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Sample records for alk1-negative anaplastic large

  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 Large Cell Lymphoma

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    Anaplastic Large Cell Lymphoma Overview Lymphoma is the most common blood cancer. The two main forms of lymphoma are ... organs, and can accumulate to form tumors. Anaplastic large cell lymphoma (ALCL) is arare type of NHL, ...

  3. Anaplastic lymphoma kinase-positive primary cutaneous anaplastic large cell lymphoma- Is it a new variant?

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    Muthu Sendhil Kumaran

    2012-01-01

    Full Text Available Anaplastic large cell cutaneous lymphomas are clinically and pathologically heterogeneous, CD30 + (Ki-1 lymphoproliferative disorders. The importance of anaplastic lymphoma kinase (ALK positivity is well known in the prognosis of primary systemic anaplastic large cell cutaneous lymphomas; however, the same in primary cutaneous anaplastic large cell cutaneous lymphomas is not much clear. Herein we report a 65-year-old male with an 18-month history of minimally pruritic localized nodulo-plaque lesion over lower back. Histology revealed cutaneous large cell lymphoma and immunohistochemical staining showed positivity for CD30, CD3 and ALK. The role of ALK positivity in pcALCL is discussed in this article.

  4. Pathobiology of Anaplastic Large Cell Lymphoma

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    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.

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

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    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.

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

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    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.

  7. 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.

  8. 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.

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

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    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.

  10. Anaplastic large cell lymphoma: A single institution experience from India

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    K C Lakshmaiah

    2013-01-01

    Full Text Available Background: Systemic anaplastic large cell lymphoma (ALCL accounts for 2-8% of non-Hodgkin′s lymphoma in adults and 10-15% in children. While there is ample data in the world literature about the clinical features and outcome of this disease, prognosis in Indian patients is largely unknown. Objective: To study the clinical, pathologic profile and outcome ALCL. Materials and Methods: Fifty patients who had pathologically proven diagnosis of systemic ALCL at our institute from June 2003 to May 2011 were included for retrospective analysis. This included 30 cases of anaplastic lymphoma kinase+ (ALK+, ALCL and 20 cases of anaplastic lymphoma kinase- (ALK−, ALCL. The hospital protocol for treatment of these patients included CHOP chemotherapy regimen in >15 years of age and MCP842 protocol with vinblastine for 1 year in <15 years of age. Event free survival was noted. These outcomes were correlated with ALK status, International Prognostic Index (IPI score, and stage at presentation. Results: At a median follow-up of 36 months (range: 6-72 months ALK− ALCL had a poor outcome. The 3 year event free survival in pediatric ALCL was 66.7%. In adults, this was 60% ALK+ ALCL was 60% and 20% in ALK− ALCL. Conclusions: Systemic ALCL is an aggressive disease. CD3 + positivity is commonly seen in ALK− ALCL and ALK+, epithelial membrane antigen + positivity is seen in ALK+ ALCL. ALK− ALCL, advanced stage III, IV and high IPI score were associated with poor prognosis. The demographic profile and outcome in our study was similar to the world literature. With new drugs like crizotinib and brentuximab vedotin the future looks very promising.

  11. A case of Primary Bone Anaplastic Large Cell Lymphoma

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    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

  12. Unusual clinical presentation of anaplastic large cell lymphoma

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    Fernando Peixoto Ferraz de Campos

    2014-03-01

    Full Text Available Anaplastic large cell lymphoma (ALCL, a well-recognized entity, presents a varied clinical picture and epidemiological characteristics associated with the expression of the anaplastic lymphoma kinase (ALK protein. When classic symptoms are present (weight loss, fever, and night sweats and combine with enlarged and easily accessible peripheral lymph nodes, diagnosis is not that difficult. But when the clinical presentation is nonspecific, a tough diagnostic task is required. HIV infection is highly associated with neoplastic disorders—mainly with those of hematological origin. However, ALCL is exceptionally associated with HIV infection, and the few reported cases are ALK– ALCL. The authors report two cases of ALK+ ALCL with the unusual clinical presentation: one is associated with the HIV infection and the other presents as a fever of unknown origin (FUO without peripheral lymphadenopathy. The latter was autopsied and was characterized by nodal and extra nodal involvement. The authors call attention to the plurality of clinical presentation of this group of lymphomas, and the early indication of bone marrow examination in cases of an FUO with elevated hepatic enzymes and lactic dehydrogenase.

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

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    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.

  14. Primary cutaneous anaplastic large-cell lymphoma: a case report.

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    Cao, Can; Zeng, Kang; Wang, Menglei; Han, Kai; Peng, Yusheng; Xiong, Hao; Wang, Qi; Li, Qian; Wang, Qian; Li, Li

    2016-07-01

    Primary cutaneous anaplastic large-cell lymphoma (PCALCL) is a part of the spectrum of CD30+ lymphoproliferative cutaneous processes. The characteristics include single or multifocal nodules that ulcerate as skin lesion, slow disease progression, autoregressive, and recurrent in few years. The present study report the case of a 16-year-old boy presenting PCALCL with single nodules, ulcer, keloid, and scab in his right-side face. He showed a good response to the treatment with systemic chemotherapy and dermatoplasty, and regained confidence after the appearance of recovery. There is no relapse of the primary lesion and organs involved till now. The chemotherapy combining with surgical excision and dermatoplasty is a good method for PCALCL, per the lesion biopsy and positron emission tomography-computed tomography before and after treatment. PMID:26970422

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

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    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...

  16. Association of Systemic Anaplastic Large Cell Lymphoma and Active Toxoplasmosis in a Child

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    Sayyahfar, Shirin; Karimi, Abdollah; Gharib, Atoosa; Fahimzad, Alireza

    2015-01-01

    Introduction: Anaplastic large cell lymphoma is a subset of non-Hodgkin lymphoma and an unusual disease in children. Case Presentation: Herein we have reported a 7- year- old girl with a large necrotic skin ulcer on the chest caused by systemic form of anaplastic large-cell lymphoma and simultaneous active toxoplasmosis diagnosed by PCR on lymph node specimen. There were few reports showing a role for toxoplasma infection to cause some malignancies such as lymphoma in adults. Conclusions: Bas...

  17. Neutrophil rich anaplastic large cell lymphoma presented as cutaneous nodules in an adolescent

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Anaplastic large cell lymphoma (ALCL),a type of lymphoma,was first described by Stain in 1985 and included in non-Hodgkin lymphoma according to REAL classification since 1998.In the absence of necrosis,neutrophils infiltration in non-Hodgkin lymphoma is uncommon.Mann et all had previously reported neutrophil rich ALCL as a variant of ALCL.In this paper,we describe a neutrophil rich,anaplastic large cell lymphoma (ALCL) which presented as cutaneous nodules in an adolescent.

  18. Cardiac anaplastic large cell lymphoma in an 8-year old boy

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    Melchior Lauten

    2014-01-01

    Full Text Available We report on an 8 year old boy with primary cardiac anaplastic large cell lymphoma (ALCL, in whom the diagnosis was challenging and who was treated with modified chemotherapy without radiation therapy according to the ALCL 99 study protocol [1]. Two years and 4 months after completion of therapy the boy is in complete remission with normal cardiac function.

  19. Cardiac anaplastic large cell lymphoma in an 8-year old boy

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    Melchior Lauten; Simon Vieth; Christopher Hart; Wilhelm Wössmann; Birte Tröger; Christoph Härtel; Martin Bethge; André Schrauder; Gunnar Cario

    2014-01-01

    We report on an 8 year old boy with primary cardiac anaplastic large cell lymphoma (ALCL), in whom the diagnosis was challenging and who was treated with modified chemotherapy without radiation therapy according to the ALCL 99 study protocol [1]. Two years and 4 months after completion of therapy the boy is in complete remission with normal cardiac function.

  20. Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features

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    Mastronuzzi, Angela; Miele, Evelina; Po, Agnese; Antonelli, Manila; Buttarelli, Francesca Romana; Colafati, Giovanna Stefania; Del Bufalo, Francesca; Faedda, Roberta; Spinelli, Gian Paolo; Carai, Andrea; Giangaspero, Felice; Gulino, Alberto; Locatelli, Franco; Ferretti, Elisabetta

    2014-01-01

    Background Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. Case presentation We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcut...

  1. Primary cutaneous anaplastic large cell lymphoma successfully treated with local thermotherapy using pocket hand warmers.

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    Honma, Masaru; Hashimoto, Makoto; Iwasaki, Takeshi; Iinuma, Shin; Takahashi, Hidetoshi; Ishida-Yamamoto, Akemi; Iizuka, Hajime

    2008-11-01

    Apart from for cutaneous deep fungal or mycobacterial infections, thermotherapy has been used for various malignant tumors. We report a case of primary cutaneous anaplastic large cell lymphoma, which responded quite well to topical thermotherapy using chemical pocket hand warmers. The treatment resulted in an immediate tumor regression without recurrence. This method is simple and might be a useful tool against solitary cutaneous lymphoma, especially of elderly patients with poor performance status or with various systemic complications. PMID:19120772

  2. 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

  3. A rare case of ALK negative CD30+ primary cutaneous anaplastic large cell lymphoma in a young adult

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    H B Sridevi

    2015-01-01

    Full Text Available Cutaneous anaplastic large cell lymphoma can present either as a primary disease or as secondary to a pre-existing systemic anaplastic lymphoma. Distinguishing primary cutaneous anaplastic lymphoma (PC-ALCL from its systemic counterpart requires a complete clinical and laboratory workup. We hereby report a case of PC-ALCL in a young adult, who presented with unusual rapidly progressive ulcerated mass in the neck. Biopsy showed anaplastic large cells, which were strongly positive for CD30 and CD25 but ALK1 gene product was negative. Clinical examination and computed tomography (CT scan ruled out extracutaneous involvement. Chemotherapy with 6 cycles of CHOP regimen was planned and on follow-up, a complete remission of the lesion was attained.

  4. Primary anaplastic large cell lymphoma of central nervous system-A case report

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    Rupani A

    2005-01-01

    Full Text Available Central nervous system (CNS involvement is extremely rare in anaplastic large cell lymphoma (ALCL. Primary ALCL of CNS on radiology is often misdiagnosed as tuberculosis. We report a fatal case of primary ALCL of CNS in a 17 year old male. He came with history of headache and left partial seizures. MRI showed a well- circumscribed lesion in the right fronto-parietal lobe eroding the skull bone. Biopsy showed large pleomorphic cells. Immunohistochemical stains showed positivity for CD30, CD43, EMA and ALK-1. In spite of radiotherapy and steroids, patient expired. Hence a high level of suspicion is essential for early diagnosis and for instituting appropriate treatment.

  5. Indium-111-oxine labeled leukocyte uptake in Ki-1-positive anaplastic large cell lymphoma

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    Chiu, W.; Amodio, J.B.; Scharf, S.C. (New York Univ., NY (United States). Dept. of Radiology); Rivlin, K.A. (Department of Hematology and Oncology, New York Univ. Medical Center, NY (United States)); Desai, P. (Department of Pathology, Hospital for Joint Diseases-Orthopaedic Inst., New York, NY (United States)); Breuer, F. (Department of Pathology, Lenox Hill Hospital, New York, NY (United States))

    1999-08-01

    Indium-111-oxine labeled leukocyte ([sup 111]In-WBC) scintigraphy is well known for its ability to localize in areas of active infection, but not in areas of lymphomatous involvement. We present a case of Ki-1-positive anaplastic large-cell lymphoma that was initially thought to be a case of multifocal osteomyelitis because of positive uptake on a [sup 111]In-WBC scan. The areas of abnormal uptake on the indium scan were demonstrated histopathologically to be sites of lymphomatous involvement in bone. (orig.) With 4 figs., 3 refs.

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

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    Mira-Perceval Juan, Gema; Alcalá Minagorre, Pedro J; Huertas Sánchez, Ana M; Segura Sánchez, Sheila; López Iniesta, Silvia; De León Marrero, Francisco J; Costa Navarro, Estela; Niveiro de Jaime, María

    2015-01-01

    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. PMID:26435869

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

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    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. 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

  9. 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

  10. Anaplastic Large-Cell Lymphoma in a Child with Type I Diabetes and Unrecognised Coeliac Disease

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    Jemima Sharp

    2012-01-01

    Full Text Available Screening for coeliac disease is recommended for children from certain risk groups, with implications for diagnostic procedures and dietetic management. The risk of a malignant complication in untreated coeliac disease is not considered high in children. We present the case of a girl with type I diabetes who developed weight loss, fatigue, and inguinal lymphadenopathy. Four years before, when she was asymptomatic, a screening coeliac tTG test was positive, but gluten was not eliminated from her diet. Based on clinical examination, a duodenal biopsy, and an inguinal lymph node biopsy were performed, which confirmed both coeliac disease and an anaplastic large-cell lymphoma. HLA-typing demonstrated that she was homozygous for HLA-DQ8, which is associated with higher risk for celiac disease, more severe gluten sensitivity, and diabetes susceptibility. She responded well to chemotherapy and has been in remission for over 4 years. She remains on a gluten-free diet. This is the first case reporting the association of coeliac disease, type I diabetes, and anaplastic large-cell lymphoma in childhood. The case highlights the malignancy risk in a genetically predisposed individual, and the possible role of a perpetuated immunologic response by prolonged gluten exposure.

  11. Anaplastic large cell lymphoma (ALCL) and breast implants: breaking down the evidence.

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    Ye, Xuan; Shokrollahi, Kayvan; Rozen, Warren M; Conyers, Rachel; Wright, Penny; Kenner, Lukas; Turner, Suzanne D; Whitaker, Iain S

    2014-01-01

    Systemic anaplastic large cell lymphoma (ALCL) is a distinct disease classification provisionally sub-divided into ALCL, Anaplastic Lymphoma Kinase (ALK)(+) and ALCL, ALK(-) entities. More recently, another category of ALCL has been increasingly reported in the literature and is associated with the presence of breast implants. A comprehensive review of the 71 reported cases of breast implant associated ALCL (iALCL) is presented indicating the apparent risk factors and main characteristics of this rare cancer. The average patient is 50 years of age and most cases present in the capsule surrounding the implant as part of the periprosthetic fluid or the capsule itself on average at 10 years post-surgery suggesting that iALCL is a late complication. The absolute risk is low ranging from 1:500,000 to 1:3,000,000 patients with breast implants per year. The majority of cases are ALK-negative, yet are associated with silicone-coated implants suggestive of the mechanism of tumorigenesis which is discussed in relation to chronic inflammation, immunogenicity of the implants and sub-clinical infection. In particular, capsulotomy alone seems to be sufficient for the treatment of many cases suggesting the implants provide the biological stimulus whereas others require further treatment including chemo- and radiotherapy although reported cases remain too low to recommend a therapeutic approach. However, CD30-based therapeutics might be a future option.

  12. Clinical features and treatment results in children with anaplastic large cell lymphoma.

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    Ataş, Erman; Kutluk, M Tezer; Akyüz, Canan; Kale, Gülsev; Varan, Ali; Yalçın, Bilgehan; Aydın, Burça; Büyükpamukçu, Münevver

    2015-01-01

    Anaplastic large cell lymphoma (ALCL) tends to have frequent relapse and good response to salvage chemotherapy. The frequency of ALCL among 1486 Non-Hodgkin's lymphoma (NHL) cases followed-up since 1972 was 1.5%, however, the percentage was 9.3% in cases diagnosed after 2000. Event-free survival (EFS) and overall survival (OS) rates for 23 children were 32.2% and 72.8% at 3 years, respectively. Disseminated diseases, no response to first line treatment, anaplastic lymphoma kinase (ALK) negativity were found as significant predictors on survival of ALCL. The proper diagnosis and early referral is essential in these children for a better survival rate. The children with ALK negative status should be monitored carefully because of the poor prognostic factors, and treated differently. The survival rates in this study are need of further improvement since the survival rates with current protocols are achievable at a level more than 80%. This is mainly related with late referral of those children with advanced disease. PMID:27411412

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

    Science.gov (United States)

    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.

  14. 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.

  15. Synchronous Occurrence of Primary Cutaneous Anaplastic Large Cell Lymphoma and Squamous Cell Carcinoma

    Science.gov (United States)

    Park, Ji-Hye; Lee, Jae Ho; Lim, Youngkyoung; Lee, You Jin

    2016-01-01

    CD30+ lymphoproliferative disorders (LPD) represent a spectrum of T-cell lymphoma including lymphomatoid papulosis and anaplastic large cell lymphoma (ALCL). Epidermis overlying cutaneous CD30+ LPD often shows epidermal hyperplasia, hyperkeratosis, crusting, and ulceration and it is difficult to distinguish from carcinoma such as keratoacanthoma (KA) or squamous cell carcinoma (SCC). Several cases of pseudocarcinomatous hyperplasia mimicking KA or SCC in CD30+ LPD have been reported. The relationship between CD30+ LPD and epithelial proliferations has not yet well understood. It was reported that a variety of mediators, including epidermal growth factor (EGF), transforming growth factor-α and EGFR from CD30+ LPD could attribute to epidermal hyperplasia. However, separate and distinct SCC occurring in CD30+ LPD has rarely been reported. Herein, we present a rare case of coexistence of SCC and cutaneous ALCL located on the same region. PMID:27489433

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

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    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.

  17. High intratumoral macrophage content is an adverse prognostic feature in anaplastic large cell lymphoma

    DEFF Research Database (Denmark)

    Pedersen, Martin B; Danielsen, Allan V; Hamilton-Dutoit, Stephen J;

    2014-01-01

    AIMS: Macrophage infiltration has been associated with prognosis in several cancers, including lymphoma, but has not been assessed systematically in anaplastic large cell lymphoma (ALCL). The aim of the study was to correlate expression of the macrophage-associated antigens CD68 and CD163 with pre......-therapeutic parameters and outcome in a cohort of treatment-naive ALCL patients. METHODS AND RESULTS: Pre-therapeutic tumour specimens from 52 patients with ALCL were included in a tissue microarray. The intratumoral macrophage content was assessed by immunohistochemical staining for CD68 and CD163, and quantified using......-free survival in ALK-negative patients (P macrophages correlates with an adverse outcome in ALK-negative ALCL....

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

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    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.

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

    Science.gov (United States)

    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.

  20. 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.

  1. 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

    2016-06-28

    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

  2. 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

  3. 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

  4. Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features

    International Nuclear Information System (INIS)

    Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcutaneous metastases in the scalp area after a ventriculo-peritoneal shunting procedure. The disease rapidly progressed and the child died despite chemotherapy and primary tumour surgical debulking. We molecularly classified the tumour as a group 3 MBL; in addition, we derived stem-like cells (SLC) from a metastatic lesion. Primary tumour, metastases and SLC were further analysed, particularly focusing on features linked to the cutaneous dissemination. Indeed, molecules involved in angiogenesis, cell invasion and epidermal growth factor signalling resulted highly expressed. The present report describes a very rare case of subcutaneous metastatic MBL. The tumour, metastases and SLC have been clinically, pathologically and molecularly characterized. Our case is an example of multidisciplinary approach aiming to characterize MBL aggressive behaviour

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

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    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.

  6. 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.

  7. 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.

