Drugs Approved for Hodgkin Lymphoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for Hodgkin lymphoma. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  4. INTRAOCULAR NON-HODGKINS-LYMPHOMA

    NARCIS (Netherlands)

    HOOYMANS, JMM; TIMMERMAN, Z

    1990-01-01

    Usually eye symptoms precede the infiltration of non-Hodgkin's lymphoma in the central nervous system or in other organs. Early treatment of the tumor by irradiation, to which it is highly sensitive, can preserve the vision and prolong the life of the patient. Such therapy however is often delayed w

  5. Iodide uptake in human anaplastic thyroid carcinoma cells after transfer of the human thyroid peroxidase gene

    Energy Technology Data Exchange (ETDEWEB)

    Haberkom, U. [Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg (Germany); Dept. of Nuclear Medicine, Univ. of Heidelberg (Germany); Altmann, A.; Jiang, S.; Morr, I.; Mahmut, M. [Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg (Germany); Eisenhut, M. [Dept. of Nuclear Medicine, Univ. of Heidelberg (Germany)

    2001-05-01

    Human thyroperoxidase (hTPO) is critical for the accumulation of iodide in thyroid tissues. Poorly differentiated and anaplastic thyroid tumours which lack thyroid-specific gene expression fail to accumulate iodide and, therefore, do not respond to iodine-131 therapy. We consequently investigated whether transfer of the hTPO gene is sufficient to restore the iodide-trapping capacity in undifferentiated thyroid and non-thyroid tumour cells. The human anaplastic thyroid carcinoma cell lines C643 and SW1736, the rat Morris hepatoma cell line MH3924A and the rat papillary thyroid carcinoma cell line L2 were used as in vitro model systems. Employing a bicistronic retroviral vector based on the myeloproliferative sarcoma virus for the transfer of the hTPO and the neomycin resistance gene, the C643 cells and SW1736 cells were transfected while the L2 cells and MH3924A cells were infected with retroviral particles. Seven recombinant C643 and seven SW1736 cell lines as well as four recombinant L2 and four MH3924A cell lines were established by neomycin selection. They were studied for hTPO expression using an antibody-based luminescence kit, followed by determination of the enzyme activity in the guaiacol assay and of the iodide uptake capacity in the presence of Na{sup 125}I. Genetically modified cell lines expressed up to 1,800 times more hTPO as compared to wild type tumour cells. The level of hTPO expression varied significantly between individual neomycin-resistant cell lines, suggesting that the recombinant retroviral DNA was integrated at different sites of the cellular genome. The accumulation of iodide, however, was not significantly enhanced in individual recombinant cell lines, irrespective of low or high hTPO expression. Moreover, there was no correlation between hTPO expression and enzyme activity in individual cell lines. The transduction of the hTPO gene per se is not sufficient to restore iodide trapping in non-iodide-concentrating tumour cells. Future

  6. The role of oestrogen receptor {alpha} in human thyroid cancer: contributions from coregulatory proteins and the tyrosine kinase receptor HER2.

    LENUS (Irish Health Repository)

    Kavanagh, Dara O

    2012-02-01

    Epidemiological, clinical, and molecular studies suggest a role for oestrogen in thyroid cancer. How oestrogen mediates its effects and the consequence of it on clinical outcome has not been fully elucidated. The participation of coregulatory proteins in modulating oestrogen receptor (ER) function and input of crosstalk with the tyrosine kinase receptor HER2 was investigated. Oestrogen induced cell proliferation in the follicular thyroid cancer (FTC)-133 cells, but not in the anaplastic 8305C cell line. Knockdown of the coactivator steroid receptor coactivator (SRC)-1 inhibited FTC-133 basal, but not oestrogen induced, cell proliferation. Oestrogen also increased protein expression of SRC-1 and the ER target gene cyclin D1 in the FTC-133 cell line. ERalpha, ERbeta, the coregulatory proteins SRC-1 and nuclear corepressor (NCoR), and the tyrosine kinase receptor HER2 were localised by immunohistochemistry and immnofluorescence in paraffin-embedded tissue from thyroid tumour patients (n=111). ERalpha was colocalised with both SRC-1 and NCoR to the nuclei of the tumour epithelial cells. Expression of ERalpha and NCoR was found predominantly in non-anaplastic tumours and was significantly associated with well-differentiated tumours and reduced incidence of disease recurrence. In non-anaplastic tumours, HER2 was significantly associated with SRC-1, and these proteins were associated with poorly differentiated tumours, capsular invasion and disease recurrence. Totally, 87% of anaplastic tumours were positive for SRC-1. Kaplan-Meier estimates of disease-free survival indicated that in thyroid cancer, SRC-1 strongly correlates with reduced disease-free survival (P<0.001), whereas NCoR predicted increased survival (P<0.001). These data suggest opposing roles for the coregulators SRC-1 and NCoR in thyroid tumour progression.

  7. Novel Brentuximab Vedotin Combination Therapies Show Promising Activity in Highly Refractory CD30+ Non-Hodgkin Lymphoma: A Case Series and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Wilfred Delacruz

    2016-01-01

    Full Text Available Non-Hodgkin lymphomas (NHLs are a heterogeneous group of hematologic malignancies which typically respond to standard first-line chemoimmunotherapy regimens. Unfortunately, patients with refractory NHL face a poor prognosis and represent an unmet need for improved therapeutics. We present two cases of refractory CD30+ NHL who responded to novel brentuximab vedotin- (BV- based regimens. The first is a patient with stage IV anaplastic large cell lymphoma (ALCL with cranial nerve involvement who failed front-line treatment with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP and second line cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate (MTX, and cytarabine (hyperCVAD with intrathecal- (IT- MTX and IT-cytarabine, but responded when BV was substituted for vincristine (hyperCBAD. The second patient was a man with stage IV diffuse large B-cell lymphoma (DLBCL with leptomeningeal involvement whose disease progressed during first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP and progressed despite salvage therapy with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP in whom addition of BV to topotecan resulted in a significant response. This report describes the first successful salvage treatments of highly aggressive, double refractory CD30+ NHL using two unreported BV-based chemoimmunotherapy regimens. Both regimens appear effective and have manageable toxicities. Further clinical trials assessing novel BV combinations are warranted.

  8. [Malignant Lymphoma of the Brain, and Dementia].

    Science.gov (United States)

    Mizutani, Saneyuki; Mizutani, Tomohiko

    2016-04-01

    A differential diagnosis of acute and subacute progressive dementias includes malignant lymphoma of the brain. We reviewed primary central nervous system lymphoma (PCNSL), intravascular lymphomatosis (IVL), lymphomatosis cerebri, and the relapse and invasion of systemic lymphomas. PCNSL is confined to the central nervous system; the infiltration and compression by the lymphoma result in adverse neurological symptoms. IVL is a rare form of malignant lymphoma that is characterized by the proliferation of primarily B-cell type lymphoma cells within the blood vessels of various organs. This causes ischemia and results in the associated neurological symptoms. Medical history and neuroimaging studies provide crucial informations to distinguish the lymphomas from other diseases that cause dementia, such an Alzheimer's disease. MRI imaging of the brain using contrast agent, and the biopsy of diseased tissues are essential for the diagnosis of the lymphomas. A histopathological examination is the most effective way to diagnose malignant lymphomas of the brain. Presently, the treatment of choice for PCNSL is the intravenous administration of high dose methotrexate with and without radiation therapy. Futhermore, Rituximab-containing chemotherapy has proved to greatly improve the prognosis of IVL. A better outcome can be achieved with the earlier diagnosis and treatment of the malignant lymphoma of the brain.

  9. Rituximab, Cyclophosphamide, Bortezomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Low-Grade Follicular Lymphoma, Waldenstrom Macroglobulinemia, or Mantle Cell Lymphoma

    Science.gov (United States)

    2016-04-13

    Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Nodal Marginal Zone Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

  10. Extranodal marginal zone (MALT) lymphoma in common variable immunodeficiency.

    NARCIS (Netherlands)

    Desar, I.M.; Keuter, M.; Raemaekers, J.M.M.; Jansen, J.B.M.J.; Krieken, J.H.J.M. van; Meer, J.W.M. van der

    2006-01-01

    We describe two patients with common variable immunodeficiency (CVID) who developed extranodal marginal zone lymphoma (formerly described as mucosa-associated lymphoid tissue lymphoma or MALT lymphoma). One patient, with documented pernicious anaemia and chronic atrophic gastritis with metaplasia, d

  11. Identifying the association between contrast enhancement pattern, surgical resection, and prognosis in anaplastic glioma patients

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yinyan; Jiang, Tao [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); Capital Medical University, Beijing Neurosurgical Institute, Beijing (China); Wang, Kai; Li, Shaowu; Ma, Jun [Capital Medical University, Department of Neuroradiology, Beijing Tiantan Hospital, Beijing (China); Wang, Jiangfei [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); Dai, Jianping [Capital Medical University, Beijing Neurosurgical Institute, Beijing (China); Capital Medical University, Department of Neuroradiology, Beijing Tiantan Hospital, Beijing (China)

    2016-04-15

    Contrast enhancement observable on magnetic resonance (MR) images reflects the destructive features of malignant gliomas. This study aimed to investigate the relationship between radiologic patterns of tumor enhancement, extent of resection, and prognosis in patients with anaplastic gliomas (AGs). Clinical data from 268 patients with histologically confirmed AGs were retrospectively analyzed. Contrast enhancement patterns were classified based on preoperative T1-contrast MR images. Univariate and multivariate analyses were performed to evaluate the prognostic value of MR enhancement patterns on progression-free survival (PFS) and overall survival (OS). The pattern of tumor contrast enhancement was associated with the extent of surgical resection in AGs. A gross total resection was more likely to be achieved for AGs with focal enhancement than those with diffuse (p = 0.001) or ring-like (p = 0.024) enhancement. Additionally, patients with focal-enhanced AGs had a significantly longer PFS and OS than those with diffuse (log-rank, p = 0.025 and p = 0.031, respectively) or ring-like (log-rank, p = 0.008 and p = 0.011, respectively) enhanced AGs. Furthermore, multivariate analysis identified the pattern of tumor enhancement as a significant predictor of PFS (p = 0.016, hazard ratio [HR] = 1.485) and OS (p = 0.030, HR = 1.446). Our results suggested that the contrast enhancement pattern on preoperative MR images was associated with the extent of resection and predictive of survival outcomes in AG patients. (orig.)

  12. Targeting TGF-β1 suppresses survival of and invasion by anaplastic thyroid carcinoma cells

    Science.gov (United States)

    Sun, Wenhai; Xu, Yanyan; Zhao, Cheng; Hao, Fengyun; Chen, Dong; Guan, Jinping; Zhang, Kejun

    2017-01-01

    Background and aims: Overexpression of transforming growth factor (TGF)-β1 has been implicated in promoting cell survival, migration and invasion in many cancers, including anaplastic thyroid cancer (ATC). In the present study, we studied the effect of suppressing TGF-β1 by RNA silencing on the survival, invasion and metastasis of ATC cells. Methods: Small interfering RNA (siRNA) constructs targeting TGF-β1 were validated and used to develop clonal derivatives of the ATC cell line, 8505C. The cells were used in several in vitro assays, including migration, invasion, survival rate, colony formation and apoptosis. A wound healing assay was used to determine the migration of cells in culture and a Boyden chamber transwell assay was used for invasion. Further, clones were used in an in vivo mouse model to study the kinetics of tumor growth and metastatic growth in lungs. Results: Targeting TGF-β1 expression in 8505C cells caused a 70% decrease in migration and a 78% decrease in invasion, as well as a 68% decrease in proliferation and a 19% increase in apoptosis in vitro. The growth of primary tumors in vivo was also inhibited when compared with parental 8505C cells; however, the number of mice bearing lung metastases was not significantly decreased. Conclusions: Targeting TGF-β1 may be effective in inhibiting primary tumor formation, but not metastasis, by ATC cells. TGF-β1 inhibition in combination with other tumor-targeted therapies may be more effective in inhibiting ATC.

  13. Anaplastic carcinoma of the pancreas: Is there a role for palliative surgical procedure?

    Directory of Open Access Journals (Sweden)

    Rajan Vaithianathan

    2014-01-01

    Full Text Available Anaplastic carcinoma (AC or undifferentiated carcinoma of the pancreas is a rare variant among the malignant pancreatic neoplasms. These tumors have a poor prognosis with survival measured in months. The role of surgical palliation to improve the quality of life is not well defined in these patients. We report a case of AC of pancreas in a 65-year-old male patient. Patient had upper abdominal pain with frequent bilious vomiting. Computed tomography scan of the abdomen showed a mass in the body of pancreas with possible infiltration of duodenojejunal flexure (DJF. Laparotomy revealed an inoperable mass with posterior fixity and involvement of the DJF. Patient underwent a palliative duodenojejunostomy. Tissue biopsy from the tumor showed pleomorphic type AC with giant cells. Patient had good symptomatic relief from profuse vomiting and progressed well at follow up. AC of pancreas is a rare and aggressive malignancy with dismal outlook. If obstructive symptoms are present due to duodenal involvement, a palliative bypass may be a worthwhile surgical option in selected cases.

  14. Langerhans cells in anaplastic Kaposi sarcoma with a paucivascular phenotype: a potential diagnostic pitfall.

    Science.gov (United States)

    Ramdial, Pratistadevi K; Sing, Yetish; Naicker, Shaun; Calonje, Eduardo; Sewram, Vikash; Singh, Bhugwan

    2011-04-01

    Anaplastic Kaposi sarcoma (AKS), a rare variant of Kaposi sarcoma, has a poorly recognized histomorphologic spectrum, including a paucivascular phenotype, that mimics a range of undifferentiated malignancies. This study, that highlights the hitherto undocumented phenomenon of S100-protein-positive Langerhans cells (SLCs) as a potential diagnostic pitfall in paucivascular AKS, involved review of nine such AKS that required diagnostic immunohistochemical (IHC) work-up. All biopsies had a predominant or exclusive spindle or epithelioid cell infiltrate. The first three tumors were diagnosed as malignant peripheral nerve sheath tumor (2) and metastatic melanoma (1), based on S100-protein immunopositivity. Biopsy of a co-existent pigmented sole lesion (patient 3) demonstrated nodular KS. Subsequent IHC investigation of these three tumors demonstrated an endothelial phenotype and HHV8 immunopositivity, confirming AKS. CD1a and langerin staining of the S100-protein-positive cells confirmed Langerhans cells as the cause of the diagnostic pitfall. Subsequently, six further paucivascular AKS with intratumoral SLCs were recognized on histomorphological and IHC appraisal. In conclusion, heightened awareness of the histomorphologic spectrum, appropriate IHC investigation, and informed appraisal thereof, are critical to the diagnosis of AKS with an undifferentiated phenotype, and the avoidance of IHC pitfalls, such as those caused by under-recognition and misinterpretation of bystander SLCs in AKS.

  15. Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma

    Directory of Open Access Journals (Sweden)

    Arai Hajime

    2007-08-01

    Full Text Available Abstract Background Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ, has demonstrated promising activity against recurrent glioma, the effects last only a few months and drug resistance develops thereafter in most cases. Induction of O6-methylguanine-DNA methyltransferase (MGMT in tumors is considered to be responsible for resistance to TMZ. Interferon-beta has been reported to suppress MGMT in an experimental glioma model. Here we report a patient with TMZ-refractory anaplastic astrocytoma (AA who was treated successfully with a combination of interferon-beta and TMZ. Case presentation A patient with recurrent AA after radiation-chemotherapy and stereotactic radiotherapy was treated with TMZ. After 6 cycles, the tumor became refractory to TMZ, and the patient was treated with interferon-beta at 3 × 106 international units/body, followed by 5 consecutive days of 200 mg/m2 TMZ in cycles of 28 days. After the second cycle the tumor decreased in size by 50% (PR. The tumor showed further shrinkage after 8 months and the patient's KPS improved from 70% to 100%. The immunohistochemical study of the initial tumor specimen confirmed positive MGMT protein expression. Conclusion It is considered that interferon-beta pre-administration increased the TMZ sensitivity of the glioma, which had been refractory to TMZ monotherapy.

  16. Radiation-induced anaplastic ependymoma mimicking a skull base meningioma: A case report

    Science.gov (United States)

    SPALLONE, ALDO; MARCHIONE, PASQUALE; DI CAPUA, MARIO; BELVISI, DANIELE

    2016-01-01

    The present study describes the case of a 63-year-old woman presenting with headache, dizziness and vomiting due to a an ovoid mass in the left pre-bulbar cistern, apparently arising from the lower clivus and the foramen magnum. The clinical history revealed the subtotal removal of a right cerebellar low-grade glioma 15 years previously and subsequent conventional 60-Gy radiotherapy. Notably, following gross total resection, histopathological examination showed microscopic features that resulted in a diagnosis of anaplastic ependymoma. The patient underwent surgery to remove the mass and post-operative chemotherapy with temozolomide. A progressive improvement of neurological signs and symptoms was observed during the postoperative course. At the 6-month follow-up, the patient was free from clinical and radiological recurrence. The unusual features of this rare secondary brain tumor were the extrassial location in the posterior fossa, the unusual age-associated location of the histological subtype and the fact that it closely mimicked a skull-base meningioma. PMID:26893630

  17. Rapid increase in cystic volume of an anaplastic astrocytoma misdiagnosed as neurocysticercosis: A case report

    Science.gov (United States)