  8. Galectin-1-mediated cell adhesion, invasion and cell death in human anaplastic large cell lymphoma: Regulatory roles of cell surface glycans

    OpenAIRE

    Suzuki, Osamu; Abe, Masafumi

    2014-01-01

    Galectin-1 is known to be one of the extracellular matrix proteins. To elucidate the biological roles of galectin-1 in cell adhesion and invasion of human anaplastic large cell lymphoma, we performed cell adhesion and invasion assays using the anaplastic large cell lymphoma cell line H-ALCL, which was previously established in our laboratory. From the cell surface lectin array, treatment with neuraminidase from Arthrobacter ureafaciens which cleaves all linkage types of cell surface sialic ac...

  9. ALK-positive anaplastic large cell lymphoma with prominent bone involvement in a 13-year-old boy

    Directory of Open Access Journals (Sweden)

    Tian C

    2016-01-01

    Full Text Available Chen Tian, Yong Yu, Hongliang Yang, Lei Zhu, Yafei Wang, Yizhuo Zhang Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China Introduction: Anaplastic lymphoma kinase-positive (ALK+ anaplastic large cell lymphoma (ALCL is a type of non-Hodgkin lymphoma, which has strong expression of cluster of differentiation (CD-30 and ALK. ALCL sometimes can involve the bone marrow, and in advanced stages, it can produce destructive bone lesions. But ALK+ ALCL with prominent bone involvement is very rare, especially in children. Case report: A 13-year-old boy presented with waist pain and low-grade fever for 8 months. The biopsy of soft tissue lesions around the thoracic spine showed that these cells were positive for ALK-1, CD30, leukocyte common antigen, CD3, CD4, and CD8, as well as being negative for epithelial membrane antigen and pan-cytokeratin, which revealed ALCL. After six cycles of a regimen consisting of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate and cytarabine (hyper-CVAD/MA and autologous hematopoietic stem cell transplantation, he achieved complete remission (CR. Conclusion: It is generally believed that the regimen consisting of cyclophosphamide, hydroxydaunorubicin (doxorubicin, vincristine, and prednisolone (CHOP is also applicable to ALCL. Because of the tendency of rapid progression and the frequency of B symptoms, ALCL in children and young adults is treated with high-grade chemotherapy such as hyper-CVAD/MA. Keywords: anaplastic large cell lymphoma, anaplastic lymphoma kinase, bone involvement, hyper-CVAD/MA

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  11. 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.

  12. 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.

  13. 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.

  14. Diffuse large B cell lymphoma of thyroid as a masquerader of anaplastic carcinoma of thyroid, diagnosed by FNA: a case report

    Directory of Open Access Journals (Sweden)

    Dehghani Mehdi

    2006-01-01

    Full Text Available Abstract Background Both thyroid lymphoma and anaplastic carcinoma of thyroid present with rapidly growing mass in eldery patients. Anaplastic carcinoma has high mortality rate and combination of surgery, radiation therapy and multidrug chemotherapy are the best chance for cure. Prognosis of thyroid lymphoma is excellent and chemotherapy for widespred lymphoms and radiotherapy with or without adjuvant chemotherapy for tumors localized to the gland, are the treatment of choice. Case report This article reports a 70 year old man presenting with diffuse neck swelling and hoarseness of few weeks duration. Fine needle aspiration was done and reported as anaplastic carcinoma of thyroid which thyroidectomy was planned. The slides were sent for second opinion. After review, with initial diagnosis of anaplastic carcinoma versus lymphoma, immunocytochemical study was performed. Smears were positive for B cell markers and negative for cytokeratin, so with the impression of diffuse large B cell lymphoma, the patient received two courses of chemotherapy by which the tumor disappeared during two weaks. Conclusion Despite previous reports, stating easy diagnosis of high-grade thyroid lymphoma on the grounds of cytomorphological features we like to emphasize, overlapping cytologic features of the curable high grade thyroid lymphoma form noncurable anaplastic thyroid carcinoma and usefulness of immunocytochemistry to differentiate these two disease.

  15. 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.

  16. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  18. 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.

  19. A nanocomplex that is both tumor cell-selective and cancer gene-specific for anaplastic large cell lymphoma

    Directory of Open Access Journals (Sweden)

    Zu Youli

    2011-01-01

    Full Text Available Abstract Background Many in vitro studies have demonstrated that silencing of cancerous genes by siRNAs is a potential therapeutic approach for blocking tumor growth. However, siRNAs are not cell type-selective, cannot specifically target tumor cells, and therefore have limited in vivo application for siRNA-mediated gene therapy. Results In this study, we tested a functional RNA nanocomplex which exclusively targets and affects human anaplastic large cell lymphoma (ALCL by taking advantage of the abnormal expression of CD30, a unique surface biomarker, and the anaplastic lymphoma kinase (ALK gene in lymphoma cells. The nanocomplexes were formulated by incorporating both ALK siRNA and a RNA-based CD30 aptamer probe onto nano-sized polyethyleneimine-citrate carriers. To minimize potential cytotoxicity, the individual components of the nanocomplexes were used at sub-cytotoxic concentrations. Dynamic light scattering showed that formed nanocomplexes were ~140 nm in diameter and remained stable for more than 24 hours in culture medium. Cell binding assays revealed that CD30 aptamer probes selectively targeted nanocomplexes to ALCL cells, and confocal fluorescence microscopy confirmed intracellular delivery of the nanocomplex. Cell transfection analysis showed that nanocomplexes silenced genes in an ALCL cell type-selective fashion. Moreover, exposure of ALCL cells to nanocomplexes carrying both ALK siRNAs and CD30 RNA aptamers specifically silenced ALK gene expression, leading to growth arrest and apoptosis. Conclusions Taken together, our findings indicate that this functional RNA nanocomplex is both tumor cell type-selective and cancer gene-specific for ALCL cells.

  20. 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.

  1. Sialylation by β-galactoside α-2,6-sialyltransferase and N-glycans regulate cell adhesion and invasion in human anaplastic large cell lymphoma

    OpenAIRE

    Suzuki, Osamu; ABE, MASAFUMI; Hashimoto, Yuko

    2015-01-01

    The interaction between cell surface glycans and extracellular matrix (ECM) including galectins is known to be closely associated with tumor cell adhesion, invasion and metastasis. We analyzed the roles of cell surface sialylation or glycosylation in galectin or ECM-mediated cell adhesion and invasion of human malignant lymphoma cells. Neuraminidase from Arthrobacter ureafaciens (AU) treatment resulted in reduction of cell adhesion to galectin-8 in human anaplastic large cell lymphoma (H-ALCL...

  2. 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

  3. 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.

  4. 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

  5. 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

  6. Anaplastic astrocytoma.

    Science.gov (United States)

    Grimm, Sean A; Chamberlain, Marc C

    2016-07-01

    Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification schemes will include molecular alterations. AA can be separated into subgroups, which share similar molecular profiles, age at diagnosis and median survival, based on 1p/19q co-deletion status and IDH mutation status. AA with co-deletion of chromosomes 1p and 19q and IDH mutation have the best prognosis. AA with IDH mutation and no 1p/19q co-deletion have intermediate prognosis and AA with wild-type IDH have the worst prognosis and share many molecular alterations with glioblastoma. Treatment of noncodeleted AA based on preliminary results from the CATNON clinical trial consists of maximal safe resection followed by radiotherapy with post-radiotherapy temozolomide (TMZ) chemotherapy. The role of concurrent TMZ and whether IDH1 subgroups benefit from TMZ is currently being evaluated in the recently completed randomized, prospective Phase III clinical trial, CATNON. PMID:27230974

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

    Directory of Open Access Journals (Sweden)

    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.

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

    OpenAIRE

    N. V. Myakova; D. A. Evstratov; D. S. Abramov; D. M. Konovalov; A. V. Pshonkin; D. V. Litvinov

    2016-01-01

    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 exper...

  9. Aberrant expression and biological significance of Sox2, an embryonic stem cell transcriptional factor, in ALK-positive anaplastic large cell lymphoma

    International Nuclear Information System (INIS)

    Sox2 (sex-determining region Y-Box) is one of the master transcriptional factors that are important in maintaining the pluripotency of embryonic stem cells (ESCs). In line with this function, Sox2 expression is largely restricted to ESCs and somatic stem cells. We report that Sox2 is expressed in cell lines and tumor samples derived from ALK-positive anaplastic large cell lymphoma (ALK+ALCL), for which the normal cellular counterpart is believed to be mature T-cells. The expression of Sox2 in ALK+ALCL can be attributed to nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the oncogenic fusion protein carrying a central pathogenetic role in these tumors. By confocal microscopy, Sox2 protein was detectable in virtually all cells in ALK+ALCL cell lines. However, the transcriptional activity of Sox2, as assessed using a Sox2-responsive reporter construct, was detectable only in a small proportion of cells. Importantly, downregulation of Sox2 using short interfering RNA in isolated Sox2active cells, but not Sox2inactive cells, resulted in a significant decrease in cell growth, invasiveness and tumorigenicity. To conclude, ALK+ALCL represents the first example of a hematologic malignancy that aberrantly expresses Sox2, which represents a novel mechanism by which NPM-ALK mediates tumorigenesis. We also found that the transcriptional activity and oncogenic effects of Sox2 can be heterogeneous in cancer cells

  10. [Molecular pathogenesis of peripheral T-cell lymphoma (1): angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified and anaplastic large cell lymphoma].

    Science.gov (United States)

    Couronné, Lucile; Bastard, Christian; Gaulard, Philippe; Hermine, Olivier; Bernard, Olivier

    2015-10-01

    Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T/NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of the histological subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. It will be published in two parts : the first is focused on the three more frequent entities, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second (which will appear in the november issue) will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma. T or NK cell lymphoproliferative disorders with leukemic presentation, primary cutaneous T-cell lymphoma and very rare subtypes of PTCL whose prevalence is less than 5% (hepatosplenic T-cell lymphoma and subcutaneous panniculitis-like T cell lymphoma) will not be discussed herein. PMID:26481023

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  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. 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.

  19. Purely cortical anaplastic ependymoma.

    Science.gov (United States)

    Romero, Flávio Ramalho; Zanini, Marco Antônio; Ducati, Luis Gustavo; Vital, Roberto Bezerra; de Lima Neto, Newton Moreira; Gabarra, Roberto Colichio

    2012-01-01

    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.

  20. 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.

  1. Diffuse large B cell lymphoma of thyroid as a masquerader of anaplastic carcinoma of thyroid, diagnosed by FNA: a case report

    OpenAIRE

    Dehghani Mehdi; Omidvari Shapour; Daneshbod Yahya; Daneshbod Khosrow; Negahban Shahrzad

    2006-01-01

    Abstract Background Both thyroid lymphoma and anaplastic carcinoma of thyroid present with rapidly growing mass in eldery patients. Anaplastic carcinoma has high mortality rate and combination of surgery, radiation therapy and multidrug chemotherapy are the best chance for cure. Prognosis of thyroid lymphoma is excellent and chemotherapy for widespred lymphoms and radiotherapy with or without adjuvant chemotherapy for tumors localized to the gland, are the treatment of choice. Case report Thi...

  2. 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.

  3. Gingival Anaplastic Large-Cell Lymphoma Mimicking Hyperplastic Benignancy as the First Clinical Manifestation of AIDS: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Rafaela Elvira Rozza-de-Menezes

    2013-01-01

    Full Text Available This paper presents an unusual case of gingival ALCL, which mimicked a benign hyperplastic lesion that occurred in a 57-year-old white man representing the first clinical manifestation of acquired immunodeficiency syndrome (AIDS. The patient was referred to the Dental Clinic of PUCPR complaining of a lobulated nodule on the gingiva of his upper central incisors. The presence of advanced chronic periodontitis and dental plaque raised suspicion for a benignancy. An excisional biopsy was performed, and large pleomorphic cells with an abundant cytoplasm, sometimes containing prominent nucleoli and “Hallmark” cells, were observed through hematoxylin and eosin staining. The tumor cells showed strong CD30 expression, EMA, Ki-67, and LCA, and negative stain for p80NPM/ALK, CKAE1/AE3, CD20, CD3, CD56, and CD15. The final diagnosis was ALCL (ALK-negative. Further laboratory tests revealed positivity for human immunodeficiency virus (HIV. The patient was submitted to chemotherapy, but four months after diagnosis, the patient died due to pneumonia and respiratory failure. Oral anaplastic large-cell lymphoma (ALCL is a rare disorder. Only 5 cases involving the gingiva have been reported, and to our knowledge, this is the first case reported of the ALCL, which mimicked a hyperplastic benignancy as the first clinical manifestation of AIDS.

  4. A 16-Gene Signature Distinguishes Anaplastic Astrocytoma from Glioblastoma

    OpenAIRE

    Soumya Alige Mahabala Rao; Sujaya Srinivasan; Irene Rosita Pia Patric; Alangar Sathyaranjandas Hegde; Bangalore Ashwathnarayanara Chandramouli; Arivazhagan Arimappamagan; Vani Santosh; Paturu Kondaiah; Manchanahalli R Sathyanarayana Rao; Kumaravel Somasundaram

    2014-01-01

    Anaplastic astrocytoma (AA; Grade III) and glioblastoma (GBM; Grade IV) are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a mo...

  5. 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.

  6. 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.

  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. 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.

  9. Primary Cutaneous CD8(+) CD30(+) Anaplastic Large Cell Lymphoma: An Unusual Case with a High Ki-67 index-A Short Review.

    Science.gov (United States)

    Nasit, Jitendra G; Patel, Smita C

    2015-01-01

    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. PMID:26288406

  10. The dichloromethane extract of the ethnomedicinal plant Neurolaena lobata inhibits NPM/ALK expression which is causal for anaplastic large cell lymphomagenesis.

    Science.gov (United States)

    Unger, Christine; Popescu, Ruxandra; Giessrigl, Benedikt; Laimer, Daniela; Heider, Susanne; Seelinger, Mareike; Diaz, Rene; Wallnöfer, Bruno; Egger, Gerda; Hassler, Melanie; Knöfler, Martin; Saleh, Leila; Sahin, Emine; Grusch, Michael; Fritzer-Szekeres, Monika; Dolznig, Helmut; Frisch, Richard; Kenner, Lukas; Kopp, Brigitte; Krupitza, Georg

    2013-01-01

    The present study investigates extracts of Neuolaena lobata, an anti-protozoan ethnomedicinal plant of the Maya, regarding its anti-neoplastic properties. Firstly, extracts of increasing polarity were tested in HL-60 cells analyzing inhibition of cell proliferation and apoptosis induction. Secondly, the most active extract was further tested in anaplastic large cell lymphoma (ALCL) cell lines of human and mouse origin. The dichloromethane extract inhibited proliferation of HL-60, human and mouse ALCL cells with an IC50 of ~2.5, 3.7 and 2.4 µg/ml, respectively and arrested cells in the G2/M phase. The extract induced the checkpoint kinases Chk1 and Chk2 and perturbed the orchestrated expression of the Cdc25 family of cell cycle phosphatases which was paralleled by the activation of p53, p21 and downregulation of c-Myc. Importantly, the expression of NPM/ALK and its effector JunB were drastically decreased, which correlated with the activation of caspase 3. Subsequently also platelet derived growth factor receptor β was downregulated, which was recently shown to be transcriptionally controlled by JunB synergizing with ALK in ALCL development. We show that a traditional healing plant extract downregulates various oncogenes, induces tumor suppressors, inhibits cell proliferation and triggers apoptosis of malignant cells. The discovery of the 'Active Principle(s)' is warranted. PMID:23135783

  11. 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.

  12. 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.

  13. 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

  14. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  16. 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.

  17. 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

  18. Primary anaplastic large cell lymphoma of the breast arising in reconstruction mammoplasty capsule of saline filled breast implant after radical mastectomy for breast cancer: an unusual case presentation

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    Sur Monalisa

    2009-04-01

    Full Text Available Abstract Background Primary non-Hodgkin lymphoma (NHL of the breast represents 0.04–0.5% of malignant lesions of the breast and accounts for 1.7–2.2% of extra-nodal NHL. Most primary cases are of B-cell phenotype and only rare cases are of T-cell phenotype. Anaplastic large cell lymphoma (ALCL is a rare T-cell lymphoma typically seen in children and young adults with the breast being one of the least common locations. There are a total of eleven cases of primary ALCL of the breast described in the literature. Eight of these cases occurred in proximity to breast implants, four in relation to silicone breast implant and three in relation to saline filled breast implant with three out of the eight implant related cases having previous history of breast cancer treated surgically. Adjuvant postoperative chemotherapy is given in only one case. Secondary hematological malignancies after breast cancer chemotherapy have been reported in literature. However in contrast to acute myeloid leukemia (AML, the association between lymphoma and administration of chemotherapy has never been clearly demonstrated. Case Presentation In this report we present a case of primary ALCL of the breast arising in reconstruction mamoplasty capsule of saline filled breast implant after radical mastectomy for infiltrating ductal carcinoma followed by postoperative chemotherapy twelve years ago. Conclusion Primary ALK negative ALCL arising at the site of saline filled breast implant is rare. It is still unclear whether chemotherapy and breast implantation increases risk of secondary hematological malignancies significantly. However, it is important to be aware of these complications and need for careful pathologic examination of tissue removed for implant related complications to make the correct diagnosis for further patient management and treatment. It is important to be aware of this entity at this site as it can be easily misdiagnosed on histologic grounds and to exclude

  19. A 16-gene signature distinguishes anaplastic astrocytoma from glioblastoma.

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    Soumya Alige Mahabala Rao

    Full Text Available Anaplastic astrocytoma (AA; Grade III and glioblastoma (GBM; Grade IV are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a more robust molecular classifier, we analysed RT-qPCR expression data of 175 differentially regulated genes across astrocytoma using Prediction Analysis of Microarrays (PAM and found the most discriminatory 16-gene expression signature for the classification of anaplastic astrocytoma and glioblastoma. The 16-gene signature obtained in the training set was validated in the test set with diagnostic accuracy of 89%. Additionally, validation of the 16-gene signature in multiple independent cohorts revealed that the signature predicted anaplastic astrocytoma and glioblastoma samples with accuracy rates of 99%, 88%, and 92% in TCGA, GSE1993 and GSE4422 datasets, respectively. The protein-protein interaction network and pathway analysis suggested that the 16-genes of the signature identified epithelial-mesenchymal transition (EMT pathway as the most differentially regulated pathway in glioblastoma compared to anaplastic astrocytoma. In addition to identifying 16 gene classification signature, we also demonstrated that genes involved in epithelial-mesenchymal transition may play an important role in distinguishing glioblastoma from anaplastic astrocytoma.

  20. 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.