    Li, Hong-Jiang; Han, Hong-Xiu; Feng, Dong-Fu

    2016-01-01

    Reports describing a rapid increase in the cystic volume of anaplastic astrocytoma (AA) in a short time frame are rare. The present study reports the case of a 68-year-old male who was admitted to the No. 9 People's Hospital, Shanghai Jiaotong University School of Medicine (Shanghai, China), with a small cystic brain lesion and positive immunological testing for cysticercosis. Head magnetic resonance imaging (MRI) showed a cystic lesion, 6 mm in diameter, in the left frontal lobe. Neurocysticercosis was suspected and the patient was treated with a clinical trial of albendazole and steroids. A period of 25 days later, the patient's condition had deteriorated, and MRI revealed a cystic lesion in the left frontal lobe; thereafter, the cystic lesion was removed and a diagnosis of AA was established. The tumor was soft, ivory white and gelatinous due to myxoid degeneration. In this case, tumor-related angiogenesis and microvascular extravasation (blood-brain barrier disruption) may have been the main cause of the rapid increase in the cystic volume in such a short time frame. The similarity of the glioma and cysticercus antigens may have been the cause of the positive reactions in the cystic fluid. The present study reports the rare occurrence of a rapid increase of cystic volume and potential diagnostic difficulties. PMID:27698865

  18. Rituximab With or Without Yttrium Y-90 Ibritumomab Tiuxetan in Treating Patients With Untreated Follicular Lymphoma

    Science.gov (United States)

    2016-06-15

    Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage II Grade 1 Contiguous Follicular Lymphoma; Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Stage II Grade 2 Contiguous Follicular Lymphoma; Stage II Grade 2 Non-Contiguous Follicular Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma

  19. Clinicopathological profile of gastrointestinal lymphomas in Kashmir

    Directory of Open Access Journals (Sweden)

    Mehnaaz Sultan Khuroo

    2016-01-01

    Full Text Available Background: The histological categorization of lymphoma has been a source of controversy for many years for both clinicians and pathologists. Clinicopathologic information of gastrointestinal lymphomas in Indian subcontinent is lacking. We studied histopathological spectrum of Primary Gastrointestinal Lymphomas (PGIL and attempted to classify the G.I. lymphomas based on the recent WHO classification in to major histological types and immunological categories. Material and Methods: This study was done to evaluate the clinicopathological pattern of 100 cases with a histopathological diagnosis of primary gastrointestinal lymphoma at a tertiary care hospital. All patients of primary gastrointestinal lymphomas were included with the help of medical records over a 11-years period that is, January 2005 to December 2015. Results: The study included 100 cases (60 males, 40 females; mean age 51.43 years; age range 4.5-90 years . The disease involved stomach in 82 (82%, small intestine in 8 (8%, large bowel and rectum in 8 (8%, gall bladder in 1 (1% and oesophagus in 1 (1%. 82 (82% of the 100 cases were Diffuse Large B cell lymphomas; 12 (12% were Extra Nodal Marginal Zone Lymphomas (ENMZL of MALT type 2 (2% IPSID 2 (2% of Mantle cell lymphoma morphology, 1 (1% Burkitt's and 1(1% enteropathy associated T cell lymphoma. The commonest presenting symptom was abdominal pain. 99 (99% of 100 tumours were classified as B-cell lymphomas immunohistochemically and majority exhibited monoclonal light chain restriction on kappa/lambda staining. In addition; Burkitt's lymphoma showed positivity for CD 10. One tumour (1% showed positivity for T-cell markers. The data demonstrated that primary GI NHL is more common among males, mainly in their fifth decade. Abdominal pain is the most common presenting symptom, with stomach being the most commonly involved site. Diffuse large cell lymphoma is the most frequent histologic subtype, followed by extranodal marginal-zone B

  20. Genetically Engineered Lymphocyte Therapy After Peripheral Blood Stem Cell Transplant in Treating Patients With High-Risk, Intermediate-Grade, B-cell Non-Hodgkin Lymphoma

    Science.gov (United States)

    2016-08-10

    Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma

  1. Primary malignant lymphoma of the parotid gland

    Directory of Open Access Journals (Sweden)

    Sudha H Metikurke

    2012-01-01

    Full Text Available Lymphoma of the salivary gland accounts for 5% of cases of extranodal lymphoma and 10% of malignant salivary gland tumors. Most primary salivary gland lymphomas are B marginal zone lymphomas arising on a background of sialadenitis associated with an autoimmune disorder such as Sjorgen′s syndrome. This report describes a case of primary B-cell lymphoma arising in the parotid gland in a middle-aged female, which was not associated with an autoimmune disorder. Immunohistochemistry studies confirmed the clonal B-cell nature of the tumor. This case highlights the fact that B-cell lymphoma in the salivary gland can go unrecognized due to its non-specific symptoms and requires immunohistochemistry studies for confirmation. We present this case for its rarity.

  2. Primary thyroid lymphoma: A rare disease

    Directory of Open Access Journals (Sweden)

    Deepti Verma

    2014-01-01

    Full Text Available Primary thyroid lymphomas are rare neoplasms comprising of 1-5% of thyroid malignancies. These are predominantly B-cell in origin. Here, we report a case of 60 years lady, a known case of lymphocytic thyroiditis, diagnosed as thyroid lymphoma (diffuse large B-cell on fine needle aspiration and confirmed histopathogically and immunohistochemically. She presented with a sudden increase in thyroid swelling. Fine needle aspiration performed showed highly cellular smears comprising predominantly of the monomorphic population of medium to large sized lymphoid cells with high nuclear/cytoplasmic ratio and scant cytoplasm. A possibility of thyroid lymphoma possibly diffuse large B-cell lymphoma was suggested which was later confirmed on biopsy. Fine needle aspiration provides an easy mode for diagnosing large cell lymphoma like diffuse large B-cell. Hence, an early diagnosis is possible for a timely intervention. Also, cases of lymphocytic thyroiditis should be regularly followed for the development of lymphoma.

  3. Composite Lymphoma: Opposite Ends of Spectrum Meet

    Science.gov (United States)

    Khan, Uqba; Hadid, Tarik; Ibrar, Warda; Sano, Dahlia; Al-Katib, Ayad

    2017-01-01

    An 18-year-old African-American female presented with an episode of syncope. Initial investigations revealed large lung mass with invasion into right atrium along with lesions in kidneys and liver. Patient also developed superior vena cava syndrome due to lung mass. Biopsy of lung mass revealed diagnosis of composite lymphoma with involvement by primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma. Patient was started on dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) with complete response to treatment. This case represents an extremely rare type of aggressive lymphoma and can guide clinicians in managing such cases since there are no standard guidelines for treatment. To the best of our knowledge, this is the first reported case of composite lymphoma of PMBCL and classical Hodgkin lymphoma successfully treated with dose-adjusted EPOCH-R regimen.

  4. Modern radiation therapy for primary cutaneous lymphomas

    DEFF Research Database (Denmark)

    Specht, Lena; Dabaja, Bouthaina; Illidge, Tim

    2015-01-01

    Primary cutaneous lymphomas are a heterogeneous group of diseases. They often remain localized, and they generally have a more indolent course and a better prognosis than lymphomas in other locations. They are highly radiosensitive, and radiation therapy is an important part of the treatment......, either as the sole treatment or as part of a multimodality approach. Radiation therapy of primary cutaneous lymphomas requires the use of special techniques that form the focus of these guidelines. The International Lymphoma Radiation Oncology Group has developed these guidelines after multinational...... meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the International Lymphoma Radiation Oncology Group steering committee on the use of radiation therapy in primary cutaneous lymphomas in the modern era....

  5. CEOP/IVE/GDP Compared With CEOP as the First-line Therapy for Newly Diagnosed Adult Patients With PTCL

    Science.gov (United States)

    2016-04-18

    Peripheral T-Cell Lymphoma; Angioimmunoblastic T Cell Lymphoma; ALK-negative Anaplastic Large Cell Lymphoma; Enteropathy Associated T Cell Lymphoma; Subcutaneous Panniculitis Like T Cell Lymphoma; Acute Adult T-Cell Leukemia/Lymphoma

  6. Lymphomas: diagnosis, treatment. Cancergram CT05

    Energy Technology Data Exchange (ETDEWEB)

    1985-01-01

    The scope of this Cancergram includes Hodgkin's disease, adenolymphoma, Burkitt's lymphoma, lymphosarcoma, lymphoblastoma, lymphocytoma, reticulum cell sarcoma, mycosis fungoides, and any not otherwise specified lymphoma. Abstracts are included which concern all clinical aspects of the various forms of lymphoma, such as diagnosis and staging, supportive care, evaluation, and therapy. Animal models, tissue culture experiments, carcinogenesis and other preclinical studies are generally excluded, except for those considered to have direct clinical relevance.