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

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    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

  2. Clinicopathologic Features of Gastrointestinal Tract Involvement of Anaplastic Large Cell Lymphoma%累及胃肠道的间变性大细胞淋巴瘤的临床病理学特点

    Institute of Scientific and Technical Information of China (English)

    孙健; 周皎琳; 陈杰; 卢朝辉

    2012-01-01

    Objective To investigate the clinicopathological characteristics of gastrointestinal tract involvement of anaplastic large cell lymphoma ( ALCL ). Methods The clinicopathological features of four patients with ALCL that involved gastrointestinal tract were retrospectively analyzed using immunohistochemical study, T-cell receptor gene rearrangement analysis, and evaluation for Epstein Barr virus infection status. Results Most tumor cells in all these four cases are large and highly pleomorphic, and all four cases were classified as the "common pattern" ALCL Tumor cells in all four tumors expressed CD30, and expressed at least one cytotoxic maker. Two patients were confirmed to be with anaplastic lymphoma kinase ( ALK) -positive ALCL, and four patients were negative during in situ hybridization for Epstein-Barr virus-encoded RNA but showed clonal T-cell receptor gene rearrangement. Conclusion Gastrointestinal tract involvement of ALCL has the unique clinicopathological features.%目的 总结累及胃肠道的间变性大细胞淋巴瘤(ALCL)的临床病理学特点.方法 收集整理4例累及胃肠道的ALCL病例标本,对其进行临床病理分析、免疫组织化学检测、EB病毒编码的RNA (EBER)原位杂交检测及T细胞受体(TCR)基因重排检测.结果 4例病例中,肿瘤细胞均以多形性大细胞为主,归为普通型ALCL;均表现为弥漫、较强地表达CD30,且至少表达1种细胞毒性抗原;2例为间变性淋巴瘤激酶(ALK)阳性ALCL;4例EBER原位杂交检测均为阴性且均存在TCR基因克隆性重排.结论 累及胃肠道的ALCL具有独特的临床病理特点.

  3. 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.

  4. 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

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    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

  5. 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%.

  6. 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.

  7. 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.

  8. 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

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

    Science.gov (United States)

    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.

  10. 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.

  11. Pleomorphic xanthoastrocytoma with anaplastic features

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    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. Clinicopathological observation of bone marrow involvement of systemic anaplastic large-cell lymphoma%系统性间变性大细胞淋巴瘤骨髓累及的临床病理学研究

    Institute of Scientific and Technical Information of China (English)

    段泽君; 高子芬; 张永红; 时云飞; 周春菊; 徐教生; 薛学敏; 李敏; 黄欣; 张志丽

    2011-01-01

    Objective To investigate the clinicopathological features, immunophenotyping and clinical biological behavior of bone marrow (BM) involvement of systemic anaplastic large-cell lymphoma (S-ALCL).Methods 34 S-ALCL including 24 ALK(+) and 10 ALK(-) cases available with the formalin-fixed, paraffin embedded (FFPE) tissue blocks of BM biopsy (n=19) or BM smear sections (n=15) were included in this study.BM samples were sent to both morphologic evaluation using H&E (Hematoxylin & Eosin)-stained sections and immunophenotypic detection by immunohistochemistry (IHC). EBV status was determined by visualization of EBERs in tumor cells using in situ hybridization (ISH). Results BM involvement was seen in 17.6 % (6/34)S-ALCL patients which were confirmed by BM biopsy. No significant difference in the incidence of BM involvement was observed between ALK(+)[16.7 % (4/24)] and ALK(-) [20.0 % (2/10) S-ALCL (P =0.3555).Age and gender were not associated with the presence or the absence of BM involvement by S-ALCL (P= 0.8089and 0.3085), tumor cells of patients with BM involvement were interstitial distribution. S-ALCL patients with BM involvement have a poor prognosis as compared to those without BM involvement (P =0.0407). Conclusion BM involvement was not frequently seen in S-ALCL. The occurrence of BM involvement by S-ALCL was not associated with age, gender or the expression of ALK protein. BM involvement is an adverse prognostic factor in S-ALCL, BM biopsy is useful to predict the prognosis of S-ALCL.%目的 探讨系统性间变性大细胞淋巴瘤(S-ALCL)骨髓累及的临床病理学特点、免疫学表型及临床生物学行为.方法 回顾性分析34例S-ALCL病例资料,进行骨髓活检(19例)或涂片(15例).其中ALK(+)24例,ALK(-)10例.HE染色、免疫组织化学染色观察病理形态及免疫表型,原位杂交法检测EB病毒.结果 6例(17.6%)S-ALCL存在骨髓累及,均经骨髓活检标本确定,15例患者骨髓涂片中均未见肿瘤累及.ALK(+)ALCL

  13. 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.

  14. 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.

  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. Cytopathological Dilemma of Anaplastic Sacral Chordoma with Radiological and Histological Corroboration

    Directory of Open Access Journals (Sweden)

    Arghya BANDYOPADHYAY

    2011-05-01

    Full Text Available Chordoma is a relatively rare locally invasive and potentially malignant tumor of fetal notochord origin, affecting the axial skeleton. Cytopathological diagnosis of chordoma is favored by the presence of characteristic physaliphorous cells, bearing abundant foamy cytoplasm dispersed in a myxoid matrix. Anaplastic chordoma or dedifferentiated chordoma, an even rarer variant, can cause a diagnostic confusion with chondrosarcoma from the cytopathological point of view, with similar chondromyxoid matrix and atypical cells. Hence, chordoma bearing anaplastic features needs to be identified and should be distinguished from chondrosarcoma on aspiration cytopathology. We present a case of anaplastic sacral chordoma in a man 59 years of age, causing extensive destruction of sacrum and invading the paravertebral tissues as evidenced by radiology. Fine needle aspiration cytopathology revealed few large pleomorphic hyperchromatic cells, admixed with characteristic physaliphorous cells and myxoid matrix. The cytopathological diagnosis has been confirmed by histopathology and immunohistochemistry. Since anaplastic chordoma bears an unfavorable prognosis, it should be suspected on preoperative aspiration cytopathology. Clinicoradiological correlation along with histopathological and immunohistochemical confirmation is necessary subsequently.

  17. Genomic Landscape of poorly Differentiated and Anaplastic Thyroid Carcinoma.

    Science.gov (United States)

    Xu, Bin; Ghossein, Ronald

    2016-09-01

    Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are aggressive thyroid tumors associated with a high mortality rate of 38-57 % and almost 100 % respectively. Several recent studies utilizing next generation sequencing techniques have shed lights on the molecular pathogenesis of these tumors, providing evidence to support a stepwise tumoral progression from well-differentiated to poorly differentiated, and finally to anaplastic thyroid carcinomas. While BRAF (V600E) and RAS mutations remain the main drivers in aggressive thyroid carcinoma, PDTC and ATC gains additional mutations, e.g., TERT promoter mutation, TP53 mutation, as well as frequent alterations in PIK3CA-PTEN-AKT-mTOR pathway, SWI-SNF complex, histomethyltransferases, and mismatch repair genes. RAS-mutated PDTCs are commonly associated with a histologic phenotype defined by Turin proposal, high frequency of distant metastasis, high thyroid differentiation score, and a RAS-like gene expression profile, whereas BRAF-mutated PDTCs are usually defined solely by the Memorial Sloan Kettering Cancer Center (MSKCC) criteria with a propensity for nodal metastasis and are less differentiated with a BRAF-like expression signature. Such demarcation is largely lost in ATC which is characterized by genomic complexity, heavy mutation burden, and profound undifferentiation. Additionally, several molecular events, e.g., EIF1AX mutation, mutation burden, and chromosome 1q gain in PDTCs, as well as EIF1AX mutation, chromosome 13q loss, and 20q gains in ATCs, may serve as adverse prognostic markers predicting poor clinical outcome. PMID:27372303

  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

    DEFF Research Database (Denmark)

    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. Anaplastic thyroid carcinoma: outcome and prognostic factors

    International Nuclear Information System (INIS)

    Purpose: Anaplastic carcinoma of the thyroid has been described as a rapidly progressive disease. We assessed the outcome and prognostic factors in patients with anaplastic thyroid carcinoma at our institution. Materials and Methods: Between 1975 and 1995, 37 patients were seen and treated at our institution with pathologically proven anaplastic carcinoma of the thyroid gland. Patients ranged in age from 49 to 97 years old (median 73 years) and females were represented in a 2:1 ratio. Many patients had history of prior benign thyroid disease (17) or low grade malignancy (6). Other medical illnesses were frequently present in these patients, including 5 with diabetes, 1 scleroderma, 1 sarcoidosis and 1 polycythemia vera. 12 patients had metastatic disease at presentation. 26 patients had locally advanced (T4) disease. The time from diagnosis to treatment was never longer than 1 month. Management was most often with biopsy only (22 patients) and local irradiation (34 patients, median dose 52.5 Gy). 15 patients had primary surgical resection, one of which had negative surgical margins. 11 patients received chemotherapy, 9 with Adriamycin-based regimens. Follow-up ranged from 4 months to 11 years, with a mean of 11 months. Results: 26 patients had a local response, either partial or complete, to their treatment regimen. However, systemic disease was an important cause of failure. 9 patients (24%) survived at least one year from diagnosis; 3 (8%) survived beyond two years. The development of metastases occurred quickly in originally localized disease, at a median of 2 months. Metastases occurred most commonly in the lung (11 of 14 cases), but also occured in brain (2), liver (1), bone (1) and pericardium (1). Performance status, sex, metastatic disease, hyperfractionation, treatment modalities, RT dose, age and response to treatment were assessed as prognostic factors for survival. On univariate analysis, age over 70 (p=.004) and failure to attain a complete response to

  20. 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.

  1. Anaplastic lymphoma kinase status in rhabdomyosarcomas.

    Science.gov (United States)

    Yoshida, Akihiko; Shibata, Tatsuhiro; Wakai, Susumu; Ushiku, Tetsuo; Tsuta, Koji; Fukayama, Masashi; Makimoto, Atsushi; Furuta, Koh; Tsuda, Hitoshi

    2013-06-01

    Rhabdomyosarcoma is a rare soft tissue sarcoma that typically affects children, adolescents, and young adults. Despite treatment via a multidisciplinary approach, the prognosis of advance-stage rhabdomyosarcomas remains poor, and a new treatment strategy is needed. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is a potential target for specific inhibitors. In this study, we investigated 116 rhabdomyosarcomas using a polymer-based ALK immunostaining method and correlated the results with clinicopathological parameters. In addition, we examined ALK status using dual-color fluorescence in situ hybridization, PCR, and sequencing. In immunohistochemical analysis, ALK was detected in 2 (6%) of 33 embryonal rhabdomyosarcomas, 42 (69%) of 61 alveolar rhabdomyosarcomas, and 0 (0%) of 22 other subtypes, including pleomorphic, adult-spindle-cell/sclerosing, and epithelioid variants. Compared with ALK-negative alveolar rhabdomyosarcomas, ALK-positive ones are presented with metastatic spread more frequently and showed a greater extent of myogenin reactivity. Overall survival was not associated with ALK expression. FOXO1 rearrangement was significantly associated with ALK immunoreactivity. The median ALK copy number was greater in ALK-positive tumors than in ALK-negative tumors. Most (93%) cases tested showed no selective increase in the ALK gene dosage. ALK selective amplification and low-level selective gain were noted in one and three cases, respectively. Further, a high-polysomy pattern (≥4 ALK copies in ≥40% of cells) was observed in seven cases. A significant increase in the ALK copy number was exclusive to the ALK-immunopositive cohort, but it was uncommon, accounting for only 30% of the 37 ALK-positive rhabdomyosarcomas. ALK gene rearrangement was not observed in either cohort, while an ALK somatic mutation (I1277T) was found in one ALK-negative embryonal case. Although it remains controversial whether ALK expression without gene rearrangement

  2. 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.

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

    LENUS (Irish Health Repository)

    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

  4. 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

  5. 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.

  6. Successful radiopeptide targeting of metastatic anaplastic meningioma: Case report

    Directory of Open Access Journals (Sweden)

    Biersack Hans-Jürgen

    2011-08-01

    Full Text Available Abstract A patient with anaplastic meningioma and lung metastases resistant to conventional treatment underwent radiopeptide therapy with 177Lu- DOTA-octreotate in our institute. The treatment resulted in significant improvement in patient's quality of life and inhibition of tumor progression. This case may eventually help to establish the value of radiopeptide therapy in patients with this rare condition.

  7. 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.

  8. 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

    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...

  9. 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.

  10. 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.

  11. 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

  12. Anaplastic astrocytoma in the spinal cord of an African pygmy hedgehog (Atelerix albiventris).

    Science.gov (United States)

    Gibson, C J; Parry, N M A; Jakowski, R M; Eshar, D

    2008-11-01

    A 2-year-old, female hedgehog presented with an 8-month history of progressive, ascending paresis/paralysis and was tentatively diagnosed with wobbly hedgehog syndrome. She died awaiting further diagnostic tests, and the owners consented to postmortem examination. Grossly, the bladder was large and flaccid and the cervical and lumbar spinal cord were regionally enlarged, light grey, and friable with multifocal hemorrhages. The thoracic spinal cord was grossly normal. Microscopically all regions of the spinal cord had similar changes, although the cervical and lumbar sections were most severely affected. These regions were completely effaced by a moderately cellular infiltration of highly pleomorphic polygonal to spindle shaped cells, mineralization, and necrosis, which were most consistent with anaplastic astrocytoma. The thoracic spinal cord white matter was similarly infiltrated by the neoplastic cells, with perivascular extension into the otherwise normal grey matter. A diagnosis of anaplastic astrocytoma was confirmed using immunohistochemical stains that were positive for glial fibrillary acidic protein and S100. PMID:18984799

  13. Anaplastic carcinoma following well-differentiated thyroid cancer: etiological considerations.

    OpenAIRE

    Kapp, D S; LiVolsi, V. A.; Sanders, M M

    1982-01-01

    Most cases of anaplastic thyroid carcinoma can be pathologically and often historically associated with the presence of low-grade (differentiated) cancer in the thyroid. That radiation therapy to the differentiated tumor plays an etiologic role in the transformation of a differentiated to an undifferentiated tumor has been suggested. If such therapy can be implicated, is there a difference in risk between external radiotherapy or radioactive iodine? Review of the literature discloses that mor...

  14. Anaplastic Thyroid Carcinoma Following Radioactive Iodine Therapy for Graves' Disease

    OpenAIRE

    Kim, Sun Hwa; Kim, Hee Young; Jung, Kwang Yoon; Choi, Dong Seop; Kim, Sin Gon

    2013-01-01

    Radioactive iodine (RAI) therapy has been used as a treatment option for Graves' disease, and it has been widely accepted to be safe. On the other hand, some evidence suggests that RAI therapy is possibly associated with a small increased risk of thyroid cancer. Herein, we report a rare case of anaplastic thyroid carcinoma (ATC) associated with Graves' disease, following RAI treatment. A 42-year-old woman had been diagnosed with Graves' disease and although she was treated with an antithyroid...

  15. Presence of anaplastic lymphoma kinase in inflammatory breast cancer

    OpenAIRE

    Robertson, Fredika M; Petricoin III, Emanuel F.; van Laere, Steven J; Bertucci, Francois; Chu, Khoi; Fernandez, Sandra V.; Mu, Zhaomei; Alpaugh, Katherine; Pei, Jianming; Circo, Rita; Wulfkuhle, Julia; Ye, Zaiming; Boley, Kimberly M; Liu, Hui; Moraes, Ricardo

    2013-01-01

    Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evalu...

  16. Anaplastic thyroid cancer Irish epidemiology and novel chemotherapeutic strategies

    OpenAIRE

    O'Neill, James Paul

    2009-01-01

    This body of work was conducted over a four year period. Within this timeframe we have conducted a National Epidemiology project, established a National Head and Neck Cancer database and completed Oncology laboratory investigations. Anaplastic thyroid cancer (ATC) is the most aggressive endocrine disease in nature. Within the thyroid gland a heterogeneous group of neoplasms may develop. These can range from well differentiated tumours with an excellent prognosis, to ATC tumours which prese...

  17. Ovarian mucinous cystadenoma with mural nodule of anaplastic carcinoma.

    OpenAIRE

    Hong, S. R.; Chun, Y. K.; Kim, Y. J.; Lim, K. T.; Kim, H S

    1998-01-01

    The occurrence of malignant mural nodule in benign cystic common epithelial tumor of the ovary have been reported in only three cases; the case one was mucinous cystadenoma with a mural nodule of fibrosarcoma and the others were of carcinomas. Our case was another rare case of ovarian mucinous cystadenoma with mural nodule of anaplastic carcinoma in a 42-year-old woman. The cystadenoma had an unilocular cystic cavity and a mural nodule with thick multinodular solid wall. The internal cystic w...

  18. DNA methylation alterations in grade II- and anaplastic pleomorphic xanthoastrocytoma

    International Nuclear Information System (INIS)

    Pleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients. Using a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences. Increasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis. Even taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation

  19. Metronomic chemotherapy in anaplastic thyroid carcinoma: a potentially feasible alternative to therapeutic nihilism.

    Science.gov (United States)

    Revannasiddaiah, Swaroop; Madabhavi, Irappa; Bodh, Anita; Thakur, Priyanka; Sharma, Mukesh

    2015-01-01

    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. PMID:26009682

  20. Metronomic chemotherapy in anaplastic thyroid carcinoma: A potentially feasible alternative to therapeutic nihilism

    Directory of Open Access Journals (Sweden)

    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.

  1. 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

  2. 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

  3. 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.

  4. Developing retroperitoneal anaplastic carcinoma with choriocarcinoma focus after ovarian non-gestastional choriocarcinoma: Case report

    Directory of Open Access Journals (Sweden)

    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

  5. Cortical Anaplastic Ependymoma with Significant Desmoplasia: A Case Report and Literature Review

    Science.gov (United States)

    Elsharkawy, Alaa Eldin; Abuamona, Raid; Bergmann, Markus; Salem, Shadi; Gafumbegete, Evariste; Röttger, Ernst

    2013-01-01

    Ectopic brain anaplastic ependymomas with no connection to the ventricles are rare. We present a rare case of a 25-year-old male who presented with generalized convulsions. Computed tomography (CT), Magnetic Resonance Imaging (MRI), and magnetic resonance spectroscopy (MRS) showed characters of an intra- and extra-axial lesion. Intraoperatively, the lesion was a cortical solid mass that had no connections to the dura or to the ventricle. The histological diagnosis showed an anaplastic ependymoma with WHO grade III with distinctive desmoplasia. A literature review of ectopic anaplastic ependymomas regarding their clinical presentations, management, and prognostic factors was performed. There is a need to establish a clinically based histopathological grading system for anaplastic ependymomas. Ectopic anaplastic ependymomas should be included in the preoperative differential diagnosis. PMID:24455359

  6. Cortical Anaplastic Ependymoma with Significant Desmoplasia: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Alaa Eldin Elsharkawy

    2013-01-01

    Full Text Available Ectopic brain anaplastic ependymomas with no connection to the ventricles are rare. We present a rare case of a 25-year-old male who presented with generalized convulsions. Computed tomography (CT, Magnetic Resonance Imaging (MRI, and magnetic resonance spectroscopy (MRS showed characters of an intra- and extra-axial lesion. Intraoperatively, the lesion was a cortical solid mass that had no connections to the dura or to the ventricle. The histological diagnosis showed an anaplastic ependymoma with WHO grade III with distinctive desmoplasia. A literature review of ectopic anaplastic ependymomas regarding their clinical presentations, management, and prognostic factors was performed. There is a need to establish a clinically based histopathological grading system for anaplastic ependymomas. Ectopic anaplastic ependymomas should be included in the preoperative differential diagnosis.