  7. Abdominal manifestations of extranodal lymphoma: pictorial essay*

    Science.gov (United States)

    Fajardo, Laís; Ramin, Guilherme de Araujo; Penachim, Thiago José; Martins, Daniel Lahan; Cardia, Patrícia Prando; Prando, Adilson

    2016-01-01

    In the appropriate clinical setting, certain aspects of extranodal abdominal lymphoma, as revealed by current cross-sectional imaging techniques, should be considered potentially diagnostic and can hasten the diagnosis. In addition, diagnostic imaging in the context of biopsy-proven lymphoma can accurately stage the disease for its appropriate treatment. The purpose of this article was to illustrate the various imaging aspects of extranodal lymphoma in the abdomen. PMID:28057966

  8. Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy

    NARCIS (Netherlands)

    Hoeve, M A; Gisbertz, I A; Schouten, H C; Schuuring, E; Bot, F J; Hermans, J; Hopman, A; Kluin, P M; Arends, J E; van Krieken, J H

    1999-01-01

    Gastric MALT lymphoma is a distinct entity related to Helicobacter pylori gastritis. Some studies suggest a role for trisomy 3 in the genesis of these lymphomas, but they mainly focused on low-grade MALT lymphoma. Gastric MALT lymphoma, however, comprises a spectrum from low- to high-grade cases. Fu

  9. Anaplastic carcinoma associated with a mucinous cystic neoplasm of the pancreas during pregnancy: Report of a case and a review of the literature

    Institute of Scientific and Technical Information of China (English)

    Kenichi Hakamada; Takuya Miura; Akitoshi Kimura; Masaki Nara; Yoshikazu Toyoki; Shunij Narumi; Mutsuo Sasak

    2008-01-01

    Oncogenesis of anaplastic carcinoma of the pancreas is a subject of controversy, because it shows sarcomatous nature with extremely poor prognosis. We herein report an unusual case of anaplastic carcinoma occurring with a recurrent mucinous cystic neoplasm in a 38-year-old female. A 10-cm retroperitoneal cystic mass was pointed out in the first pregnancy and a probable diagnosis of mucinous cystic neoplasm was made in October 2000. She refused surgery first and delivered her baby uneventfully. During her second pregnancy in 2002, however, she presented hematemesis and underwent urgent distal pancreatectomy, splenectomy and partial resection of the gastric wall where the tumor perforated. A diagnosis of borderline-type mucinous cystic neoplasm with ovarian-like stroma was made. Nine months later, CT visualized a recurrent cystic tumor near the pancreatic stump, which was subsequently resected. Pathology revealed that the tumor was composed of two different components of borderline-type mucinous cystic neoplasm and anaplastic carcinoma. The latter was intensely positive for vimentin, CD68, p53 and focally for cytokeratin, suggesting both sarcomatous and carcinomatous differentiation. She survived four years after the second surgery without tumor recurrence. Although the origin of anaplastic carcinoma has not been determined yet, it should be remembered that anaplastic carcinoma can occur in association with mucinous cystic neoplasm of more benign histology.

  10. Hepatitis Virus Infection and Hodgkin's Lymphoma: A Review of the Literature

    Directory of Open Access Journals (Sweden)

    Viroj Wiwanitkit

    2007-11-01

    of the HCV- encoded proteins seem to serve as substrates for host cell protein kinases (8. The identification of these small polypeptide elements and the subsequent development of strategies to inhibit protein-protein interactions involving them may be the first step towards reducing the chronicity and/or of the carcinogenicity of the virus (8.Considering the lymphoma genesis due to HCV infection, Quinn et al. proposed that some HCV-associated lymphomas originated from B cells that were initially activated by the HCV-E2 protein and might explain the association between HCV infection and some B-cell lymphoproliferative disorders (9. Indeed, Montella et al. said that HCV was an RNA virus that could not be integrated with the host genome, however, exerted its oncogenetic potential indirectly by contributing to the modulator effects of the host immune system, probably through a capacity to elude the immune system (10. Fiorilli et al. said that molecular data indicated a close relationship between HCV-associated B-non Hodgkin's lymphoma and type II mixed cryoglobulinemia (11. They noted that the latter disorder appeared to reflect the benign monoclonal proliferation of B cells expressing a specific cross-reactive idiotype that might recognize an antigen of HCV, perhaps the E2 protein then genetic abnormalities occurring during this phase of antigen-induced clonal expansion might drive the neoplastic transformation into low- or high-grade lymphoma (11.Concerning the relationship between HCV infection and Hodgkin's lymphoma, there are only a few reports. Keresztes et al. proposed that HCV positivity in patients with Hodgkin's disease differs significantly (about 1.5 times from that in blood donors (1. They also noted that there was no significant difference between hepatitis positive and negative patients concerning mean age at the time of diagnosis, sex, disease stage, histology type, treatment, risk factors in the history of infection, and liver enzymes (1. According to

  11. Entourage: the immune microenvironment following follicular lymphoma

    OpenAIRE

    2012-01-01

    In follicular lymphoma, nonmalignant immune cells are important. Follicular lymphoma depends on CD4+ cells, but CD8+ cells counteract it. We hypothesized that the presence of follicular lymphoma is associated with higher CD4+ than CD8+ cell numbers in the tumor microenvironment but not in the immune system. Using flow cytometry, pre-treatment and follow-up CD4/CD8 ratios were estimated in the bone marrow, blood and lymph nodes of untreated follicular lymphoma patients in two independent data ...

  12. Ongoing trials in low-grade lymphoma

    Directory of Open Access Journals (Sweden)

    Alexander Burchardt

    2011-10-01

    Full Text Available There are many therapies available for the management of low-grade lymphoma. With follicular lymphoma, for example, combination of chemotherapy and rituximab (immuno-chemo - therapy and consecutive maintenance therapy for 2 years is the current standard of care. To date, the most widely used regimen seems to be rituximab combined with cyclo phosphamide, doxorubicin, vincristine, and prednisone (RCHOP. Substitution of liposomal doxorubicin in place of conventional doxorubicin may improve outcomes in this indication, although evidence for its use in low-grade lymphoma is not as relevant as in aggressive lymphoma. Bendamustine, in combination with rituximab, has shown very good efficacy and tolerability in several lymphoma types, particularly follicular lymphoma and other low-grade lymphomas. Other combinations, such as those including bortezomib and lenalidomide, are under investigation in low-grade lymphoma, and the duration of rituximab maintenance therapy following bendamustine−rituximab-containing induction is being researched by the German Study Group for Indolent Lymphoma (StiL.

  13. Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment.

    Science.gov (United States)

    Rosebeck, Shaun; Lucas, Peter C; McAllister-Lucas, Linda M

    2011-05-01

    Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a prototypical cancer that occurs in the setting of chronic inflammation and an important model for understanding how deregulated NF-κB transcriptional activity contributes to malignancy. Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics. However, in a subset of MALT lymphomas, chromosomal translocations are acquired that render the lymphoma antigen-independent. The recurrent translocation t(11;18)(q21;q21) is associated with failure to respond to antibiotic therapy and increased rate of dissemination. This translocation creates the API2-MALT1 fusion oncoprotein, which comprises the amino terminus of inhibitor of apoptosis 2 (API2 or cIAP2) fused to the carboxy terminus of MALT1. A common characteristic of chromosomal translocations in MALT lymphoma, including t(11;18), is that genes involved in the regulation of the NF-κB transcription factor are targeted by the translocations, and these genetic perturbations thereby result in deregulated, constitutive NF-κB stimulation. In the last decade, great insights into the roles of API2 and MALT1 in NF-κB signaling have been made. For example, recent pivotal studies have uncovered the long sought-after proteolytic activity of MALT1 and have demonstrated its critical involvement in the survival of certain lymphomas. Here, we review the current understanding of the role of MALT1 in normal lymphocyte function and lymphomagenesis. We then highlight our recent work that has revealed an intriguing link between the proteolytic activity of the API2-MALT1 fusion and its ability to influence lymphomagenesis by cleaving a key NF-κB regulatory protein, NF-κB-inducing kinase.

  14. Molecular genetics of cutaneous lymphomas.

    Science.gov (United States)

    Whittaker, S

    2001-09-01

    The underlying molecular basis of primary cutaneous lymphomas has not yet been clarified. However, abnormalities of cell cycle control genes and well-defined tumor suppressor genes such as p53 are common and may contribute to disease progression and treatment resistance. Biallelic inactivation of tumor suppressor genes usually occurs by a combination of deletion, point mutation, and/or promotor hypermethylation. The detection of UVB-specific mutations of p53 requires confirmation but may have important implications for the management of patients with mycosis fungoides. Molecular cytogenetic studies have identified common regions of chromosomal deletion and amplification, which suggests the presence and location of genes that are of critical importance in the pathogenesis of cutaneous lymphoma.