  7. Combination chemotherapy (COMP protocol) and radiotherapy of anaplastic supratentorial gliomas

    International Nuclear Information System (INIS)

    Postoperative survival time and recurrence-free intervals in 116 consecutive patients with supratentorial grade III and IV gliomas (glioblastomas, gliosarcomas, anaplastic astrocytomas, and ependymomas) were compared in unselected groups receiving different forms of treatment. Postoperative high-voltage radiotherapy (31 patients, dosage 4,000-6,000 rads) and combined chemotherapy consisting of CCNU, vincristine, amethopterine, and procarbazine in 15-day circles (COMP protocol) (12 patients) showed the same median survival time of 10.6 months and comparable recurrence-free intervals of 6.8 and 7.0 months, respectively. These results were significantly different from a control group (39 patients) receiving best postoperative supportive (conventional) care (median survival 5.4 months, free interval 3.7 months). Combination of postoperative radiotherapy with simultaneous polychemotherapy (COMP protocol), evaluated in 18 patients, did not significantly change the recurrence-free interval (median 7.0 months), but increased the median survival time to 12.9 months, which was significantly superior to the two other treatment groups. The toxic side effects of COMP therapy were moderate and essentially haematological. In general, simultaneous radiation and chemical treatment was well tolerated after major tumour resection. These preliminary results of postoperative combination of radiation and polychemotherapy for anaplastic supratentorial gliomas appear encouraging, but further trials for optimization of combined therapeutic strategies are warranted. (author)

  8. 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. PMID:26305586

  9. Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Junor, E.J.; Paul, J.; Reed, N.S. (Beatson Oncology Centre, Glasgow (United Kingdom))

    1992-04-01

    Ninety-one patients with histologically proven anaplastic carcinoma of the thyroid were referred to the Beatson Oncology Centre between 1961 and 1986. The female:male ratio was 2.4:1 and the median age at presentation was 70 (range 38-92) years. All patients had a thyroid mass at presentation and the most common symptoms were dyspnoea, dyspnagia and dysphonia. Five patients had a total thyroidectomy and 28 partial thyroidectomy. Ninety five per cent of patients received external beam radiotherapy. Results show dyspnoea to be the only symptom strongly influencing survival. Total or partial thyroidectomy is associated with increased survival. This association is most marked for patients presenting without dyspnoea. Eighty per cent of patients responded to radiotherapy. (Author).

  10. Long-term control of disseminated pleomorphic xanthoastrocytoma with anaplastic features by means of stereotactic irradiation

    OpenAIRE

    Koga, Tomoyuki; Morita, Akio; Maruyama, Keisuke; Tanaka, Minoru; Ino, Yasushi; Shibahara, Junji; Louis, David N.; Reifenberger, Guido; Itami, Jun; Hara, Ryusuke; SAITO, Nobuhito; Todo, Tomoki

    2009-01-01

    Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm of the brain. Some PXAs are accompanied by anaplastic features and are difficult to manage because of frequent recurrences that lead to early death. No previous reports have demonstrated consistent efficacy of adjuvant radiotherapy or chemotherapy for this disease. We report a case of PXA with anaplastic features treated with stereotactic irradiation (STI) that resulted in long-term control of repeatedly recurring nodules throu...

  11. Cortical Anaplastic Ependymoma with Significant Desmoplasia: A Case Report and Literature Review

    OpenAIRE

    Alaa Eldin Elsharkawy; Raid Abuamona; Markus Bergmann; Shadi Salem; Evariste Gafumbegete; Ernst Röttger

    2013-01-01

    Ectopic brain anaplastic ependymomas with no connection to the ventricles are rare. We present a rare case of a 25-year-old male who presented with generalized convulsions. Computed tomography (CT), Magnetic Resonance Imaging (MRI), and magnetic resonance spectroscopy (MRS) showed characters of an intra- and extra-axial lesion. Intraoperatively, the lesion was a cortical solid mass that had no connections to the dura or to the ventricle. The histological diagnosis showed an anaplastic ependym...

  12. Focused Ultrasound Surgery for the Treatment of Recurrent Anaplastic Astrocytoma: A Preliminary Report

    Science.gov (United States)

    Park, Jung-Wuk; Jung, Shin; Jung, Tae-Young; Lee, Min-Cheol

    2006-05-01

    Anaplastic glioma is a highly aggressive tumor in the central nervous system. The conventional treatment for patients with anaplstic glioma consists of the combination of surgery, chemotherapy and radiotherapy. However, the effect of the currently available therapies is limited, and the prognosis is very poor in these patients. The purpose of this abstract is to introduce our preliminary experience of using focused ultrasound surgery (FUS) for the treatment of patients with recurrent anaplastic astrocytoma.

  13. 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).

  14. Carfilzomib potentiates CUDC-101-induced apoptosis in anaplastic thyroid cancer

    Science.gov (United States)

    Zhang, Lisa; Boufraqech, Myriem; Lake, Ross; Kebebew, Electron

    2016-01-01

    Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with no effective treatment currently available. Previously, we identified agents active against ATC cells, both in vitro and in vivo, using quantitative high-throughput screening of 3282 clinically approved drugs and small molecules. Here, we report that combining two of these active agents, carfilzomib, a second-generation proteasome inhibitor, and CUDC-101, a histone deacetylase and multi-kinase inhibitor, results in increased, synergistic activity in ATC cells. The combination of carfilzomib and CUDC-101 synergistically inhibited cellular proliferation and caused cell death in multiple ATC cell lines harboring various driver mutations observed in human ATC tumors. This increased anti-ATC effect was associated with a synergistically enhanced G2/M cell cycle arrest and increased caspase 3/7 activity induced by the drug combination. Mechanistically, treatment with carfilzomib and CUDC-101 increased p21 expression and poly (ADP-ribose) polymerase protein cleavage. Our results suggest that combining carfilzomib and CUDC-101 would offer an effective therapeutic strategy to treat ATC. PMID:26934320

  15. Anaplastic Lymphoma Kinase Rearrangement in Digestive Tract Cancer: Implication for Targeted Therapy in Chinese Population.

    Directory of Open Access Journals (Sweden)

    Jianming Ying

    Full Text Available Anaplastic lymphoma kinase (ALK rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.Tissue microarray (TMA was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH, real-time polymerase chain reaction (qRT-PCR, target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.Among the tested cases, 2 (0.44% CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4-ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1. One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.

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

    DEFF Research Database (Denmark)

    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...... molecules triggered by NPM/ALK remain, however, largely unidentified. Here we report that NPM/ALK induces continuous activation of STAT3. STAT3 displayed tyrosine phosphorylation and DNA binding in all (four of four) ALK+ TCL cell lines tested. The activation of STAT3 was selective because none of the other...... 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...

  17. Meningiomas with Rhabdoid or Papillary Components : Prognosis and Comparison with Anaplastic Meningiomas.

    Science.gov (United States)

    Kim, Jeong-Kwon; Jung, Tae-Young; Jung, Shin; Lee, Kyung-Hwa; Kim, Seul-Kee; Lee, Eun Jung

    2016-07-01

    Papillary and rhabdoid meningiomas are pathologically World Health Organization (WHO) grade III. Any correlation between clinical prognosis and pathologic component is not clear. We analyzed the prognoses of patients with meningiomas with a rhabdoid or papillary component compared to those of patients with anaplastic meningiomas. From 1994 to June 2013, 14 anaplastic meningiomas, 6 meningiomas with a rhabdoid component, and 5 meningiomas with papillary component were pathologically diagnosed. We analyzed magnetic resonance imaging (MRI) findings, extent of removal, adjuvant treatment, progression-free survival (PFS), overall survival (OS), and pathologic features of 14 anaplastic meningiomas (group A), 5 meningiomas with a predominant (≥50%) papillary or rhabdoid component (group B1), and 6 meningiomas without a predominant (aggressive behavior than group B2 tumors. In group B2 cases, the pathologic findings of non-rhabdoid/papillary portion could be considered for further adjuvant treatment. PMID:27446516

  18. 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.

  19. Presence of anaplastic lymphoma kinase in inflammatory breast cancer.

    Science.gov (United States)

    Robertson, Fredika M; Petricoin Iii, Emanuel F; Van Laere, Steven J; Bertucci, Francois; Chu, Khoi; Fernandez, Sandra V; Mu, Zhaomei; Alpaugh, Katherine; Pei, Jianming; Circo, Rita; Wulfkuhle, Julia; Ye, Zaiming; Boley, Kimberly M; Liu, Hui; Moraes, Ricardo; Zhang, Xuejun; Demaria, Ruggero; Barsky, Sanford H; Sun, Guoxian; Cristofanilli, Massimo

    2013-01-01

    Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF-02341066/Xalkori®, Pfizer Inc), induced both cytotoxicity (IC50 = 0.89 μM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK(+) IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics. PMID:24102046

  20. 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.

  1. Impact of histopathological transformation and overall survival in patients with progressive anaplastic glioma.

    Science.gov (United States)

    Ho, Allen L; Koch, Matthew J; Tanaka, Shota; Eichler, April F; Batchelor, Tracy T; Tanboon, Jantima; Louis, David N; Cahill, Daniel P; Chi, Andrew S; Curry, William T

    2016-09-01

    Progression of anaplastic glioma (World Health Organization [WHO] grade III) is typically determined radiographically, and transformation to glioblastoma (GB) (WHO grade IV) is often presumed at that time. However, the frequency of actual histopathologic transformation of anaplastic glioma and the subsequent clinical impact is unclear. To determine these associations, we retrospectively reviewed all anaplastic glioma patients who underwent surgery at our center at first radiographic progression, and we examined the effects of histological diagnosis, clinical history, and molecular factors on transformation rate and survival. We identified 85 anaplastic glioma (39 astrocytoma, 24 oligodendroglioma, 22 oligoastrocytoma), of which 38.8% transformed to GB. Transformation was associated with shorter overall survival (OS) from the time of diagnosis (3.4 vs. 10.9years, p=0.0005) and second surgery (1.0 vs. 3.5years, p<0.0001). Original histologic subtype did not significantly impact the risk of transformation or OS. No other factors, including surgery, adjuvant therapy or molecular markers, significantly affected the risk of transformation. However, mutations in isocitrate dehydrogenase 1 (IDH1) was associated with longer time to progression (median 4.6 vs. 1.4years, p=0.008) and OS (median 10.0 vs. 4.2years, p=0.046). At radiographic progression, tissue diagnosis may be warranted as histologic grade may provide valuable prognostic information and affect therapeutic clinical trial selection criteria for this patient population. PMID:27279154

  2. Non-anaplastic peripheral T-cell lymphoma in children and adolescents--a retrospective analysis of the NHL-BFM study group.

    Science.gov (United States)

    Kontny, Udo; Oschlies, Ilske; Woessmann, Willi; Burkhardt, Birgit; Lisfeld, Jasmin; Salzburg, Janina; Janda, Ales; Attarbaschi, Andishe; Niggli, Felix; Zimmermann, Martin; Reiter, Alfred; Klapper, Wolfram

    2015-03-01

    Mature (peripheral) T-cell lymphoma (PTCL) other than anaplastic large cell lymphoma is a heterogeneous group of diseases and exceedingly rare in children and adolescents. Survival rates range between 46% and 85%. This study reports the disease characteristics, treatment and outcome of all patients with the diagnosis of mature TCL registered in the Berlin-Frankfurt-Munster non-Hodgkin lymphoma database between 1986 and 2012. All diagnoses were centrally reviewed and revised by clinico-pathological correlation according to the criteria of the current World Health Organization classification. Of the 69 patients originally registered as having PTCL, the diagnosis was confirmed in 38 of them. Most patients were treated with an anaplastic large cell lymphoma (ALCL)-like therapy regimen. Patients with PTCL-not otherwise specified comprised the largest group and showed a 5-year event-free survival rate of 61 ± 11%. Patients suffering from Natural Killer/T-cell- and hepatosplenic TCL had the poorest outcome. Our results suggest that the outcomes of children with mature TCL other than ALCL depend on the subtype and are worse than in all other paediatric lymphomas. The clinical experience presented in this largest study on paediatric mature TCL may serve as basis for future collaborative international prospective clinical trials. PMID:25395120

  3. Large

    OpenAIRE

    Toufik Berri; Said Azizi

    2014-01-01

    Cystic lymphangioma (CL) of the parotid gland is an uncommon benign congenital tumor and very few cases have been reported in adults. We report and discuss the case of a large CL of the parotid gland in a 66-year-old woman. On computed tomography (CT) the tumor appeared as a large, well defined, unilocular cyst of the parotid region. The lesion was surgically removed and the diagnosis was confirmed on postoperative histology. CL of the parotid gland in adults presents difficult challenges ...

  4. Transformation of p53-positive papillary thyroid carcinoma to anaplastic carcinoma of the liver following postoperative radioactive iodine-131 therapy

    OpenAIRE

    Takeshita, Yumie; Takamura, Toshinari; Minato, Hiroshi; Misu, Hirofumi; Ando, Hitoshi; Yamashita, Tatsuya; IKEDA, HIROKO; Nakanuma, Yasuni; Kaneko, Shuichi

    2008-01-01

    Multiple liver metastases were incidentally detected in the lobe of the liver of an 81-year-old woman following total thyroidectomy and ablative radioactive iodine administration for the treatment of papillary thyroid carcinoma. A biopsy specimen taken from the metastatic liver tumor was histologically diagnosed as anaplastic carcinoma. Immunohistochemical staining for p53 was positive in both the primary tumor and liver biopsy specimens. We considered this to have been caused by anaplastic t...

  5. 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.

  6. 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.

  7. COMBINED CHEMOTHERAPY INCLUDING PROCARBAZINE (NATULAN IN THE TREATMENT OF ANAPLASTIC OLIGODENDROGLIOMAS

    Directory of Open Access Journals (Sweden)

    D. R. Naskhletashvili

    2012-01-01

    Full Text Available Our investigation has demonstrated the high efficiency of combined chemotherapy (CT including procarbazine + lomustine or procarbazine + lomustine + vincristine in patients with anaplastic oligodendrogliomas. Postoperative CT has been recently recommended for patients with deletion of chromosomes 1p and 19q, by taking into account the good prognosis of a therapeutic effect, better parameters of time till progression in this patient group, and a risk for cognitive impairments after brain radiotherapy.

  8. AT-36PANOBINOSTAT IN COMBINATION WITH BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA AND ANAPLASTIC GLIOMA

    OpenAIRE

    Lee, Eudocia; Reardon, David; Schiff, David; Drappatz, Jan; Muzikansky, Alona; Grimm, Sean; Norden, Andrew; Nayak, Lakshmi; Beroukhim, Rameen; Rinne, Mikael; Chi, Andrew; Batchelor, Tracy; Hempfling, Kelly; McCluskey, Christine; Smith, Katrina

    2014-01-01

    Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma models and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab. Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as...

  9. 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.

  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. PMID:25873174

  11. 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.

  12. P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Ryohei Katayama

    2016-01-01

    Full Text Available The anaplastic lymphoma kinase (ALK fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC. Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1 overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.

  13. 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.

  14. 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

  15. Cytotoxic effects of Gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells

    Directory of Open Access Journals (Sweden)

    Rotiroti Domenicoantonio

    2004-09-01

    Full Text Available Abstract Background Identification of effective systemic antineoplastic drugs against anaplastic thyroid carcinomas has particularly important implications. In fact, the efficacy of the chemotherapeutic agents presently used in these tumours, is strongly limited by their low therapeutic index. Methods In this study gemcitabine was entrapped within a pegylated liposomal delivery system to improve the drug antitumoral activity, thus exploiting the possibility to reduce doses to be administered in cancer therapy. The cytotoxic effects of free or liposome-entrapped gemcitabine was evaluated against a human thyroid tumour cell line. ARO cells, derived from a thyroid anaplastic carcinoma, were exposed to different concentrations of the drug. Liposomes formulations were made up of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-MPEG (8:3:1 molar ratio. Cell viability was assessed by both trypan bleu dye exclusion assay and fluorimetric analysis of cell DNA content. Results A cytotoxic effect of free gemcitabine was present only after 72 h incubation (ARO cell mortality increased of approximately 4 fold over control at 1 μM, 7 fold at 100 μM. When gemcitabine was encapsulated in liposomes, a significant effect was observed by using lower concentrations of the drug (increased cell mortality of 2.4 fold vs. control at 0.3 μM and earlier exposure time (24 h. Conclusion These findings show that, in vitro against human thyroid cancer cells, the gemcitabine incorporation within liposomes enhances the drug cytotoxic effect with respect to free gemcitabine, thus suggesting a more effective drug uptake inside the cells. This may allow the use of new formulations with lower dosages (side effect free for the treatment of anaplastic human thyroid tumours.

  16. FDG PET staging compared to C.T. in children with Hodgkin's disease or anaplastic lymphoma

    International Nuclear Information System (INIS)

    The accuracy of initial staging in Hodgkin's disease and anaplastic lymphoma is very important since treatment depends on the initial staging disease. An error of assessment can have serious consequences on evolution and survival. To judge PET scan performances initial staging was done on our patients by both conventional imaging and PET scan. Methods: 21 children (10 girls, 11 boys), median age 14,9 years (8 to 22) had a PET scan for the initial staging (17 Hodgkin's disease, 4 anaplastic lymphomas). Conventional staging for imaging included: Thorax x-ray, thorax and abdomen C.T., abdominal echography, and also two bone marrow biopsies. Others exams were done in accordance with special clinical data. PET scan was done on a C PET scan ADAC one hour after IV injection of 2 MBq/Kg of 18 FDG. C.T. and PET scan images were revised blindly and separately by radiologist and nuclearist with no knowledge of clinical data. Results: the staging by C.I. and PET scan were concordant in 84% of cases. In 16% of cases PET scan displayed localisation not seen by C.I., particularly bone lesions. The staging changed grading status from stage III to stage IV. The clinical cases will be presented. PET scan upgrading were confirmed by resonance imaging or bone scintigraphy. The change of stage led in each child an intensification of chemotherapy (6 courses instead of 4). Conclusion: FDG PET is a useful diagnostic tool in children with Hodgkin's disease or anaplastic lymphoma to achieve with a single exam an accurate staging allowing to choose the best treatment

  17. A significant response to sunitinib in a patient with anaplastic thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Enrique Grande

    2013-01-01

    Full Text Available Anaplastic thyroid cancer (ATC is a rare disease with an incidence of less than three cases per million of habitants in western countries. ATC accounts for 1-10% of all tumors derived from the thyroid gland. Classic chemotherapy approach based on platinum and anthracyclines regimens have been considered standard for the last decades. Novel multitarget agents have shown promising responses; however, no positive randomized clinical trials are available up to now. To our knowledge, the case we are presenting here is the first reported case showing clinical and visual activity using sunitinib as a salvage treatment in an ATC patient who was not fit to receive systemic chemotherapy treatment.

  18. 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.

  19. Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening

    OpenAIRE

    Lee, Jeeyun; Kim, Hee Cheol; Hong, Jung Yong; Wang, Kai; Kim, Sun Young; Jang, Jiryeon; Kim, Seung Tae; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Young Suk; Lee, Jiyun; Lee, Woo Yong; Park, Yoon Ah; Huh, Jung Wook

    2015-01-01

    Purpose Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. Experimental designs Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgica...