  15. NOVEL DRUGS IN FOLLICULAR LYMPHOMA

    Directory of Open Access Journals (Sweden)

    Giuseppe Rossi

    2016-11-01

    Full Text Available Follicular lymphoma(FL is the most common indolent non-Hodgkin lymphoma and constitutes 15% to 30% of lymphoma diagnoses. The natural history of the disease is characterized by recurrent relapses and progressively shorter remissions with a median survival of 10yrs. The impossibility of a chieving a definite cure, have prompted investigations into the possible role of more effective and less toxic strategies with innovative therapeutic agents.  Recently Casulo et al demonstrated that approximately 20% of patients with FL actually relapse within 2 years after achieving remission with R-CHOP and have a poor prognosis. It is conceivable that this particularly chemoresistant population would benefit from specifically targeting the biologic and genetic factors that likely contribute to their poor prognosis. Evolving strategies for difficult to treat FL patients have recently considered  immunomodulatory agents, new monoclonal antibodies as well as drugs targeting selective intracellular pathways. The importance of targeting the microenvironment together with the malignant FL cell has been particularly underscored. We review the most promising approaches, such as the combination of anti-CD20 antibodies with immunomodulatory drugs (Lenalidomide, with mAbs directed against other surface antigens such as CD22 and CD23 (epratuzumab, lumiliximab, with immunomodulatory antibodies such as PD-1, or with inhibitors of key steps in the B-cell receptor pathway signaling such as PI3K inibithors(idelalisib, duvelisib. Another highly attractive approach is the application of the bi-specific T-cell engaging (BiTE antibody blinatumomab which targets both CD19 and CD3 antigens. Moreover, we highlight the potential of these therapies,  taking into account their toxicity. Of course we must wait for Phase III trials results to confirm the benefit of these new treatment strategies toward a new era of chemotherapy-free treatment for follicular lymphoma.

  16. Hodgkin lymphoma: answers take time!

    Science.gov (United States)

    Friedberg, Jonathan W

    2011-05-19

    In this issue of Blood, Straus and colleagues on behalf of the Cancer and Leukemia Group B (CALGB) present the outcome of a phase 2 trial of doxorubicin, vinblastine,and gemcitabine for patients with early-stage, non-bulky, Hodgkin lymphoma.The complete response rate and progression-free survival were inferior to comparable series, emphasizing the challenges of improving outcome in this highly curable population.

  17. Autologous Stem Cell Transplant Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoma

    Science.gov (United States)

    2016-02-23

    Prolymphocytic Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma; T-Cell Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  18. Early B-cell Specific Inactivation of ATM Synergizes with Ectopic CyclinD1 Expression to Promote Pre-germinal center B-cell Lymphomas in Mice

    Science.gov (United States)

    Yamamoto, Kenta; Lee, Brian J.; Li, Chen; Dubois, Richard L.; Hobeika, Elias; Bhagat, Govind; Zha, Shan

    2017-01-01

    Ataxia Telangiectasia Mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin Lymphomas (B-NHL), including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B-cells causes cell-autonomous, clonal mature B cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly naïve B cell specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. While EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increased the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas towards pre-GC derived small lymphocytic neoplasms sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naïve B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.g. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-germinal center B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL. PMID:25676421

  19. Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice.

    Science.gov (United States)

    Yamamoto, K; Lee, B J; Li, C; Dubois, R L; Hobeika, E; Bhagat, G; Zha, S

    2015-06-01

    Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL.

  20. Molecular pathways: targeting MALT1 paracaspase activity in lymphoma.

    Science.gov (United States)

    Fontán, Lorena; Melnick, Ari

    2013-12-15

    MALT1 mediates the activation of NF-κB in response to antigen receptor signaling. MALT1, in association with BCL10 and CARD11, functions as a scaffolding protein to activate the inhibitor of IκB kinase (IKK) complex. In addition, MALT1 is a paracaspase that targets key proteins in a feedback loop mediating termination of the NF-κB response, thus promoting activation of NF-κB signaling. Activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL), which tend to be more resistant to chemotherapy, are often biologically dependent on MALT1 activity. Newly developed MALT1 small-molecule inhibitors suppress the growth of ABC-DLBCLs in vitro and in vivo. This review highlights the recent advances in the normal and disease-related functions of MALT1. Furthermore, recent progress targeting MALT1 proteolytic activity raises the possibility of deploying MALT1 inhibitors for the treatment of B-cell lymphomas and perhaps autoimmune diseases that involve increased B- or T-cell receptor signaling.

  1. Composite lymphoma: EBV-positive classic Hodgkin lymphoma and peripheral T-cell lymphoma: a case report.

    Science.gov (United States)

    Gualco, Gabriela; Chioato, Lucimara; Van Den Berg, Anke; Weiss, Lawrence M; Bacchi, Carlos E

    2009-01-01

    Composite lymphomas are rare and defined as hematopoietic neoplasms with more than 1 malignant lymphomatous clone showing different phenotypic features. Of all possible combinations between non-Hodgkin lymphomas, B cell or T cell, and Hodgkin lymphoma, the least frequent are the ones combining T-cell non-Hodgkin lymphoma and classic Hodgkin lymphoma. We report a case of a 55-year-old woman with cervical and mediastinal lymphadenopathy, fever, weight loss, and night sweats. A cervical lymph node biopsy revealed a composite lymphoma with classic Hodgkin lymphoma and peripheral T-cell lymphoma components. The bone marrow was not involved. The patient refused treatment and died of disease progression 2 months after diagnosis. The biopsied lymph node showed 2 distinct populations, one composed of large cells including typical Reed-Sternberg cells and their variants, with expression of CD30, CD15, PAX5, and LMP-1. The other component was more abundant and comprised polymorphic medium-sized cells with convoluted nuclei; CD3, CD5, CD2, and CD4 expression; and negativity for CD30, cytotoxic granules, and B-cell markers. Epstein-Barr virus DNA of subtype A was identified only in the Hodgkin cells. Clonal T-cell receptor gamma and beta gene rearrangements were detected in the T-cell component, whereas monoclonal immunoglobulin H gene rearrangement was found in the Hodgkin cells.

  2. {sup 18}F-fluorodeoxyglucose positron emission tomography and computed tomography in anaplastic thyroid cancer

    Energy Technology Data Exchange (ETDEWEB)

    Poisson, Thomas [Institut Gustave Roussy and University Paris-Sud XI, Department of Nuclear Medicine and Endocrine Oncology, Villejuif Cedex (France); Service de Medecine Nucleaire, Hopital Bichat, Paris (France); Deandreis, Desiree; Leboulleux, Sophie; Lumbroso, Jean; Baudin, Eric [Institut Gustave Roussy and University Paris-Sud XI, Department of Nuclear Medicine and Endocrine Oncology, Villejuif Cedex (France); Bidault, Francois [Institut Gustave Roussy and University Paris-Sud XI, Department of Radiology, Villejuif Cedex (France); Bonniaud, Guillaume [Institut Gustave Roussy and University Paris-Sud XI, Department of Medical Physics, Villejuif Cedex (France); Baillot, Sylvain; Auperin, Anne [Institut Gustave Roussy and University Paris-Sud XI, Department of Epidemiology, Villejuif Cedex (France); Ghuzlan, Abir Al [Institut Gustave Roussy and University Paris-Sud XI, Department of Pathology, Villejuif Cedex (France); Travagli, Jean-Paul [Institut Gustave Roussy and University Paris-Sud XI, Department of Endocrine Surgery, Villejuif Cedex (France); Schlumberger, Martin [Institut Gustave Roussy and University Paris-Sud XI, Department of Nuclear Medicine and Endocrine Oncology, Villejuif Cedex (France); Institut Gustave Roussy, Service de Medecine Nucleaire et de Cancerologie Endocrinienne, Villejuif (France)

    2010-12-15

    Our aim was to evaluate in anaplastic thyroid carcinoma (ATC) patients the value of {sup 18}F-FDG PET/CT compared with total body computed tomography (CT) using intravenous contrast material for initial staging, prognostic assessment, therapeutic monitoring and follow-up. Twenty consecutive ATC patients underwent PET/CT for initial staging. PET/CT was performed again during follow-up. The gold standard was progression on imaging follow-up (CT or PET/CT) or confirmation with another imaging modality. A total of 265 lesions in 63 organs were depicted in 18 patients. Thirty-five per cent of involved organs were demonstrated only with PET/CT and one involved organ only with CT. In three patients, the extent of disease was significantly changed with PET/CT that demonstrated unknown metastases. Initial treatment modalities were modified by PET/CT findings in 25% of cases. The volume of FDG uptake ({>=}300 ml) and the intensity of FDG uptake (SUV{sub max} {>=}18) were significant prognostic factors for survival. PET/CT permitted an earlier assessment of tumour response to treatment than CT in 4 of the 11 patients in whom both examinations were performed. After treatment with combined radiotherapy and chemotherapy, only the two patients with a negative control PET/CT had a confirmed complete remission at 14 and 38 months; all eight patients who had persistent FDG uptake during treatment had a clinical recurrence and died. FDG PET/CT appears to be the reference imaging modality for ATC at initial staging and seems promising in the early evaluation of treatment response and follow-up. (orig.)

  3. SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas.

    Directory of Open Access Journals (Sweden)

    Ahmed Idbaih

    Full Text Available Anaplastic oligodendrogliomas (AOD are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19(q10;p10, IDH1, IDH2, CIC and FUBP1 mutations.To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA," has been supported by the Institut National du Cancer (InCA. Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.