  20. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951

    NARCIS (Netherlands)

    M.C.M. Kouwenhoven (Mathilde); T.S. Gorlia (Thierry); J.M. Kros (Johan); A. Ibdaih (Ahmed); A. Brandes (Alba); J.E.C. Bromberg (Jacolien); K. Mokhtari (Karima); S.G. van Duinen (Sjoerd); J.L.J.M. Teepen; P. Wesseling (Pieter); F. Vandenbos (Fanny); W. Grisold (Wolfgang); L. Sipos (László); R.O. Mirimanoff; C.J. Vecht (Charles); A. Allgeier (Anouk); D. Lacombe (Denis); M.J. van den Bent (Martin)

    2009-01-01

    textabstractRecent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth f

  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. 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.

  4. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951.

    Science.gov (United States)

    Kouwenhoven, Mathilde C M; Gorlia, Thierry; Kros, Johan M; Ibdaih, Ahmed; Brandes, Alba A; Bromberg, Jacolien E C; Mokhtari, Karima; van Duinen, Sjoerd G; Teepen, Johannes L; Wesseling, Pieter; Vandenbos, Fanny; Grisold, Wolfgang; Sipos, László; Mirimanoff, Rene; Vecht, Charles J; Allgeier, Anouk; Lacombe, Denis; van den Bent, Martin J

    2009-12-01

    Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR(amp) were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients

  5. 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.

  6. Impact of 1p/19q Codeletion and Histology on Outcomes of Anaplastic Gliomas Treated With Radiation Therapy and Temozolomide

    Energy Technology Data Exchange (ETDEWEB)

    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.

  7. 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.

  8. Small cell anaplastic carcinoma of primary lung tumor in a miniature schnauzer dog

    International Nuclear Information System (INIS)

    A seven-year-old male, an intact miniature Schnauzer dog with history of vomiting, abdominal distention, anorexia, and dyspnea was referred for further evaluation and treatment. Thoracic radiographs showed the well marginated solitary mass with soft density in the right caudal lung field, and abdominal radiographs showed signs of ascites, such as abdominal distention and moderate serosal detail loss. On ultrasonograph and computed tomograph, it was observed that the mass compressed the caudal vena cava (CVC) and adhered to the heart. Exploratory thoracotomy was performed, and then it was showed that mass adhered heart, CVC, and diaphragm. The mass was fully rejected although adhered part of CVC could not be completely rejected. On histopathological findings, the mass was diagnosed as small-cell anaplastic carcinoma

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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

  12. An infant with hyperalertness, hyperkinesis, and failure to thrive: a rare diencephalic syndrome due to hypothalamic anaplastic astrocytoma

    OpenAIRE

    Stival, Alessia; Lucchesi, Maurizio; Farina, Silvia; Buccoliero, Anna Maria; Castiglione, Francesca; Genitori, Lorenzo; de Martino, Maurizio; Sardi, Iacopo

    2015-01-01

    Background Diencephalic Syndrome is a rare clinical condition of failure to thrive despite a normal caloric intake, hyperalertness, hyperkinesis, and euphoria usually associated with low-grade hypothalamic astrocytomas. Case presentation We reported an unusual case of diencephalic cachexia due to hypothalamic anaplastic astrocytoma (WHO-grade III). Baseline endocrine function evaluation was performed in this patient before surgery. After histological diagnosis, he enrolled to a chemotherapy p...

  13. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951

    OpenAIRE

    Kouwenhoven, Mathilde C. M.; Gorlia, Thierry; Kros, Johan M; Ibdaih, Ahmed; Brandes, Alba A.; Bromberg, Jacolien E.C.; Mokhtari, Karima; van Duinen, Sjoerd G.; Teepen, Johannes L.; Wesseling, Pieter; Vandenbos, Fanny; Grisold, Wolfgang; Sipos, László; Mirimanoff, Rene; Vecht, Charles J

    2009-01-01

    Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFRamp), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, ...

  14. 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.

  15. 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.

  16. 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

  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. Flavonoid Fraction of Citrus reticulata Juice Reduces Proliferation and Migration of Anaplastic Thyroid Carcinoma Cells.

    Science.gov (United States)

    Celano, Marilena; Maggisano, Valentina; De Rose, Roberta Francesca; Bulotta, Stefania; Maiuolo, Jessica; Navarra, Michele; Russo, Diego

    2015-01-01

    Effects of flavonoids extracted from Citrus reticulata (mandarin) juice on proliferation and migration of 3 human anaplastic thyroid carcinoma (ATC) cell lines were evaluated. Flavonoid components of Mandarin juice extract (MJe) were analyzed by uHPLC. Proliferation of CAL-62, C-643, and 8505C cells, measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, was significantly reduced by MJe in a concentration- and time-dependent way, with maximal effect elicited at 0.5 mg/ml concentration after 48 h. Cytofluorimetric analysis showed a block in the G2/M phase of the cell cycle, accompanied by low cell mortality owed to autophagic death. The extract caused also a reduction of cell migration, associated with decreased activity of the metalloproteinase MMP-2. These findings demonstrate that the flavonoid fraction of mandarin juice exerts in vitro antiproliferative effects on ATC cells, associated with a reduction of migration, suggesting for such a functional food a potential use as adjuvant in the treatment of thyroid cancer. PMID:26365817

  19. A bone metastases model of anaplastic thyroid carcinoma in athymic nude mice

    International Nuclear Information System (INIS)

    Anaplastic thyroid carcinoma (ATC), an aggressive form of thyroid cancer, represents less than 2% of all thyroid cancers. The survival of patients with ATC remains low especially when accompanied with bone metastasis. This study aims to establish a reproducible animal model of bone metastasis of ATC which may be useful for further research on novel treatment strategy. Eight 6-8 week old female athymic nude mice were randomly selected. ATC cell line ARO cells were injected into the left ventricular cavity of each mouse respectively. Each mouse was imaged using a dedicated small-animal PET/CT scanner after successful injection of [18F]-FDG under deep anesthesia. Pathological examination was carried out to confirm the bone metastases of ATC. Histopathology established ATC bone metastases in five nude mice’s tibia. Similarly, PET image displayed significantly increased radioactivity (P<0.01) in the established bone metastasis compared with the control normal tibia. Both micro-PET/CT and histomorphometric measurement confirmed the bone metastases model of ATC in nude mice by left ventricular cavity injection of ARO cell line. The bone metastases model of ATC will thus facilitate the understanding of its pathogenesis and aid in the development of novel therapies.

  20. 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.)

  1. 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.

  2. Testing for anaplastic lymphoma kinase rearrangement to target crizotinib therapy: oncology, pathology and health economic perspectives.

    Science.gov (United States)

    Lee, James A; Bubendorf, Lukas; Stahel, Rolf; Peters, Solange

    2013-05-01

    Crizotinib is a first-in-class oral anaplastic lymphoma kinase (ALK) inhibitor targeting ALK-rearranged non-small-cell lung cancer. The therapy was approved by the US FDA in August 2011 and received conditional marketing approval by the European Commission in October 2012 for advanced non-small-cell lung cancer. A break-apart FISH-based assay was jointly approved with crizotinib by the FDA. This assay and an immunohistochemistry assay that uses a D5F3 rabbit monoclonal primary antibody were also approved for marketing in Europe in October 2012. While ALK rearrangement has relatively low prevalence, a clinical benefit is exhibited in more than 85% of patients with median progression-free survival of 8-10 months. In this article, the authors summarize the therapy and alternative test strategies for identifying patients who are likely to respond to therapy, including key issues for effective and efficient testing. The key economic considerations regarding the joint companion diagnostic and therapy are also presented. Given the observed clinical benefit and relatively high cost of crizotinib therapy, companion diagnostics should be evaluated relative to response to therapy versus correlation alone whenever possible, and both high inter-rater reliability and external quality assessment programs are warranted. PMID:23617353

  3. Multidisciplinaly total-cell-kill treatment of bronchogenic small cell anaplastic carcinoma

    International Nuclear Information System (INIS)

    Survival time of the patients with bronchogenic small cell anaplastic cancer was studied. Combined treatment with six-drug combination chemotherapy ''METVFC'' (mitomycin C + cyclophosphamide + toyomycin + vincristine + 5-FU + cytosine arabinoside) and radiotherapy (5,000 rads in total) was given to 14 cases of limited disease of small cell carcinoma. Median survival was 8 months, one year and two year survival rates were 47% and 27%, respectively. Combined treatment with METVFC and small dose radiotherapy of 100 or 200 rads irradiation 4 hours before chemotherapy, followed by remission consolidation of 3,000 -- 4,000 rads radiotherapy, thereafter second line chemotherapy of ''COAM'' (cyclophosphamide + vincristine + ACNU + methotrexate) was given to 4 cases of limited disease of small cell carcinoma. All cases survived more than 1.5 years and two of them have retained complete remission more than 1.5 years. There are 6 cases with small cell carcinoma survived more than 3 years out of total 128 cases. They are all those of limited disease. They received combined treatment of chemotherapy and radiotherapy simultaneously or alternatively, followed by remission maintenance chemotherapy. One case of them died from cancer. Two cases died from another disease without lung cancer. Three cases survived healthy more than 3 to 8 years. In the limited disease, small cell carcinoma of the lung might be curable if the complete remission could continue more than three years. (author)

  4. Comparison of primary thyroid lymphoma with anaplastic thyroid carcinoma on computed tomographic imaging

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, Hitoshi; Mitsuhashi, Norio; Niibe, Hideo [Gunma Univ., Maebashi (Japan). School of Medicine; Tamaki, Yoshio; Takahashi, Mitsuhiro; Higuchi, Keiko; Sakaino, Kouji; Nonaka, Tetsuo; Shioya, Mariko [Gunma Cancer Center, Ota (Japan)

    2002-02-01

    Primary non-Hodgkin's lymphoma (LY) and anaplastic carcinoma (AC) of the thyroid gland are rare malignant tumors, and the initial symptoms of these diseases are very similar. The aim of our study was to compare the characteristics of the two diseases using computed tomographic (CT) scans in order to make an accurate differential diagnosis. Ten patients with LY and 10 with AC were analyzed. Differences in the CT findings of the two diseases were evaluated before treatment and statistically tested with either Student's t-test or the chi-square test. In the analysis of characteristics of CT imaging, the existence of calcification and necrosis, and heterogeneous tumor were dominant findings in AC, and there was a statistically significant difference in frequency between the two diseases (p<0.01). Calcification detected in AC was usually multiple and/or gross (mean size: {phi}8.2 mm). All lymphadenopathies were delineated as having the same homogeneous attenuation as the tumors in the thyroid gland in LY, but were shown as irregular rim enhancement in AC. The CT features of the two diseases are characteristic in terms of calcification, necrosis, and tumor composition. Evaluation by means of CT imaging is useful in distinguishing between LY and AC. (author)

  5. 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.

  6. 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.

  7. First case of bilateral, synchronous anaplastic variant of spermatocytic seminoma treated with radical orchifunicolectomy as single approach: Case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Giorgio Gentile

    2014-03-01

    Full Text Available Spermatocytic Seminoma (SS is less common than the Classic variant, as its incidence ranges between 1.3% and 2.3% of all seminomas. Generally SS is diagnosed in men older than 50 years. The Anaplastic variant of Spermatocytic Seminoma is characterized by an earlier onset when compared to SS, but a benign behavior in spite of its histological patterns similar to Classic Seminoma. We reported the first case of bilateral, largest and synchronous Anaplastic Spermatocytic Seminoma, in a patient treated with radical orchifunicolectomy alone and with long-term follow-up. The currently available data show that Anaplastic SS reveals a clinically benign behavior, and no distant metastases have been reported so far. A close surveillance after surgery could be considered a valid option in the management of this rare testicular neoplasm.

  8. Tumor-associated macrophages (TAMs form an interconnected cellular supportive network in anaplastic thyroid carcinoma.

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    Bernard Caillou

    Full Text Available BACKGROUND: A relationship between the increased density of tumor-associated macrophages (TAMs and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC is one of the most aggressive solid tumors in humans. TAMs (type M2 have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC. METHODOLOGY/PRINCIPAL FINDINGS: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs. In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells. CONCLUSION: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic

  9. 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.

  10. Role of pulmonary macrophages in initiation of lung metastasis in anaplastic thyroid cancer.

    Science.gov (United States)

    Li, Xiu Juan; Gangadaran, Prakash; Kalimuthu, Senthilkumar; Oh, Ji Min; Zhu, Liya; Jeong, Shin Young; Lee, Sang-Woo; Lee, Jaetae; Ahn, Byeong-Cheol

    2016-12-01

    Several clinical studies have demonstrated that increased macrophage infiltration into tumors confers metastatic potential and poor prognosis in cancer. Preclinical studies are needed to develop new strategies for countering metastasis. Our study was designed to investigate the impact of pulmonary macrophages on lung metastasis of anaplastic thyroid cancer (ATC). ATC (CAL-62) and macrophage (Raw264.7) were transfected with the effluc (CAL-62/effluc, Raw264.7/effluc). Coculture and migration assays were used to assess the effect of Raw264.7 or THP1 (human macrophage) (or conditioned medium) on the proliferation and/or migration of CAL-62/effluc cells in vitro. The effect of clodro-lipo or PBS-lipo on macrophage depletion was confirmed in vitro and in vivo. CAL-62/effluc cells (1 × 10(6) ) were intravenously injected into nude mice 24 h after clodro-lipo or PBS-lipo administration. Effect of clodro-lipo on the lung metastasis of CAL-62/effluc was assessed by bioluminescence imaging (BLI). Micro computed tomography (micro-CT) and histology. BLI signals of CAL-62/effluc and Raw264.7/effluc increased to cell number. Raw264.7 cells and THP1 cells promoted CAL-62/effluc proliferation, and conditioned medium of Raw264.7 cells promoted CAL-62/effluc migration. Clodro-lipo significantly depleted pulmonary macrophages in vitro and in vivo. Intensity of BLI signals in ATC lung metastasis was weaker in the clodro-lipo group than PBS-lipo control. Micro-CT imaging and hematoxylin/eosin staining revealed smaller tumor masses in the clodro-lipo group than PBS-lipo control. Our findings indicate that pulmonary macrophages have an important role in initiation of lung metastasis of ATC. New therapeutic strategies that preclude initiation of pulmonary metastasis could potentially be developed by targeting pulmonary macrophages. PMID:27537102

  11. 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

  12. Dosimetric comparison between helical tomotherapy and volumetric modulated arc-therapy for non-anaplastic thyroid cancer treatment

    International Nuclear Information System (INIS)

    To evaluate and compare dosimetric parameters of volumetric modulated arctherapy (VMAT) and helical tomotherapy (HT) for non-anaplastic thyroid cancer adjuvant radiotherapy. Twelve patients with non-anaplastic thyroid cancer at high risk of local relapse received adjuvant external beam radiotherapy with curative intent in our institution, using a two-dose level prescription with a simultaneous integrated boost approach. Each patient was re-planned by the same physicist twice using both VMAT and HT. Several dosimetric quality indexes were used: target coverage index (proportion of the target volume covered by the reference isodose), healthy tissue conformity index (proportion of the reference isodose volume including the target volume), conformation number (combining both previous indexes), Dice Similarity Coefficient (DSC), and homogeneity index ((D2%-D98%)/prescribed dose). Dose-volume histogram statistics were also compared. HT provided statistically better target coverage index and homogeneity index for low risk PTV in comparison with VMAT (respectively 0.99 vs. 0.97 (p = 0.008) and 0.22 vs. 0.25 (p = 0.016)). However, HT provided poorer results for healthy tissue conformity index, conformation number and DSC with low risk and high risk PTV. As regards organs at risk sparing, by comparison with VMAT, HT statistically decreased the D2% to medullary canal (25.3 Gy vs. 32.6 Gy (p = 0.003)). Besides, HT allowed a slight sparing dose for the controlateral parotid (Dmean: 4.3 Gy vs. 6.6 Gy (p = 0.032)) and for the controlateral sub-maxillary gland (Dmean: 29.1 Gy vs. 33.1 Gy (p = 0.041)). Both VMAT and HT techniques for adjuvant treatment of non-anaplastic thyroid cancer provide globally attractive treatment plans with slight dosimetric differences. However, helical tomotherapy clearly provides a benefit in term of medullary canal sparing

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

    Science.gov (United States)

    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.

  14. Primary anaplastic astrocytoma of the brain after prophylactic cranial irradiation in a case of acute lymphoblastic leukemia: Case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Imtiaz Ahmed

    2014-01-01

    Full Text Available A 6½-year-old boy had developed acute lymphoblastic leukemia and was treated with systemic chemotherapy, intrathecal triple drug regimen and prophylactic cranial irradiation. After 10 years he developed anaplastic astrocytoma of the postero-superior cerebellum on the left side while leukemia was in remission. He was treated with surgical excision, followed by adjuvant three dimensional conformal radiotherapy and is on salvage chemotherapy with temozolamide. It is possible that the anaplastic astrocytoma may be a radiation induced malignancy.

  15. 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.

  16. Non-anaplastic peripheral T cell lymphoma in children and adolescents-an international review of 143 cases.

    Science.gov (United States)

    Mellgren, K; Attarbaschi, A; Abla, O; Alexander, S; Bomken, S; Bubanska, E; Chiang, A; Csóka, M; Fedorova, A; Kabickova, E; Kapuscinska-Kemblowska, L; Kobayashi, R; Krenova, Z; Meyer-Wentrup, F; Miakova, N; Pillon, M; Plat, G; Uyttebroeck, A; Williams, D; Wróbel, G; Kontny, U

    2016-08-01

    Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients event-free survival was (pEFS) 0.45 ± 0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78 ± 0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13 ± 0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29 ± 0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL. PMID:27270301

  17. 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

  18. A model of a patient-derived IDH1 mutant anaplastic astrocytoma with alternative lengthening of telomeres.

    Science.gov (United States)

    Borodovsky, Alexandra; Meeker, Alan K; Kirkness, Ewen F; Zhao, Qi; Eberhart, Charles G; Gallia, Gary L; Riggins, Gregory J

    2015-02-01

    Mutations in isocitrate dehydrogenase 1 (IDH1) have been found in the vast majority of low grade and progressive infiltrating gliomas and are characterized by the production of 2-hydroxyglutarate from α-ketoglutarate. Recent investigations of malignant gliomas have identified additional genetic and chromosomal abnormalities which cluster with IDH1 mutations into two distinct subgroups. The astrocytic subgroup was found to have frequent mutations in ATRX, TP53 and displays alternative lengthening of telomeres. The second subgroup with oligodendrocytic morphology has frequent mutations in CIC or FUBP1, and is linked to co-deletion of the 1p/19q arms. These mutations reflect the development of two distinct molecular pathways representing the majority of IDH1 mutant gliomas. Unfortunately, due to the scarcity of endogenously derived IDH1 mutant models, there is a lack of accurate models to study mechanism and develop new therapy. Here we report the generation of an endogenous IDH1 anaplastic astrocytoma in vivo model with concurrent mutations in TP53, CDKN2A and ATRX. The model has a similar phenotype and histopathology as the original patient tumor, expresses the IDH1 (R132H) mutant protein and exhibits an alternative lengthening of telomeres phenotype. The JHH-273 model is characteristic of anaplastic astrocytoma and represents a valuable tool for investigating the pathogenesis of this distinct molecular subset of gliomas and for preclinical testing of compounds targeting IDH1 mutations or alternative lengthening of telomeres. PMID:25471051

  19. MGMT-STP27 Methylation Status as Predictive Marker for Response to PCV in Anaplastic Oligodendrogliomas and Oligoastrocytomas. A Report from EORTC Study 26951

    NARCIS (Netherlands)

    van den Bent, Martin J.; Erdem-Eraslan, Lale; Idbaih, Ahmed; de Rooi, Johan; Eilers, Paul H. C.; Spliet, Wim G. M.; den Dunnen, Wilfred F. A.; Tijssen, Cees; Wesseling, Pieter; Smitt, Peter A. E. Sillevis; Kros, Johan M.; Gorlia, Thierry; French, Pim J.