  4. Treatment and Prognosis of Anaplastic Thyroid Carcinoma: A Clinical Study of 50 Cases

    Science.gov (United States)

    Long, Zhen; Wei, Fan-Qin; Zhuang, Shi-Min; Sun, Xiao-Mei; Xie, Liang-En; Mu, Jia-Sheng; Zhang, Guan-Ping; Fan, Yi

    2016-01-01

    Introduction Although anaplastic thyroid carcinoma (ATC) is rare, it is one of the most aggressive human cancers. The optimal multimodal therapy policy of ATC is still debated, and a standardized treatment strategy remains to be established. This study aimed to evaluate the management aspect and prognosis of ATC. Materials and Methods The data were analyzed retrospectively for 50 patients with ATC to evaluate the clinical characters, management and factors influencing survival. Survival analysis was performed by Kaplan-Merier method and log-rank test, and multivariate analysis was performed using Cox proportional hazard model. Results The 1-year and 2-year overall survival rates (OS) were 48.0% and 26.0% respectively in all patients, with the 2-year OS of 40.0% and 31.0% and 6.3% for stage IVA, IVB and IVC respectively (P <0.05). In stage IVA and IVB patients, combined surgery with radiotherapy improved overall survival, and the 2-year OS were 50.0% and 35.7% respectively in the group with combined surgery with radiotherapy and the group with surgery with only (P <0.05). Postoperative radiotherapy improved local control rate in stage IVA and IVB patients (P <0.05). However, surgery, radiotherapy or chemotherapy could not improve the survival of stage IVC patients. Multivariate analysis showed that distant metastases, surgery, radiotherapy and tumor residue could predict the prognosis. Conclusion Combined surgery and radiotherapy could improve overall survival in stage IVA and IVB patients. Patients with ATC have a bad prognosis. Distant metastases, surgery, radiotherapy and tumor residue are the most important factors affecting the prognosis. PMID:27760217

  5. CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin.

    Directory of Open Access Journals (Sweden)

    Susan Friedman

    Full Text Available BACKGROUND: Anaplastic thyroid cancer (ATC is one of the most lethal human malignancies. Its rapid onset and resistance to conventional therapeutics contribute to a mean survival of six months after diagnosis and make the identification of thyroid-cancer-initiating cells increasingly important. METHODOLOGY/PRINCIPAL FINDINGS: In prior studies of ATC cell lines, CD133(+ cells exhibited stem-cell-like features such as high proliferation, self-renewal and colony-forming ability in vitro. Here we show that transplantation of CD133(+ cells, but not CD133(- cells, into immunodeficient NOD/SCID mice is sufficient to induce growth of tumors in vivo. We also describe how the proportion of ATC cells that are CD133(+ increases dramatically over three months of culture, from 7% to more than 80% of the total. This CD133(+ cell pool can be further separated by flow cytometry into two distinct populations: CD133(+/high and CD133(+/low. Although both subsets are capable of long-term tumorigenesis, the rapidly proliferating CD133(+/high cells are by far the most efficient. They also express high levels of the stem cell antigen Oct4 and the receptor for thyroid stimulating hormone, TSHR. Treating ATC cells with TSH causes a three-fold increase in the numbers of CD133(+ cells and elicits a dose-dependent up-regulation of the expression of TSHR and Oct4 in these cells. More importantly, immunohistochemical analysis of tissue specimens from ATC patients indicates that CD133 is highly expressed on tumor cells but not on neighboring normal thyroid cells. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first report indicating that CD133(+ ATC cells are solely responsible for tumor growth in immunodeficient mice. Our data also give a unique insight into the regulation of CD133 by TSH. These highly tumorigenic CD133(+ cells and the activated TSH signaling pathway may be useful targets for future ATC therapies.

  6. Anaplastic thyroid carcinoma and foscarnet use in a multitarget treatment documented by 18F-FDG PET/CT

    Science.gov (United States)

    Giannetta, Elisa; Isidori, Andrea M.; Durante, Cosimo; Di Gioia, Cira; Longo, Flavia; Tombolini, Vincenzo; Bulzonetti, Nadia; Graziadio, Chiara; Pofi, Riccardo; Gianfrilli, Daniele; Verrienti, Antonella; Carletti, Raffaella; Filetti, Sebastiano; Lenzi, Andrea; Baroli, Alberto

    2017-01-01

    Abstract Rationale: The case reported the rapid remission of disease recurrence achieved adding foscarnet, a DNA polymerase inhibitor that interacts with fibroblast growth factor 2, to low molecular weight heparin and sunitinib for the first time in a patient with an anaplastic thyroid cancer (ATC). Patient concerns: A 65-year-old woman with a multinodular goiter referred for a rapid enlargement of a nodule. Histological examination revealed an ATC with a little area of papillary thyroid cancer (PTC). The patient was resistant to selective single-target treatment. DIagnoses: Immunophenotyping and gene analyses found a significant increase in FGF2 and FGFR1 expression in the primary ATC area (FGF2 = 38.2 ± 6.2% in ATC vs 34.6 ± 6.0% in the differentiated area of PTC, P FGFR4 in ATC. Low molecular wight heparin and Sunitinib were coadministere to limiti metastatic progression and on neck tumor masse, respectively. Outcomes: The rationale for the clinical response to this innovative multitarget association with foscarnet is based on the histological and genetic finding that fibroblast growth factors and their receptor super-family are up-regulated in the primary anaplastic thyroid tumor and in the metastatic lymph node of our patient. Lessons: We propose that fibroblast growth factors and their receptor super-family play a key role as potential therapeutic targets in anaplastic thyroid cancer and the positive relevance of this suggestion for patient care, especially for an individualized management. PMID:28178124

  7. Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas

    Science.gov (United States)

    2016-08-24

    Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic

  8. Expression patterns of nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase in human malignant lymphomas

    DEFF Research Database (Denmark)

    Olesen, Uffe Høgh; Hastrup, Nina; Sehested, Maxwell

    2011-01-01

    lymphomas (diffuse large B-cell lymphoma, follicular B-cell lymphoma, Hodgkin's lymphoma and peripheral T-cell lymphoma). The expression of NAMPT was generally high in the more aggressive malignant lymphomas, with >80% strong expression, whereas the expression in the more indolent follicular lymphoma (FL...

  9. Primary effusion lymphoma associated with Human Herpes Virus-8 and Epstein Barr virus in an HIV-infected woman from Kampala, Uganda: a case report

    Directory of Open Access Journals (Sweden)

    Osuwat Lawrence O

    2011-02-01

    Full Text Available Abstract Introduction Primary effusion lymphoma is a recently recognized entity of AIDS related non-Hodgkin lymphomas. Despite Africa being greatly affected by the HIV/AIDS pandemic, an extensive MEDLINE/PubMed search failed to find any report of primary effusion lymphoma in sub-Saharan Africa. To our knowledge this is the first report of primary effusion lymphoma in sub-Saharan Africa. We report the clinical, cytomorphologic and immunohistochemical findings of a patient with primary effusion lymphoma. Case presentation A 70-year-old newly diagnosed HIV-positive Ugandan African woman presented with a three-month history of cough, fever, weight loss and drenching night sweats. Three weeks prior to admission she developed right sided chest pain and difficulty in breathing. On examination she had bilateral pleural effusions. Haematoxylin and eosin stained cytologic sections of the formalin-fixed paraffin-embedded cell block made from the pleural fluid were processed in the Department of Pathology, Makerere University, College of Health Sciences, Kampala, Uganda. Immunohistochemistry was done at the Institute of Haematology and Oncology "L and A Seragnoli", Bologna University School of Medicine, Bologna, Italy, using alkaline phosphatase anti-alkaline phosphatase method. In situ hybridization was used for detection of Epstein-Barr virus. The tumor cells were CD45+, CD30+, CD38+, HHV-8 LANA-1+; but were negative for CD3-, CD20-, CD19-, and CD79a- and EBV RNA+ on in situ hybridization. CD138 and Ki-67 were not evaluable. Our patient tested HIV positive and her CD4 cell count was 127/μL. Conclusions A definitive diagnosis of primary effusion lymphoma rests on finding a proliferation of large immunoblastic, plasmacytoid and anaplastic cells; HHV-8 in the tumor cells, an immunophenotype that is CD45+, pan B-cell marker negative and lymphocyte activated marker positive. It is essential for clinicians and pathologists to have a high index of suspicion of

  10. Follicular Lymphoma Presenting with Leptomeningeal Disease

    OpenAIRE

    Rubens Costa; Ricardo Costa; Renata Costa

    2014-01-01

    Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Central nervous system metastasis is a very rare complication portending a very poor prognosis. We report a rare case of follicular lymphoma presenting with leptomeningeal involvement achieving a complete remission after initial therapy.