    2013-01-01

    Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treat

  20. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic Oligodendrogliomas and Oligoastrocytomas. A report from EORTC study 26951

    NARCIS (Netherlands)

    Bent, M.J. van den; Erdem-Eraslan, L.; Idbaih, A.; Rooi, J. de; Eilers, P.H.; Spliet, W.G.; Dunnen, W.F. den; Tijssen, C.; Wesseling, P.; Smitt, P.A.; Kros, J.M.; Gorlia, T.; French, P.J.

    2013-01-01

    PURPOSE: The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treat

  1. Late intervention with anti-BRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer.

    Science.gov (United States)

    Nehs, Matthew A; Nucera, Carmelo; Nagarkatti, Sushruta S; Sadow, Peter M; Morales-Garcia, Dieter; Hodin, Richard A; Parangi, Sareh

    2012-02-01

    Human anaplastic thyroid cancer (ATC) is a lethal disease with an advanced clinical presentation and median survival of 3 months. The BRAF(V600E) oncoprotein is a potent transforming factor that causes human thyroid cancer cell progression in vitro and in vivo; therefore, we sought to target this oncoprotein in a late intervention model of ATC in vivo. We used the human ATC cell line 8505c, which harbors the BRAF(V600E) and TP53(R248G) mutations. Immunocompromised mice were randomized to receive the selective anti-BRAF(V600E) inhibitor, PLX4720, or vehicle by oral gavage 28 d after tumor implantation, 1 wk before all animals typically die due to widespread metastatic lung disease and neck compressive symptoms in this model. Mice were euthanized weekly to evaluate tumor volume and metastases. Control mice showed progressive tumor growth and lung metastases by 35 d after tumor implantation. At that time, all control mice had large tumors, were cachectic, and were euthanized due to their tumor-related weight loss. PLX4720-treated mice, however, showed a significant decrease in tumor volume and lung metastases in addition to a reversal of tumor-related weight loss. Mouse survival was extended to 49 d in PLX4720-treated animals. PLX4720 treatment inhibited cell cycle progression from 28 d to 49 d in vivo. PLX4720 induces striking tumor regression and reversal of cachexia in an in vivo model of advanced thyroid cancer that harbors the BRAF(V600E) mutation.

  2. A Case of Orbital Metastasis as Disease Progression of Anaplastic Lymphoma Kinase-Positive Lung Cancer Treated with Crizotinib

    Directory of Open Access Journals (Sweden)

    Yoshihiko Sakata

    2015-01-01

    Full Text Available Orbital metastasis of lung cancer is rare. It often causes visual disorder. To date, there are only a few case reports. Crizotinib is an anaplastic lymphoma kinase (ALK tyrosine kinase inhibitor that leads to responses in most patients with ALK-positive non-small-cell lung cancer. Visual disorder is one of the popular adverse events of crizotinib, but the symptom almost decreases over time. We report a case of orbital metastasis as the disease progression of ALK-positive lung cancer treated with crizotinib. It should be kept in mind that orbital metastasis can be the disease progression of lung adenocarcinoma with ALK translocation treated with crizotinib. When physicians encounter a patient receiving crizotinib with visual disorder, we must distinguish between adverse events and orbital metastasis.

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

    Science.gov (United States)

    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.

  4. 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...... of contamination of the aspirates with normal cells was determined by differential counts. The ratio of the peak channel numbers for the G1 phase of the tumor cells to that of the diploid standard (DNA index) was calculated and used for ploidy identification. Twenty-nine patients were evaluable with respect to DNA...... of the detection limit set by the methodology used and the restricted number of samples studied in each patient indicate that the true occurrence of clonal heterogeneity in small-cell carcinoma of the lung may be much higher....

  5. Synergistic antitumor effect between gefitinib and fractionated irradiation in anaplastic oligodendrogliomas cannot be predicted by the Egfr signaling activity.

    Directory of Open Access Journals (Sweden)

    Sophie Pinel

    Full Text Available In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment "gefitinib + radiotherapy" and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas (TCG2, TCG3 and TCG4 harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib (GEF 75 mg/kg/day x 5 days/week, for 2 weeks and/or fractionated radiotherapy (RT: 5x2Gy/week for 2 weeks. Our results showed that GEF and/or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an "EGFR-addictive" behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for "EGFR-addictive" tumors. Unfortunately, neither the usual molecular markers (EGFR amplification, PTEN loss nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.

  6. 131I therapy for hyperthyroidism and consequent appearing of anaplastic carcinoma of the thyroid: simple case-report or real pathophysiologic link?

    Directory of Open Access Journals (Sweden)

    G. Scanelli

    2013-05-01

    Full Text Available BACKGROUND 131I is usually employed for the therapy of hyperfunctioning thyroid diseases. This β-emitting radioisotope acts releasing its radiations in small tissue volumes, but it is mandatory to consider, also for the small doses, the carcinogenic risk, well documented with the high 131I dosages used to cure differentiated thyroid cancers. METHODS We describe a case of anaplastic thyroid carcinoma appeared 4 years after therapy with 131I for Graves’ disease. The patient was treated both surgically and with thyonamides for Graves’ disease 20 years before; thereafter she underwent simple nephrectomy owing to Grawitz disease. After some years of well being, she was treated with 131I for a relapse of Graves’ disease. Four years later, she was treated with interleukin-2 and TNF-α, owing to distant metastases (pancreas, liver and lung of Grawitz cancer. Some months later, because of a rapid enlargement of the thyroid gland, she was thyroidectomized and anaplastic thyroid cancer was histologically documented. DISCUSSION AND CONCLUSIONS It is very difficult to investigate the possible transformation of a benign thyroid lesion to a malignant one, and data from the literature are conflicting. Fractioned doses of 131I are known to induce less cancers than high doses: they allow DNA to repair. Nevertheless, in patients with altered or non valid genetic repair’s mechanisms (i.e. patients with p53 mutations and, for this reason, prone to develop cancers, even low doses of 131I can induce carcinogenetic effects. In a patient with a history of cancer, who subsequently develops hyperthyroidism, even low doses of 131I can induce anaplastic thyroid cancer; in these subjects, therefore, other treatments than 131I could be preferred for the therapy of Graves’ disease. In our peculiar case, moreover, some studies have noteworthy demonstrated that certain cytokines (IL-1, TGF-β1 e TNF-α can, rather than inhibit, induce anaplastic thyroid cancer cells

  7. Multiple metastases to the small bowel from large cell bronchial carcinomas

    Institute of Scientific and Technical Information of China (English)

    Davor Tomas; Mario Ledinsky; Mladen Belicza; Bozo Kru(s)lin

    2005-01-01

    AIM: Metastases from lung cancer to gastrointestinal tract are not rare atpostmortem studies but the development of clinically significant symptoms from the gastrointestinal metastases is very unusual.METHODS: Formalin-fixed, paraffin-embedded tissues were cut into 5 μm thick sections and routinely stained with hematoxylin and eosin. Some slides were also stained with Alcian-PAS. Antibodies used were primary antibodies to pancytokeratin, cytokeratin 7, cytokeratin 20, epithelial membrane antigen, vimentin, smooth muscle actin and CD-117.RESULTS: We observed three patients who presented with multiple metastases from large cell bronchial carcinoma to small intestine. Two of them had abdominal symptoms (sudden onset of abdominal pain, constipation and vomiting) and in one case the tumor was incidentally found during autopsy. Microscopically, all tumors showed a same histological pattern and consisted almost exclusively of strands and sheets of poorly cohesive, polymorphic giant cells with scanty, delicate stromas. Few smaller polygonal anaplastic cells dispersed between polymorphic giant cells,were also observed. Immunohistochemistry showed positive staining of the tumor cells with cytokeratin and vimentin. Microscopically and immunohistochemically all metastases had a similar pattern to primary anaplastic carcinoma of the small intestine.CONCLUSION: In patients with small intestine tumors showing anaplastic features, especially with multiple tumors, metastases from large cell bronchial carcinoma should be first excluded, because it seems that they are more common than expected.

  8. The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells.

    Science.gov (United States)

    Kim, Si Hyoung; Kang, Jun Goo; Kim, Chul Sik; Ihm, Sung-Hee; Choi, Moon Gi; Yoo, Hyung Joon; Lee, Seong Jin

    2015-04-01

    The effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an hsp90 inhibitor, alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma (ATC) was evaluated. In 8505C and CAL62 cells, after treatment of 17-AAG, cell viability decreased, and the percentage of dead cells increased. 17-AAG did not cause cleavage of caspase-3 protein, and change expression of IAPs. Pretreatment of z-VAD-fmk did not alter cell viability and the percentage of dead cells. In 17-AAG-treated cells, knockdown of p53 rescued growth inhibition, while cycloheximide attenuated cell death. When cells were treated with both 17-AAG and paclitaxel, all of the combination index values were higher than 1, indicating antagonism between 17-AAG and paclitaxel. In 17-AAG- and paclitaxel-treated cells, compared with paclitaxel alone-treated cells, the protein levels of hsp90, hsp70, and hsc70 increased. In conclusion, our results suggest that 17-AAG induces non-apoptotic cell death requiring de novo protein synthesis in ATC cells. Moreover, these results demonstrate that 17-AAG antagonizes paclitaxel with concomitant alterations in hsp90 client proteins in ATC cells. PMID:25096912

  9. 甲状腺间变癌的CT影像特点%CT imaging features of anaplastic thyroid carcinoma

    Institute of Scientific and Technical Information of China (English)

    史震山; 庄茜; 游瑞雄; 曹代荣; 李跃明

    2013-01-01

    目的 分析甲状腺间变癌的CT表现,评价CT在明确甲状腺间变癌诊断及鉴别诊断中的价值.方法 回顾性分析经手术、病理证实的10例甲状腺间变癌的临床及CT资料,女7例、男3例;发病年龄25~78岁,中位年龄为61岁;均采用MSCT行平扫及增强扫描.结果 10例中8例为单侧病灶,其中2例病灶较大侵及峡部;2例病灶累及双侧甲状腺.肿瘤最大径为2.9~12.8 cm,平均(4.5±1.4)cm;病灶边缘均不光整且有甲状腺被膜外侵征象;病灶平扫密度不均匀,病灶内均可见坏死区;病灶内伴钙化者7枚,钙化形态各异,以单发粗颗粒钙化状较多见(5个病灶).增强后病灶均呈明显不均匀强化,实性部分明显强化(强化幅度>40 HU);平扫及增强后病灶与对侧胸锁乳突肌CT值比值分别为0.69~0.82(0.76±0.18),1.25~1.41(1.33±0.28).伴颈部淋巴结肿大者6例,增强后不规则环形强化或均匀明显强化,1例淋巴结内见砂粒状钙化.结论 直径较大、单发、粗颗粒钙化、甲状腺包膜不完整,并见坏死及明显不均匀强化伴颈部肿大淋巴结是甲状腺间变癌CT较为特征性的表现.%Objective To investigate the CT characteristics of anaplastic thyroid carcinoma and evaluate the diagnostic value of CT in this disease.Methods The CT findings of 10 patients with pathologically proved anaplastic thyroid carcinoma were retrospectively reviewed.The patients included 7 females and 3 males.Their age ranged from 25.0 to 78 years with median of 61 years.Multi-slices plain and post contrast CT scans were performed in all patients.Results Unilateral thyroid was involved in 6 patients.Unilateral thyroid and thyroid isthmus were both involved in 2 patients due to big size.Bilateral thyroid were involved in 2 patients.The maximum diameter of anaplastic thyroid carcinoma ranged from 2.9-12.8 cm with mean of (4.5 ± 1.4) cm.All lesions demonstrated unclear margins and envelope invasion

  10. Plastic surgery for large wound defects using vascularized flops in treatment of skin and soft-tissue tumors

    International Nuclear Information System (INIS)

    The results were presented on plastic and reconstructive -anaplastic surgery in resection of locally spread and relapse tumors of the skin and soft tissues after multiple courses of radiation and combined treatment. 38 patients with skin melanoma and softtissue sarcomas received radio- and/or chemotherapy in preoperative period under conditions of local hyperthermia of the tumor. Two types of plasty of large wound defects using vascularized flaps were considered

  11. Anaplastic lymphoma kinase gene copy number gain in inflammatory breast cancer (IBC: prevalence, clinicopathologic features and prognostic implication.

    Directory of Open Access Journals (Sweden)

    Min Hwan Kim

    Full Text Available Inflammatory breast cancer (IBC is the most aggressive form of breast cancer, and its molecular pathogenesis still remains to be elucidated. This study aimed to evaluate the prevalence and implication of anaplastic lymphoma kinase (ALK copy number change in IBC patients.We retrospectively collected formalin-fixed, paraffin-embedded tumor tissues and medical records of IBC patients from several institutes in Korea. ALK gene copy number change and rearrangement were assessed by fluorescence in situ hybridization (FISH assay, and ALK expression status was evaluated by immunohistochemical (IHC staining.Thirty-six IBC patients including those with HER2 (+ breast cancer (16/36, 44.4% and triple-negative breast cancer (13/36, 36.1% were enrolled in this study. ALK copy number gain (CNG was observed in 47.2% (17/36 of patients, including one patient who harbored ALK gene amplification. ALK CNG (+ patients showed significantly worse overall survival compared to ALK CNG (- patients in univariate analysis (24.9 months vs. 38.1 months, p = 0.033. Recurrence free survival (RFS after curative mastectomy was also significantly shorter in ALK CNG (+ patients than in ALK CNG (- patients (n = 22, 12.7 months vs. 43.3 months, p = 0.016. Multivariate Cox regression analysis with adjustment for HER2 and ER statuses showed significantly poorer RFS for ALK CNG (+ patients (HR 5.63, 95% CI 1.11-28.44, p = 0.037.This study shows a significant presence of ALK CNG in IBC patients, and ALK CNG was associated with significantly poorer RFS.

  12. 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.

  13. miR-4295 promotes cell proliferation and invasion in anaplastic thyroid carcinoma via CDKN1A

    Energy Technology Data Exchange (ETDEWEB)

    Shao, Mingchen; Geng, Yiwei [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Lu, Peng [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Xi, Ying [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Wei, Sidong [Liver Transplantation Hepatobiliary Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Wang, Liuxing; Fan, Qingxia [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Ma, Wang, E-mail: doctormawang@126.com [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China)

    2015-09-04

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in anaplastic thyroid carcinoma (ATC), has remained elusive. Here, we identified that miR-4295 promotes ATC cell proliferation by negatively regulates its target gene CDKN1A. In ATC cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-4295, while miR-4295 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-4295 mimics significantly promoted the migration and invasion of ATC cells, whereas miR-4295 inhibitors significantly reduced cell migration and invasion. luciferase assays confirmed that miR-4295 directly bound to the 3'untranslated region of CDKN1A, and western blotting showed that miR-4295 suppressed the expression of CDKN1A at the protein levels. This study indicated that miR-4295 negatively regulates CDKN1A and promotes proliferation and invasion of ATC cell lines. Thus, miR-4295 may represent a potential therapeutic target for ATC intervention. - Highlights: • miR-4295 mimics promote the proliferation and invasion of ATC cells. • miR-4295 inhibitors inhibit the proliferation and invasion of ATC cells. • miR-4295 targets 3′UTR of CDKN1A in ATC cells. • miR-4295 negatively regulates CDKN1A in ATC cells.

  14. A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1.

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    Barbara Klink

    Full Text Available Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

  15. Immunoexpression of TTF-1 and Ki-67 in a coexistent anaplastic and follicular thyroid cancer with rare long-life surviving.

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    Jerzy Sowinski

    2009-01-01

    Full Text Available We report the immunohistochemical diagnosis, including TTF-1 (thyroid transcription factor 1 and Ki-67, of a rare mixed thyroid neoplasm composed of minimally invasive well differentiated follicular areas and highly aggressive undifferentiated anaplastic areas. A 75 old female presented to our clinic with a rapidly growing neck mass. Considering the dynamics of the disease and the multiple challenges presented by the patient: advanced age, tumor size, history of a longstanding goiter we decided to transfer her to the department of surgery. The intraoperative findings were an enlarged right lobe with tracheal and surrounding tissues infiltration. Total thyroidectomy, radical neck lymph nodes dissection and tracheostomy were performed. The histopathological and immunohistochemical examination revealed a coexistent anaplastic and follicular thyroid carcinoma. The proliferation index Ki-67, a cell proliferation marker, was found to be significantly higher in the anaplastic areas (30 +/- 5% in the comparison with the follicular areas (2 +/- 1%. The evaluation of the thyroid transcription factor 1 (TTF-1 expression revealed a correlation with the tumor cells aggressiveness accordingly to the cancer areas. After a radical surgery an external adjuvant radiation was applied. The patient is alive and more than five years after diagnosis she presented an increase of the serum thyroglobulin level suggesting, probably, a recurrence of the follicular form of the cancer. According to our survey we suggest that in thyroid cancers TTF-1 and Ki-67 could provides useful information on the differentiation activities of thyroid tumor cells and may be helpful to distinguish well differentiated and undifferentiated areas in a mixed thyroid cancer.

  16. 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

    International Nuclear Information System (INIS)

    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

  17. Long-term stabilization by radiosurgery of a secondary focal anaplastic transformation in a surgically treated WHO grade II oligodendroglioma. A case report.

    Science.gov (United States)

    Yordanova, Y N; Rodriguez-Arribas, M-A; Duffau, H

    2015-02-01

    We report on a young woman with a left temporal diffuse low-grade glioma treated initially by a subtotal resection. A focal anaplastic area appeared 5years later and was treated by radiosurgery. A long-time stabilization was therefore obtained and lasted even after pregnancy, which is a known factor of faster tumour progression. This report shows that radiosurgery could be an option in the multimodal treatment of a selected group of patients with focal malignant transformation of diffuse low-grade glioma. It could permit long-term stabilization of the tumour without any other adjuvant treatment and without compromising the quality of life.

  18. Successful radiation treatment of anaplastic thyroid carcinoma metastatic to the right cardiac atrium and ventricle in a pacemaker-dependent patient

    International Nuclear Information System (INIS)

    Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy, which is known to metastasize to the heart. We report a case of a patient with ATC with metastatic involvement of the pacemaker leads within the right atrium and right ventricle. The patient survived external beam radiation treatment to his heart, with a radiographic response to treatment. Cardiac metastases are usually reported on autopsy; to our knowledge, this is the first report of the successful treatment of cardiac metastases encasing the leads of a pacemaker, and of cardiac metastases from ATCs, with a review of the pertinent literature

  19. Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities.