  11. Studying microRNAs in lymphoma

    NARCIS (Netherlands)

    Kluiver, Joost; Slezak-Prochazka, Izabella; van den Berg, Anke

    2013-01-01

    MicroRNAs (miRNAs) play important roles in development, differentiation, homeostasis, and also in diseases such as lymphoma. This chapter describes methods to study the role of miRNAs in lymphoma. First, we describe a multiplex RT reaction followed by qPCR that can be used to determine differential

  12. Primary testicular lymphoma: a case report

    Directory of Open Access Journals (Sweden)

    Cengiz Demir

    2010-06-01

    Full Text Available Primary testicular lymphomas are rare malignancy. We discussed the patient who had referred with mass into left testis at 73 years old diagnosis as diffuse large B-cell testicular lymphoma. Systemic chemotherapy (R-CHOP was given to the patient. Prophylactic radiotherapy was performed for the contralateral testis and central nervous system. Complete remission was achieved in the patient.

  13. Gene Therapy Shows Promise for Aggressive Lymphoma

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_163824.html Gene Therapy Shows Promise for Aggressive Lymphoma Over one-third ... TUESDAY, Feb. 28, 2017 (HealthDay News) -- An experimental gene therapy for aggressive non-Hodgkin lymphoma beat back more ...

  14. Primary Testicular B-cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Aykut Buğra Şentürk

    2015-12-01

    Full Text Available Primary testicular lymphoma constitutes only 1-7% of all testicular neoplasms and less than 1% of all non-Hodgkin lymphoma. We report a 69-year-old man who presented with a painful right testicular mass. Treatment modalities consist of surgical excision, chemotherapy and radiation therapy, however there are no standardized treatment options.

  15. PCR clonality detection in Hodgkin lymphoma.

    NARCIS (Netherlands)

    Hebeda, K.M.; Altena, M.C. van; Rombout, P.D.M.; Krieken, J.H.J.M. van; Groenen, P.J.T.A.

    2009-01-01

    B-cell clonality detection in whole tissue is considered indicative of B-cell non-Hodgkin lymphoma (NHL). We tested frozen tissue of 24 classical Hodgkin lymphomas (cHL) with a varying tumor cell load with the multiplex polymerase chain reaction (PCR) primer sets for IGH and IGK gene rearrangement (

  16. Autoimmune hemolytic anaemia in Hodgkin's lymphoma.

    Science.gov (United States)

    Shah, Mihir B; Nanjapp, Veena; Devaraj, H S; Sindhu, K S

    2013-07-01

    Autoimmune hemolytic anaemia is a rare presentation of Hodgkin's lymphoma though its association with Non- Hodgkin's lymphoma is well known. It is usually detected at the time of diagnosis when it accompanies Hodgkin's and rarely precedes it. It is a warm immune hemolytic anemia which is responsive to steroids and rituximab. We hereby report a case of advanced Hodgkin's disease who presented as AIHA.

  17. Follicular Lymphoma Presenting with Leptomeningeal Disease

    Directory of Open Access Journals (Sweden)

    Rubens Costa

    2014-01-01

    Full Text Available Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Central nervous system metastasis is a very rare complication portending a very poor prognosis. We report a rare case of follicular lymphoma presenting with leptomeningeal involvement achieving a complete remission after initial therapy.

  18. Anaplastic Ependymoma in a Child With Sickle Cell Anemia: A Case Report Highlighting Treatment Challenges for Young Children With Central Nervous System Tumors and Underlying Vasculopathy.

    Science.gov (United States)

    Crotty, Erin E; Meier, Emily R; Wells, Elizabeth M; Hwang, Eugene I; Packer, Roger J

    2016-03-01

    A 3-year-old boy with sickle cell anemia (SCA) presented with progressive daily emesis and was found to have an anaplastic ependymoma. Radiation therapy and chemotherapy are usually employed after subtotal resections of anaplastic ependymomas, although the benefits from chemotherapy are unclear. To mitigate the risks of adjuvant treatment in this patient at risk for SCA-associated vasculopathy, renal impairment, and other end-organ damage, proton beam irradiation without chemotherapy was chosen. Scheduled packed red blood cell transfusions were instituted to maintain sickle hemoglobin levels less than 30%. This case highlights treatment complexities for malignant brain tumors in patients predisposed to treatment-related adverse effects.

  19. Down-regulation of transcription elogation factor A (SII like 4 (TCEAL4 in anaplastic thyroid cancer

    Directory of Open Access Journals (Sweden)

    Miyamoto Shizuyo

    2006-11-01

    Full Text Available Abstract Background Anaplastic thyroid cancer (ATC is one of the most aggressive human malignancies and appears to arise mainly from transformation of pre-existing differentiated thyroid cancer (DTC. However, the carcinogenic mechanism of anaplastic transformation remains unclear. Previously, we investigated specific genes related to ATC based on gene expression profiling using cDNA microarray analysis. One of these genes, transcription elongation factor A (SII-like 4 (TCEAL4, encodes a member of the transcription elongation factor A (SII-like gene family. The detailed function of TCEAL4 has not been described nor has any association between this gene and human cancers been reported previously. Methods To investigate the role of TCEAL4 in ATC carcinogenesis, we examined expression levels of TCEAL4 in ACLs as well as in other types of thyroid cancers and normal human tissue. Results Expression of TCEAL4 was down-regulated in all 11 ACLs as compared to either normal thyroid tissues or papillary and follicular thyroid cancerous tissues. TCEAL4 was expressed ubiquitously in all normal human tissues tested. Conclusion To our knowledge, this is the first report of altered TCEAL4 expression in human cancers. We suggest that loss of TCEAL4 expression might be associated with development of ATC from DTC. Further functional studies are required.

  20. A North American brain tumor consortium phase II study of Poly-ICLC for adult patients with recurrent anaplastic gliomas

    Science.gov (United States)

    Butowski, Nicholas; Lamborn, Kathleen R.; Lee, Bee L; Prados, Michael D.; Cloughesy, Timothy; DeAngelis, Lisa M.; Abrey, Lauren; Fink, Karen; Lieberman, Frank; Mehta, Minesh; Robins, H. Ian; Junck, Larry; Salazar, Andres M.; Chang, Susan M.

    2011-01-01

    Purpose This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). Methods and Materials This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Results 55 patients were enrolled in the study. 10 were ineligible after central review of pathology. 11% of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Conclusions Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide. PMID:18850068

  1. Radiation therapy of CNS lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Imai, Yutaka; Wako, Tadashi (Shinshu Univ., Matsumoto, Nagano (Japan). Faculty of Medicine)

    1983-08-01

    Six cases of the CNS malignant lymphoma occurring among 165 cases seen between 1975 -- 1981 were reviewed. Two cases had primary brain mass lesions and one case had a secondary brain mass in the systemic remission period. Two cases had primary extradural spinal mass lesions and one case had a secondary extradural spinal mass in the systemic relapse period. All patients were treated with radiotherapy. Irradiation fields, doses and those effects were discussed. Whole brain irradiation more than 40 Gy was recommended for brain lesion. Prognosis of the secondary case without systemic remission was poor.

  2. Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2)

    NARCIS (Netherlands)

    Kort, Anita; Sparidans, Rolf; Wagenaar, Els; Beijnen, Jacob; Schinkel, Alfred H.

    2015-01-01

    We aimed to clarify the roles of the multidrug transporters ABCB1 and ABCG2 in oral availability and brain accumulation of ceritinib, an oral anaplastic lymphoma kinase (ALK) inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) after progression on crizotinib. Importantly, NSCLC is

  3. Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer

    NARCIS (Netherlands)

    Weiss, Jonathan; Sos, Martin L.; Seidel, Danila; Peifer, Martin; Zander, Thomas; Heuckmann, Johannes M.; Ullrich, Roland T.; Menon, Roopika; Maier, Sebastian; Soltermann, Alex; Moch, Holger; Wagener, Patrick; Fischer, Florian; Heynck, Stefanie; Koker, Mirjam; Schoettle, Jakob; Leenders, Frauke; Gabler, Franziska; Dabow, Ines; Querings, Silvia; Heukamp, Lukas C.; Balke-Want, Hyatt; Ansen, Sascha; Rauh, Daniel; Baessmann, Ingelore; Altmueller, Janine; Wainer, Zoe; Conron, Matthew; Wright, Gavin; Russell, Prudence; Solomon, Ben; Brambilla, Elisabeth; Brambilla, Christian; Lorimier, Philippe; Sollberg, Steinar; Brustugun, Odd Terje; Engel-Riedel, Walburga; Ludwig, Corinna; Petersen, Iver; Saenger, Joerg; Clement, Joachim; Groen, Harry; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert; Heideman, Danielle; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Hallek, Michael; Beroukhim, Rameen; Pao, William; Klebl, Bert; Baumann, Matthias; Buettner, Reinhard; Ernestus, Karen; Stoelben, Erich; Wolf, Juergen; Nuernberg, Peter; Perner, Sven; Thomas, Roman K.