    Science.gov (United States)

    Watanabe, Yuko; Shido, Kosuke; Niihori, Tetsuya; Niizuma, Hidetaka; Katata, Yu; Iizuka, Chie; Oba, Daiju; Moriya, Kunihiko; Saito-Nanjo, Yuka; Onuma, Masaei; Rikiishi, Takeshi; Sasahara, Yoji; Watanabe, Mika; Aiba, Setsuya; Saito, Ryuta; Sonoda, Yukihiko; Tominaga, Teiji; Aoki, Yoko; Kure, Shigeo

    2016-01-01

    Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets. PMID:26360803

  20. In vitro identification and characterization of CD133(pos cancer stem-like cells in anaplastic thyroid carcinoma cell lines.

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    Giovanni Zito

    Full Text Available BACKGROUND: Recent publications suggest that neoplastic initiation and growth are dependent on a small subset of cells, termed cancer stem cells (CSCs. Anaplastic Thyroid Carcinoma (ATC is a very aggressive solid tumor with poor prognosis, characterized by high dedifferentiation. The existence of CSCs might account for the heterogeneity of ATC lesions. CD133 has been identified as a stem cell marker for normal and cancerous tissues, although its biological function remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: ATC cell lines ARO, KAT-4, KAT-18 and FRO were analyzed for CD133 expression. Flow cytometry showed CD133(pos cells only in ARO and KAT-4 (64+/-9% and 57+/-12%, respectively. These data were confirmed by qRT-PCR and immunocytochemistry. ARO and KAT-4 were also positive for fetal marker oncofetal fibronectin and negative for thyrocyte-specific differentiating markers thyroglobulin, thyroperoxidase and sodium/iodide symporter. Sorted ARO/CD133(pos cells exhibited higher proliferation, self-renewal, colony-forming ability in comparison with ARO/CD133(neg. Furthermore, ARO/CD133(pos showed levels of thyroid transcription factor TTF-1 similar to the fetal thyroid cell line TAD-2, while the expression in ARO/CD133(neg was negligible. The expression of the stem cell marker OCT-4 detected by RT-PCR and flow cytometry was markedly higher in ARO/CD133(pos in comparison to ARO/CD133(neg cells. The stem cell markers c-KIT and THY-1 were negative. Sensitivity to chemotherapy agents was investigated, showing remarkable resistance to chemotherapy-induced apoptosis in ARO/CD133(pos when compared with ARO/CD133(neg cells. CONCLUSIONS/SIGNIFICANCE: We describe CD133(pos cells in ATC cell lines. ARO/CD133(pos cells exhibit stem cell-like features--such as high proliferation, self-renewal ability, expression of OCT-4--and are characterized by higher resistance to chemotherapy. The simultaneous positivity for thyroid specific factor TTF-1 and onfFN suggest

  1. Anaplastic thyroid cancer

    Science.gov (United States)

    ... or MRI of the neck may show a tumor growing from the thyroid gland. A thyroid biopsy makes the diagnosis. An examination ... the thyroid Images ... Saunders; 2016:chap 226. Lai SY, Mandel SJ, Weber RS. Management of thyroid neoplasms. In: Flint PW, Haughey BH, Lund LJ, et ...

  2. 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.

  3. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Energy and protein intake and nutritional status in non-surgically treated patients with small cell anaplastic carcinoma of the lung

    Energy Technology Data Exchange (ETDEWEB)

    Enig, B.; Winther, E.; Hessov, I.

    The spontaneous food intake and nutritional status was assessed in 23 patients with small cell anaplastic carcinoma of the lung before and two times during a treatment period of 6 weeks. Radiation therapy was given for 2 weeks followed by a course of chemotherapy and another 2 weeks of radiation therapy. The energy intake decreased during the treatment from 146 to 130 per cent of basal metabolic rate. The protein intake remained unchanged (mean 0.9 g/kg body weight). There were insignificant and small losses of weight, body fat, free body mass and arm muscle circumference, and no changes were seen in serum albumin and serum transferrin. However, 6 patients suffered a weight loss of 5 per cent or more. No correlation existed between the nutritional parameters measured before treatment and the changes during treatment. Patients who suffered a loss of body weight could therefore not be singled out before the treatment.

  6. 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.

  7. Anaplastic Thyroid Cancer: The Addition of Systemic Chemotherapy to Radiotherapy Led to an Observed Improvement in Survival—A Single Centre Experience and Review of the Literature

    Science.gov (United States)

    Lowe, Natalie M.; Loughran, Sean; Slevin, Nicholas J.; Yap, Beng K.

    2014-01-01

    Introduction. Anaplastic thyroid carcinoma (ATC) is rare yet accounts for up to 50% of all thyroid cancer deaths. This study reviews outcomes of patients with confirmed ATC referred to a tertiary oncology centre plus reviews the literature to explore how poor outcomes may be improved. Materials and Methods. The management and outcomes of 20 patients with ATC were reviewed. Results. Median age at diagnosis was 69.5 years. 19 patients died due to ATC, 40% of whom died from asphyxiation. Median survival for all cases was 59 days. Patients who had previous surgery prior to other treatment modalities had a longer median survival overall compared to those who had not had previous surgery (142 days compared to 59 days) and produced the one long-term survivor. Chemotherapy followed by radiotherapy (without previous surgery) was associated with longer median survival (220 days). Palliative radiotherapy alone did not decrease the rate of death by asphyxiation when compared to other single modality treatments. Conclusion. Multimodality treatment including surgery when feasible remains the best strategy to improve survival and prevent death from asphyxiation in the management of ATC. The addition of chemotherapy to our institutional protocol led to improved survival but prognosis remains very poor. PMID:25184150

  8. Anaplastic Thyroid Cancer: The Addition of Systemic Chemotherapy to Radiotherapy Led to an Observed Improvement in Survival—A Single Centre Experience and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Natalie M. Lowe

    2014-01-01

    Full Text Available Introduction. Anaplastic thyroid carcinoma (ATC is rare yet accounts for up to 50% of all thyroid cancer deaths. This study reviews outcomes of patients with confirmed ATC referred to a tertiary oncology centre plus reviews the literature to explore how poor outcomes may be improved. Materials and Methods. The management and outcomes of 20 patients with ATC were reviewed. Results. Median age at diagnosis was 69.5 years. 19 patients died due to ATC, 40% of whom died from asphyxiation. Median survival for all cases was 59 days. Patients who had previous surgery prior to other treatment modalities had a longer median survival overall compared to those who had not had previous surgery (142 days compared to 59 days and produced the one long-term survivor. Chemotherapy followed by radiotherapy (without previous surgery was associated with longer median survival (220 days. Palliative radiotherapy alone did not decrease the rate of death by asphyxiation when compared to other single modality treatments. Conclusion. Multimodality treatment including surgery when feasible remains the best strategy to improve survival and prevent death from asphyxiation in the management of ATC. The addition of chemotherapy to our institutional protocol led to improved survival but prognosis remains very poor.

  9. Rapid and dramatic response to alectinib in an anaplastic lymphoma kinase rearranged non-small-cell lung cancer patient who is critically ill.

    Science.gov (United States)

    Yoshida, Tatsuya; Hida, Toyoaki; Yatabe, Yasushi

    2016-07-01

    Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising clinical activity in the treatment of non-small-cell lung cancer (NSCLC) that harbors ALK rearrangement. The next-generation ALK-TKI, alectinib, has been reported to have potent efficacy in ALK-positive NSCLC patients including on mutations that confer resistance to crizotinib, which was the first ALK-TKI approved for ALK-positive NSCLC. The efficacy and safety of ALK-TKIs, including crizotinib and alectinib, as the first-line treatment in critically ill patients is unclear. We report one ALK-positive NSCLC patient with poor performance status (PS) and disseminated intravascular coagulation because of respiratory failure and multiple metastases, and experienced the rapid and dramatic response to alectinib without adverse events that can lead to discontinuation and dose reduction of the drug. After a couple of months of treatment with alectinib, radiological review indicated a complete response. The present case is the first reported case of rapid and marked response to alectinib in ALK-positive NSCLC patients who had poor PS and severe organ dysfunction, such as disseminated intravascular coagulation. Further investigation of the safety and efficacy of ALK-TKI for ALK-positive NSCLC patients who are critically ill is warranted. PMID:26938871

  10. The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells.

    Science.gov (United States)

    Kim, Si Hyoung; Kang, Jun Goo; Kim, Chul Sik; Ihm, Sung-Hee; Choi, Moon Gi; Yoo, Hyung Joon; Lee, Seong Jin

    2016-02-01

    The influence of the heat shock protein 90 (hsp90) inhibitor SNX5422 alone or in combination with the histone deacetylase (HDAC) inhibitors PXD101, suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA) on survival of anaplastic thyroid carcinoma (ATC) cells was investigated. In 8505C and CAL62 cells, SNX5422 caused cell death with concomitant changes in the expression of hsp90 client proteins. After treatment of both SNX5422 and PXD101, SAHA and TSA, compared with treatment of SNX5422 alone, cell viability was diminished, whereas inhibition rate and cytotoxic activity were enhanced. All of the combination index values were lower than 1.0, suggesting the synergism between SNX5422 and PXD101, SAHA and TSA in induction of cell death. In cells treated with both SNX5422 and PXD101, SAHA and TSA, compared with cells treated with SNX5422 alone, the protein levels of Akt, phospho-4EBP1, phospho-S6 K, and survivin were diminished, while those of γH2AX, acetyl. histone H3, acetyl. histone H4, cleaved PARP, and cleaved caspase-3 were enhanced. In conclusion, these results demonstrate that SNX5422 has a cytotoxic activity in conjunction with alterations in the expression of hsp90 client proteins in ATC cells. Moreover, SNX5422 synergizes with HDAC inhibitors in induction of cytotoxicity accompanied by the suppression of PI3K/Akt/mTOR signaling and survivin, and the overexpression of DNA damage-related proteins in ATC cells. PMID:26219406

  11. Evaluation of Lentiviral-Mediated Expression of Sodium Iodide Symporter in Anaplastic Thyroid Cancer and the Efficacy of In Vivo Imaging and Therapy

    Directory of Open Access Journals (Sweden)

    Chien-Chih Ke

    2011-01-01

    Full Text Available Anaplastic thyroid carcinoma (ATC is one of the most deadly cancers. With intensive multimodalities of treatment, the survival remains low. ATC is not sensitive to 131I therapy due to loss of sodium iodide symporter (NIS gene expression. We have previously generated a stable human NIS-expressing ATC cell line, ARO, and the ability of iodide accumulation was restored. To make NIS-mediated gene therapy more applicable, this study aimed to establish a lentiviral system for transferring hNIS gene to cells and to evaluate the efficacy of in vitro and in vivo radioiodide accumulation for imaging and therapy. Lentivirus containing hNIS cDNA were produced to transduce ARO cells which do not concentrate iodide. Gene expression, cell function, radioiodide imaging and treatment were evaluated in vitro and in vivo. Results showed that the transduced cells were restored to express hNIS and accumulated higher amount of radioiodide than parental cells. Therapeutic dose of 131I effectively inhibited the tumor growth derived from transduced cells as compared to saline-treated mice. Our results suggest that the lentiviral system efficiently transferred and expressed hNIS gene in ATC cells. The transduced cells showed a promising result of tumor imaging and therapy.

  12. Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis

    Directory of Open Access Journals (Sweden)

    Walter Arancio

    2015-01-01

    Full Text Available It has been suggested that cancer stem cells (CSC may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2, in the control cell cycle (TP53, CCND1, and in mitochondrial activity (COX8A. The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated.

  13. 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

  14. 伴鳞样成分的甲状腺间变性癌临床病理分析%Clinicopathologic Analysis of Anaplastic Thyroid Carcinoma with Squamoid Cell Component

    Institute of Scientific and Technical Information of China (English)

    潘毅; 孙保存

    2011-01-01

    目的:探讨伴鳞样成分的甲状腺间变性癌(anaplastic thyroid carcinoma with squamoid cell component,ATC-SCC)的诊断、鉴别诊断及临床病理特征.方法:回顾性分析85例少见甲状腺肿瘤的临床病理资料,通过HE切片进行形态学观察,对5例ATC-SCC,6例甲状腺鳞状细胞癌(squamous cell carcinoma,SCC),8例甲状腺呈胸腺样分化癌(carcinoma showing thymus-like ele?ments,CASTLE)和2 例甲状腺降钙素阴性的神经内分泌肿瘤(calcitonin-negative neuroendocrine tumor of the thyroid gland,CNNETT)进行9项免疫组织化学染色,包括Cytokeratin(CK)、Vimentin(VM)、Chromogranin A(CgA)、Synaptophysin(SYN)、CD117、CD5、Calcitonin(CT)、Thyroglobulin(TG)和Thyroid transcription factor-1(TTF-1),并对结果进行分析.结果:5例ATC-SCC中,男性2例,女性3例;年龄41~79岁,平均年龄53.2岁;肿物位于左腺叶3例,右腺叶2例.临床表现为无痛性颈部肿物.肿物通常体积较大,质地硬实,与周围组织粘连.镜下可见肿瘤组织由梭形细胞、多形性巨细胞、破骨样细胞和鳞状上皮样细胞以不同比例混合而成,并可见胞浆红染的横纹肌样细胞及大片坏死.免疫组织化学染色显示5例ATC-SCC的肿瘤细胞CK和VM均阳性.鳞状上皮样细胞为主要成分时需要与SCC、CASTLE和CNNETT进行鉴别.结论:ATC-SCC多见于老年人,女性较多见,生长迅速,常扩展至甲状腺外累犯颈部软组织,预后非常差,手术和放化疗相结合是治疗ATC-SCC的基本原则.%Objective: To investigate the clinicopathologic features, diagnosis, and differential diagnosis of anaplastic thyroid carcinoma with squamoid cell component ( ATC-SCC ).Methods: The data of 85 cases with rare thyroid neoplasms were retrospectively analyzed.Morphological observation of the sections from all cases was conducted after H&E staining.Five cases of ATC-SCC, 6 cases of thyroid squamous cell carcinoma ( TSCC ), 8 cases of with thyroid carcinoma showing thymus

  15. Wild-type p53 enhances the cytotoxic effect of radionuclide gene therapy using sodium iodide symporter in a murine anaplastic thyroid cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yong Jin [Seoul National University College of Medicine, Department of Nuclear Medicine, Chongno-gu, Seoul (Korea); Seoul National University College of Medicine, Cancer Research Institute, Chongno-gu, Seoul (Korea); Seoul National University College of Medicine, Tumor Immunity Medical Research Center, Chongno-gu, Seoul (Korea); Korea Institute of Radiological and Medical Sciences, Molecular Imaging Research Center, Nowon-Gu, Seoul (Korea); Chung, June-Key [Seoul National University College of Medicine, Department of Nuclear Medicine, Chongno-gu, Seoul (Korea); Seoul National University College of Medicine, Cancer Research Institute, Chongno-gu, Seoul (Korea); Seoul National University College of Medicine, Tumor Immunity Medical Research Center, Chongno-gu, Seoul (Korea); Kang, Joo Hyun [Korea Institute of Radiological and Medical Sciences, Molecular Imaging Research Center, Nowon-Gu, Seoul (Korea); Jeong, Jae Min [Seoul National University College of Medicine, Department of Nuclear Medicine, Chongno-gu, Seoul (Korea); Seoul National University College of Medicine, Cancer Research Institute, Chongno-gu, Seoul (Korea); Lee, Dong Soo; Lee, Myung Chul [Seoul National University College of Medicine, Department of Nuclear Medicine, Chongno-gu, Seoul (Korea)

    2010-02-15

    To evaluate the role of p53 in radionuclide gene therapy, we investigated the cytotoxic effect of {sup 131}I and {sup 188}Re following cotransfection of the sodium iodide symporter (NIS) and wild-type p53 (wt-p53) genes into cancer cells. The NIS gene was transfected to human anaplastic thyroid carcinoma cells (ARO) expressing mutant p53 (mt-p53) using liposomes. The uptakes of {sup 125}I and {sup 188}Re were measured in the transfected (ARO-N) and wild-type cell lines (ARO). A recombinant adenovirus-5 vector containing a CMV promoter and wt-p53 cDNA, called Ad-p53, was established and transduced to ARO and ARO-N cells. After incubating cells with {sup 131}I and {sup 188}Re, the survival rate of each cell line was measured using a clonogenic assay. For radionuclide gene therapy in an animal model, Ad-p53 was injected directly into ARO and ARO-N tumours which were transplanted to nude mice. Two days later, {sup 188}Re or saline was injected intraperitoneally into the mice, and the tumours were measured using a calliper for 4 weeks. In ARO-N cells, the uptakes of {sup 125}I and {sup 188}Re were 505.16{+-}21.30 pmol/10{sup 6} cells and 13,875.20{+-}504.85 cpm/10{sup 6} cells at 30 min, respectively. There was no difference between the survival rates of ARO cells and ARO-N cells after incubation with {sup 131}I or {sup 188}Re. When Ad-p53 was transduced to ARO-N cells, the survival rate of wt-p53-expressing ARO-N cells incubated with {sup 131}I (18.5 MBq/5 ml) and {sup 188}Re (18.5 MBq/5 ml) decreased to 48.8{+-}18.4% and 32.6{+-}23.5%, respectively. In the nude mice experiment, ARO and ARO-N tumours gradually grew up to six to eight times larger than the initial volume. ARO and ARO-N tumours transduced with Ad-p53 continued to grow. However, the ARO-N tumours treated with Ad-p53 and 185 MBq of {sup 188}Re regressed to 20% of the initial volume. Growth of ARO-N tumour treated with {sup 131}I or {sup 188}Re was significantly inhibited by Ad-p53 transduction in vivo as

  16. 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.

  17. 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

    Directory of Open Access Journals (Sweden)

    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.

  18. Improved Correlation of the Neuropathologic Classification According to Adapted World Health Organization Classification and Outcome After Radiotherapy in Patients With Atypical and Anaplastic Meningiomas

    International Nuclear Information System (INIS)

    Purpose: To evaluate the correlation between the 1993 and 2000/2007 World Health Organization (WHO) classification with the outcome in patients with high-grade meningiomas. Patients and Methods: Between 1985 and 2004, 73 patients diagnosed with atypical or anaplastic meningiomas were treated with radiotherapy. Sections from the paraffin-embedded tumor material from 66 patients (90%) from 13 different pathology departments were re-evaluated according to the first revised WHO classification from 1993 and the revised classifications from 2000/2007. In 4 cases, the initial diagnosis meningioma was not reproducible (5%). Therefore, 62 patients with meningiomas were analyzed. Results: All 62 tumors were reclassified according to the 1993 and 2000/2007 WHO classification systems. Using the 1993 system, 7 patients were diagnosed with WHO grade I meningioma (11%), 23 with WHO grade II (37%), and 32 with WHO grade III meningioma (52%). After scoring using the 2000/2007 system, we found 17 WHO grade I meningiomas (27%), 32 WHO grade II meningiomas (52%), and 13 WHO grade III meningiomas (21%). According to the 1993 classification, the difference in overall survival was not statistically significant among the histologic subgroups (p = .96). Using the 2000/2007 WHO classifications, the difference in overall survival became significant (p = .02). Of the 62 reclassified patients 29 developed tumor progression (47%). No difference in progression-free survival was observed among the histologic subgroups (p = .44). After grading according to the 2000/2007 WHO classifications, significant differences in progression-free survival were observed among the three histologic groups (p = .005). Conclusion: The new 2000/2007 WHO classification for meningiomas showed an improved correlation between the histologic grade and outcome. This classification therefore provides a useful basis to determine the postoperative indication for radiotherapy. According to our results, a comparison of the

  19. 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

  20. Targeting Transforming Growth Factor-Beta1 (TGF-β1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFκkB-PUMA Signaling.