    2010-01-01

    Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous

  4. Identification of CARS-ALK fusion in primary and metastatic lesions of an inflammatory myofibroblastic tumor

    NARCIS (Netherlands)

    Debelenko, LV; Arthur, DC; Pack, SD; Helman, LJ; Schrump, DS; Tsokos, M

    2003-01-01

    Inflammatory myofibroblastic tumor (IMT) is a rare childhood neoplasm. The natural history of this disease is poorly understood. Recently chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene have been implicated in this tumor. We have studied a case of ALK-positive soft tis

  5. An International Interpretation Study Using the ALK IHC Antibody D5F3 and a Sensitive Detection Kit Demonstrates High Concordance between ALK IHC and ALK FISH and between Evaluators

    NARCIS (Netherlands)

    Wynes, Murry W.; Sholl, Lynette M.; Dietel, Manfred; Schuuring, Ed; Tsao, Ming S.; Yatabe, Yasushi; Tubbs, Raymond R.; Hirsch, Fred R.

    2014-01-01

    Introduction: The goal of personalized medicine is to treat patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or toxic therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK-positive non

  6. Cholecalciferol in Improving Survival in Patients With Newly Diagnosed Cancer With Vitamin D Insufficiency

    Science.gov (United States)

    2016-12-20

    Aggressive Non-Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B-Cell Lymphoma; Enteropathy-Associated T-Cell Lymphoma; Hepatosplenic T-Cell Lymphoma; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Nasal Type Extranodal NK/T-Cell Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise Specified; Primary Cutaneous Anaplastic Large Cell Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Small Lymphocytic Lymphoma; Subcutaneous Panniculitis-Like T-Cell Lymphoma

  7. Novel insights into the molecular pathogenesis of gastric MALT lymphoma

    OpenAIRE

    2010-01-01

    Gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) represents a distinct class of extranodal lymphoma that evolves against a background of chronic inflammation induced by persistent infection with the bacterium Helicobacter pylori. In its early stages, MALT lymphoma is an antigen-dependent disease characterised by an indolent clinical course and in most cases is treatable by antibiotic eradication therapy alone. Low grade MALT lymphomas c...

  8. Primary marginal zone B-cell lymphoma of appendix

    Directory of Open Access Journals (Sweden)

    Radha S

    2008-07-01

    Full Text Available Primary lymphomas of appendix are extremely rare tumors. The first case of primary lymphoma of appendix was reported by Warren in the year 1898. Incidence of primary lymphoma of appendix is 0.015% of all gastrointestinal lymphomas. This is a report of primary marginal zone B-cell lymphoma of appendix which presented as appendicular mass. As some cases are incidentally discovered, this case emphasizes that histological examination of all appendicectomy specimens is mandatory.

  9. Influence of insurance status and income in anaplastic astrocytoma: an analysis of 4325 patients.

    Science.gov (United States)

    Shin, Jacob Y; Yoon, Ja Kyoung; Diaz, Aidnag Z

    2016-11-18

    To determine the impact of insurance status and income for anaplastic astrocytoma (AA). Data were extracted from the National Cancer Data Base. Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 4325 patients with AA diagnosed from 2004 to 2013 were identified. 2781 (64.3%) had private insurance, 925 (21.4%) Medicare, 396 (9.2%) Medicaid, and 223 (5.2%) were uninsured. Those uninsured were more likely to be Black or Hispanic versus White or Asian (p < 0.001), have lower median income (p < 0.001), less educated (p < 0.001), and not receive adjuvant chemoradiation (p < 0.001). 1651 (38.2%) had income ≥$63,000, 1204 (27.8%) $48,000-$62,999, 889 (20.5%) $38,000-$47,999, and 581 (13.4%) had income <$38,000. Those with lower income were more likely to be Black or Hispanic versus White or Asian (p < 0.001), uninsured (p < 0.001), reside in a rural area (p < 0.001), less educated (p < 0.001), and not receive adjuvant chemoradiation (p < 0.001). Those with private insurance had significantly higher overall survival (OS) than those uninsured, on Medicaid, or on Medicare (p < 0.001). Those with income ≥$63,000 had significantly higher OS than those with lower income (p < 0.001). On multivariate analysis, age, insurance status, income, and adjuvant therapy were independent prognostic factors for OS. Being uninsured and having income <$38,000 were independent prognostic factors for worse OS in AA. Further investigations are warranted to help determine ways to ensure adequate medical care for those who may be socially disadvantaged so that outcome can be maximized for all patients regardless of socioeconomic status.

  10. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target.

    Science.gov (United States)

    Chiarle, Roberto; Simmons, William J; Cai, Honjying; Dhall, Girish; Zamo, Alberto; Raz, Regina; Karras, James G; Levy, David E; Inghirami, Giorgio

    2005-06-01

    Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma

  11. EBV AND HIV-RELATED LYMPHOMA

    Directory of Open Access Journals (Sweden)

    Michele Bibas

    2009-12-01

    Full Text Available HIV-associated lymphoproliferative disorders represent a heterogeneous group of diseases, arising in the presence of HIV-associated immunodeficiency. The overall prevalence of HIV-associated lymphoma is significantly higher compared to that of the general population and it continues to be relevant even after the wide availability of highly active antiretroviral therapy (HAART (1. Moreover, they still represent one of the most frequent cause of death in HIV-infected patients. Epstein–Barr virus (EBV, a γ-Herpesviruses, is involved in human lymphomagenesis, particularly in HIV immunocompromised patients. It has been largely implicated in the development of B-cell lymphoproliferative disorders as Burkitt lymphoma (BL, Hodgkin disease (HD, systemic non Hodgkin lymphoma (NHL, primary central nervous system lymphoma (PCNSL, nasopharyngeal carcinoma (NC. Virus-associated lymphomas are becoming of significant concern for the mortality of long-lived HIV immunocompromised patients, and therefore, research of advanced strategies for AIDS-related lymphomas is an important field in cancer chemotherapy. Detailed understanding of the EBV  lifecycle and related cancers at the molecular level is required for novel strategies of molecular-targeted cancer chemotherapy The linkage of HIV-related lymphoma with EBV infection of the tumor clone has several pathogenetic, prognostic and possibly therapeutic implications which are reviewed herein

  12. Aggressive lymphoma in the elderly.

    Science.gov (United States)

    Lichtman, S M

    2000-02-01

    Persons 65 years of age and older are the fastest growing segment of the United States population. Over the next 30 years they will comprise approximately 20% of the population. There will be a parallel rise in the number of patients with non-Hodgkin's lymphoma. Age has long been known to be an adverse prognostic factor. Clinical trials of older patients are complicated by the effect of comorbid illness, particularly its effect on overall survival. CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) remains the standard therapy for all patients with aggressive non-Hodgkin's lymphoma. There are a number of regimens which may be beneficial for older patients with significant comorbidity and poor performance status. The randomized trials in the elderly has reaffirmed CHOP and emphasize the need for adequate dosing, maintaining schedule and anthracyclines. Relapsed patients have a poor prognosis but selected fit older patients may benefit from aggressive reinduction regimens and possibly bone marrow transplantation. Future research should include defining the role of comorbidity, measurement of organ dysfunction and assessment of performance status with geriatric functional scales. New drug treatments should also be explored.

  13. Thymidine kinases in archaea

    DEFF Research Database (Denmark)

    Clausen, A.R.; Matakos, A.; Sandrini, Michael;

    2006-01-01

    Twenty-six fully sequenced archaeal genomes were searched for genes coding for putative deoxyribonucleoside kinases (dNKs). We identified only 5 human-like thymidine kinase 1 genes (TK1s) and none for non-TK1 kinases. Four TK1s were identified in the Euryarchaea and one was found in the Crenarchaea...... that a functional deoxyribonucleoside salvage pathway is not crucial for the archaeal cell....

  14. [Pulmonary Langerhans histiocytosis and Hodgkin's lymphoma].

    Science.gov (United States)

    Paris, A; Dib, M; Rousselet, M-C; Urban, T; Tazi, A; Gagnadoux, F

    2011-09-01

    Pulmonary Langerhans histiocytosis (PLH) is a rare disease due to the accumulation of Langerhans cells at the level of the bronchioles. These dendritic immunocytes form granulomata and destroy the wall of the airway. We report a case of PLH developing at the same time as Hodgkin's lymphoma in a young woman who smoked tobacco and cannabis. We observed a complete remission of the PLH lesions parallel to the remission of the Hodgkin's lymphoma after chemotherapy, in the absence of any change in the consumption of tobacco and cannabis. This observation leads us to discuss the potential relationships between PLH on one hand, and smoking, the lymphoma and its treatment on the other.

  15. CONSOLIDATIVE PRIMARY PULMONARY LYMPHOMA: THREE MISDIAGNOSED CASES

    Institute of Scientific and Technical Information of China (English)

    陈恩国; 余碧芸; 洪武军; 应可净

    2003-01-01

    Objective: To investigate the clinical features and the reason of misdiagnosis of consolidative primary p