    Science.gov (United States)

    Yin, Qiang; Liu, Shan; Dong, Anbing; Mi, Xiufang; Hao, Fengyun; Zhang, Kejun

    2016-01-01

    BACKGROUND The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in promoting tumor growth. TGF-β1was found to be overexpressed in anaplastic thyroid cancer (ATC). We therefore tested our hypothesis that targeting TGF-β1 inhibits tumorigenesis of ATC cells. MATERIAL AND METHODS Effects of TGF-β1 stimulation or TGF-β1 inhibition by small interfering RNA (TGF-β1siRNA) on proliferation, colony formation, and apoptosis in 8505C cells in vitro was detected using siRNAs and inhibitors to examine the TGF-β1 signaling pathway. A subcutaneously implanted tumor model of 8505C cells in nude mice was used to assess the effects of TGF-β1 inhibition on tumorigenesis development. RESULTS TGF-β1siRNAs decreased proliferation and colony formation, and increased apoptosis in 8505C cells in vitro and inhibited tumor growth in vivo. TGF-β1siRNA inhibited phosphorylation ERK1/2 (pERK1/2) and increased p65-dependant PUMA mRNA and protein expression. Knockdown of p65 or PUMA by siRNA reduced TGF-β1siRNA-induced apoptosis, as well as caspase-3 and PARP activation. Upregulation of p65 or PUMA expression by TGF-β1siRNA requires pERK1/2 inhibition. TGF-β1 shRNA inhibited tumor growth in vivo. CONCLUSIONS Therapies targeting the TGF-β1 pathway may be more effective to prevent primary tumor formation. The ability of this therapy to decrease tumorigenesis may be related to ERK1/2/NF-κB/PUMA signaling. PMID:27356491

  1. Exploratory evaluation of two-dimensional and three-dimensional methods of FDG PET quantification in pediatric anaplastic astrocytoma: a report from the Pediatric Brain Tumor Consortium (PBTC)

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Gethin; Treves, S. Ted [Harvard Medical School, Joint Program in Nuclear Medicine, Children' s Hospital Boston, Boston, MA (United States); Fahey, Frederic H. [Harvard Medical School, Joint Program in Nuclear Medicine, Children' s Hospital Boston, Boston, MA (United States); Harvard Medical School, Division of Nuclear Medicine, Department of Radiology, Children' s Hospital Boston, Boston, MA (United States); Kocak, Mehmet; Boyett, James M.; Kun, Larry E. [St Jude Children' s Research Hospital, Memphis, TN (United States); Pollack, Ian F. [Children' s Hospital Pittsburgh, Pittsburgh, PA (United States); Young Poussaint, Tina [Harvard Medical School, Division of Neuroradiology, Department of Radiology, Children' s Hospital Boston, Boston, MA (United States)

    2008-09-15

    The rationale of this study was to investigate the feasibility of three-dimensional (3D) methods to analyze {sup 18}F-fluoro-deoxy-glucose (FDG) uptake in children with anaplastic astrocytoma (AA) in a multi-institutional trial, to compare 3D and two-dimensional (2D) methods and explore data associations with progression-free survival (PFS). 3D tumor volumes from pretreatment MR images (fluid attenuation inversion recovery and postgadolinium) of children with recurrent AA on a phase I trial of imatinib mesylate were coregistered to FDG positron emission tomography (PET) images. PET data were normalized. Four metrics were defined: the maximum ratio (maximum pixel value within the 3D tumor volume, normalized), the total ratio (cumulative pixel values within the tumor volume, normalized) and tumor mean ratio (total pixel value divided by volume, normalized). 2D analysis methods were compared. Cox proportional hazards models were used to estimate the association between these methods and PFS. Strongest correlations between 2D and 3D methods were with analyses using postcontrast T1 images for volume of interest (VOI). The analyses suggest 3D maximum tumor and mean tumor ratios, whether normalized by gray matter or white matter, were associated with PFS. This study of a series of pretreatment AA patients suggests that 3D PET methods using VOIs based on postcontrast T1 correlate with 2D methods and are related to PFS. These methods yield an estimate of metabolically active tumor burden and may add prognostic information after tumor grade is determined. Future rigorous multi-institutional protocols with larger numbers of patients will be required for validation. (orig.)

  2. Anaplastic lymphoma kinase gene rearrangements in patients with advanced-stage non-small-cell lung cancer: CT characteristics and response to chemotherapy

    International Nuclear Information System (INIS)

    Few articles have been published on the imaging findings of anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). To investigate the radiological findings of ALK-positive NSCLC in the advanced stage, CT scans were examined. In addition, the response to chemotherapy was evaluated. Of the 36 patients with ALK-rearranged NSCLC, a mass and a nodule were identified in 17 (47.2%) and 16 (44.4%), respectively, indicating that more than 40% had a small-sized tumor. Overall, 31 (86.1%) patients had lymphadenopathy, seven (19.4%) had extranodal lymph node invasion, and three (8.3%) had lymphangitis. A pleural effusion was seen in 15 patients (41.7%). All but one patient had no ground-glass opacity (GGO) lesions, indicating that most ALK-positive tumors showed a solid growth pattern without GGO on CT. Twenty were evaluable for response to chemotherapy; 10 (50.0%) had a partial response (PR), nine (45.0%) had stable disease (SD), and one (5.0%) had progressive disease (PD) with first-line chemotherapy. With second-line chemotherapy, five (26.3%) had PR, 11 (57.9%) had SD, and three (15.8%) had PD. The five patients with PR were all treated by using crizotinib. Time to progression was 8.2 months with first-line chemotherapy, and 6.0 months with second-line chemotherapy. Advanced-stage ALK-positive tumors have a relatively aggressive phenotype, which cannot be inferred from the size of the tumor alone. ALK-positive patients have a good response to first-line cytotoxic drugs and to crizotinib as second-line therapy, but a relatively poor response to cytotoxic drugs as second-line therapy

  3. 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.

  4. O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma

    Science.gov (United States)

    Bobola, Michael S.; Alnoor, Mohammad; Chen, John Y.-S.; Kolstoe, Douglas D.; Silbergeld, Daniel L.; Rostomily, Robert C.; Blank, A.; Chamberlain, Marc C.; Silber, John R.

    2014-01-01

    Background CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies. Methods We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP). Results Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P ≤ 0.001) and continuous (P ≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P ≤ 0.005) and longer PFS (P ≤ 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P ≤ 0.005), and among unmethylated tumors with less than median activity (P ≤ 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs. Conclusions Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas. General significance MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status. PMID:25558448

  5. Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Hwanjeong [Department of Nuclear Medicine, College of Medicine, Wonkwang University, Iksan, Jellabuk-do 570-711 (Korea, Republic of); Kim, Yu-Ri [Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Kim, Ki-Nam [Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Choe, Jae-Gol [Department of Nuclear Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Chung, June-Key [Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul 110-774 (Korea, Republic of); Cancer Research Institute, College of Medicine, Seoul National University, Seoul 110-774 (Korea, Republic of); Kim, Meyoung-Kon [Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of)]. E-mail: jerrykim@korea.ac.kr

    2006-10-15

    The plasma membrane glycoprotein sodium/iodide symporter (NIS) is crucial for thyroid hormone biosynthesis and mediates the iodide uptake of thyrocytes. It has been shown that retinoic acid (RA) alters NIS gene expression in thyroid carcinoma lines and stimulates their iodide uptake. Here, we generated an ARO human thyroidal cancer cell line that expresses the NIS gene (ARO-NIS) and found that its baseline {sup 125}I uptake was threefold higher than that of its parental ARO cells. However, a 1-{mu}M all-trans retinoic acid (tRA) treatment significantly increased this {sup 125}I uptake up to approximately {approx}6.5-fold on Day 3. tRA also elevated NIS mRNA expression in ARO-NIS cells, with peaks of expression being observed on Day 3. To investigate the underlying genomic mechanisms involved in these tRA-induced phenotypic changes, we subjected tRA-treated and untreated ARO-NIS cells to cDNA microarray analysis. Of 1152, genes spotted onto the microarray membrane, 18 were up-regulated (z ratio>2.0) and 33 were down-regulated (z ratio<-2.0) in ARO-NIS cells after 3 days of tRA treatment. More specifically, tRA increased the expression of BCL3, CSRP3, v-fos, and CDK5 genes and decreased the expression of the FGF12 and IGFBP6 genes. Thus, tRA treatment of human anaplastic thyroid carcinoma cells stably expressing the NIS gene significantly elevates their NIS-mediated radioiodine uptake and alters the expression of many genes involved in cell growth and cellular differentiation. Therefore, tRA treatment and NIS gene transfection are potential tools for the diagnosis and treatment of thyroid cancer.

  6. Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: a report of radiation therapy oncology group 83-02

    International Nuclear Information System (INIS)

    Purpose: Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial. Methods and Materials: One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyper fractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment. Results: The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL (p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival. Conclusion: The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis

  7. Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss, genomic instability, and angiogenic gene expression

    Science.gov (United States)

    Reyes-Botero, German; Dehais, Caroline; Idbaih, Ahmed; Martin-Duverneuil, Nadine; Lahutte, Marion; Carpentier, Catherine; Letouzé, Eric; Chinot, Olivier; Loiseau, Hugues; Honnorat, Jerome; Ramirez, Carole; Moyal, Elisabeth; Figarella-Branger, Dominique; Ducray, François; Desenclos, Christine; Sevestre, Henri; Menei, Philippe; Michalak, Sophie; Al Nader, Edmond; Godard, Joel; Viennet, Gabriel; Carpentier, Antoine; Eimer, Sandrine; Dam-Hieu, Phong; Quintin-Roué, Isabelle; Guillamo, Jean-Sebastien; Lechapt-Zalcman, Emmanuelle; Kemeny, Jean-Louis; Verrelle, Pierre; Faillot, Thierry; Gaultier, Claude; Tortel, Marie Christine; Christov, Christo; Le Guerinel, Caroline; Aubriot-Lorton, Marie-Hélène; Ghiringhelli, Francois; Berger, François; Lacroix, Catherine; Parker, Fabrice; Dubois, François; Maurage, Claude-Alain; Gueye, Edouard-Marcel; Labrousse, Francois; Jouvet, Anne; Bauchet, Luc; Rigau, Valérie; Beauchesne, Patrick; Vignaud, Jean-Michel; Campone, Mario; Loussouarn, Delphine; Fontaine, Denys; Vandenbos, Fanny; Campello, Chantal; Roger, Pascal; Fesneau, Melanie; Heitzmann, Anne; Delattre, Jean-Yves; Elouadhani, Selma; Mokhtari, Karima; Polivka, Marc; Ricard, Damien; Levillain, Pierre-Marie; Wager, Michel; Colin, Philippe; Diebold, Marie-Danièle; Chiforeanu, Dan; Vauleon, Elodie; Langlois, Olivier; Laquerriere, Annie; Motsuo Fotso, Marie Janette; Peoc'h, Michel; Andraud, Marie; Mouton, Servane; Chenard, Marie-Pierre; Noel, Georges; Desse, Nicolas; Soulard, Raoulin; Amiel-Benouaich, Alexandra; Uro-Coste, Emmanuelle; Dhermain, Frederic

    2014-01-01

    Background The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). Methods The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. Results Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. Conclusion In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume. PMID:24353325

  8. 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.

  9. 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

  10. Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines: final report of RTOG 86-12, phase I-II study

    International Nuclear Information System (INIS)

    Purpose: This study evaluated the toxicity and tumor efficacy of the halopyrimidine IUdR as a chemical modifier of radiation response in patients with malignant glioma. The preliminary results published in 1993 demonstrated no real advantage in the group of patients with glioblastoma. However, a benefit appeared to be evolving in the group of patients with Anaplastic Astrocytoma (AA). We are now presenting the results on the long-term follow-up of patients with AA. Methods and Materials: Between August 1987 and October 1991, 79 patients were entered in a prospective study with newly diagnosed malignant glioma. Twenty-one of 79 were AA. The study was designed to have a fixed dose of radiation consisting of 60.16 Gy in 32 fractions in 6.5 weeks but varying the dose schedule of IUdR, delivered in a continuous intravenous infusion of long (96 h) or short (48 and 24 h) duration, every week for the 6.5 weeks of radiation treatment. Results: The last AA patient was entered in March 1991. Ninety-five percent of the AA patients were under 59 years of age and 86% had a Karnofsky score 80. Thirty-eight percent had a tumor diameter of less than 5 cm and 52% had a tumor diameter between 5-10 cm. Seventy-six percent had partial or total tumor resection. The toxicity of this treatment was acceptable and has already been published elsewhere. At the time of this report, 14 out of 21 patients with AA are dead. The median survival, calculated from the Kaplan-Meier, is 3.2 years. Thirty-three percent of the patients have survived 5 years. These results compare favorably with the best results reported in the literature with postoperative external radiation plus chemotherapy, median survival time (MST) of 3 years, and previous Radiation Therapy Oncology Group (RTOG) experience with radiation alone, MST of 2 years. Conclusions: Our findings in patients with AA corroborate the improved therapeutic results published recently when combining external radiation with 'long' infusion of i

  11. {sup 18}F-FDG PET/CT-Negative Recurrent High-Grade Anaplastic Astrocytoma Detected by {sup 18}F-FDOPA PET-CT

    Energy Technology Data Exchange (ETDEWEB)

    Karunanithi, Sellam; Singh, Harmandeep; Sharma, Punit; Gupta, Deepak Kumar; Bal, Chandrasekhar [All India Institute of Medical Sciences, New Delhi (India)

    2013-12-15

    A 37-year-old woman with grade 3 anaplastic astrocytoma (AA) of the left frontal lobe, underwent surgical excision, chemotherapy and external beam radiation therapy in 2004. After being in remission for 5 years, recurrence was suspected clinically when she presented with seizures. The result of contrast-enhanced magnetic resonance imaging (MRI) was equivocal for recurrence and radiation necrosis (not available ). The patient was then referred for {sup 18}F-fluorodeoxyglucose ({sup 18}F-FDG) positron emission tomography-computed tomography (PET-CT), as the initial primary tumour was high grade in nature. {sup 18}F-FDG PET-CT was negative for recurrence and demonstrated only post-operative changes in the left frontal region (Fig. 1a, b, arrow). Due to strong clinical suspicion, 3,4-dihydroxy-6-{sup 18}F-fluoro-L-phenylalanine ({sup 18}F-FDOPA) PET-CT was done, 5 days after {sup 18}F-FDG PET-CT. The study revealed an {sup 18}F-FDOPA-avid mass lesion in the left frontal region (Fig. 1c, d, arrow), thereby confirming the presence of recurrent disease. The patient underwent surgical resection of the mass, and it was confirmed by histopathology as grade 3 AA. However, after a short asymptomatic period of 4 months the patient became symptomatic again. Follow-up MRI after 6 months of surgery revealed presence of ipsilateral and contralateral multifocal contrast enhancing recurrent mass lesions (Fig. 1e, f, arrow), suggesting the progression of disease. The patient was started on temozolamide but she died after 8 months' follow-up. Though MRI is routinely used in assessment of brain tumours, its ability to differentiate between treatment-induced changes and residual or recurrent tumour is limited. {sup 18}F-FDG PET was the first tracer used for assessment of brain tumours; however, it has a low tumour-to-background ratio in brain, limiting its utility. {sup 18}F-FDG uptake correlates with tumour grade, with high-grade gliomas (grades III and IV) showing higher uptake

  12. Large ethics.

    Science.gov (United States)

    Chambers, David W

    2008-01-01

    This essay presents an alternative to the traditional view that ethics means judging individual behavior against standards of right and wrong. Instead, ethics is understood as creating ethical communities through the promises we make to each other. The "aim" of ethics is to demonstrate in our own behavior a credible willingness to work to create a mutually better world. The "game" of ethics then becomes searching for strategies that overlap with others' strategies so that we are all better for intending to act on a basis of reciprocal trust. This is a difficult process because we have partial, simultaneous, shifting, and inconsistent views of the world. But despite the reality that we each "frame" ethics in personal terms, it is still possible to create sufficient common understanding to prosper together. Large ethics does not make it a prerequisite for moral behavior that everyone adheres to a universally agreed set of ethical principles; all that is necessary is sufficient overlap in commitment to searching for better alternatives.

  13. 儿童间变型大细胞非霍奇金淋巴瘤临床特点及疗效分析%Clinical features and therapeutic evaluation in children with anaplastic large cell non-Hodgkin's lymphoma

    Institute of Scientific and Technical Information of China (English)

    梁爱斌; 谢晓恬; 石苇; 邵越霞; 刘兴元; 傅晓燕; 王耀平

    2001-01-01

    为探讨儿童间变型大细胞非霍奇金淋巴瘤(CALCL)临床特点、方案选择及疗效分析,对4例儿童间变型大细胞性非霍奇金淋巴瘤患儿进行临床诊断、免疫分型、治疗、随访及疗效总结。结果:4例CALCL患儿中,CD30+3例,T细胞型3例,B细胞型1例;部分缓解1例,完全缓解3例,其中1例CR 7月后脑膜复发。结论:间变型大细胞淋巴瘤(ALCL)为非霍奇金淋巴瘤的一种特殊类型,临床表现多样,与其他恶性淋巴瘤相比恶性程度稍低,较少累及骨髓,预后较好,但与免疫分型及临床分期密切相关。

  14. 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.

  15. Role of Evaluating MGMT Status and 1p36 Deletion in Radiosurgery-Induced Anaplastic Ependymoma That Rapidly and Completely Resolved by Temozolomide Alone: Case Report and Review of the Literature.

    Science.gov (United States)

    Hirono, Seiichiro; Iwadate, Yasuo; Kambe, Michiyo; Hiwasa, Takaki; Takiguchi, Masaki; Nakatani, Yukio; Saeki, Naokatsu

    2015-07-01

    Stereotactic gamma knife surgery (GKS)-induced brain tumors are extremely rare, and no ependymal tumors induced by GKS have been reported. Therefore, little is known about their clinical, pathologic, and genetic features. In addition, a regimen of adjuvant chemotherapy for anaplastic ependymoma (AE) has not been established. A 77-year-old man presented with a gait disturbance and left-side cerebellar ataxia more than 19 years after GKS performed for a cerebellar arteriovenous malformation. Imaging studies demonstrated an enhancing mass in the irradiated field with signs of intraventricular dissemination. Surgical resection confirmed the diagnosis of AE. Temozolomide (TMZ) was administrated postoperatively because the methylated promoter region of O(6)-methylguanine-DNA methyltransferase (MGMT) and 1p36 deletion were observed. Surprisingly, images 16 days after TMZ initiation demonstrated a complete resolution of the residual tumor that was maintained after three cycles of TMZ. This first case report of GKS-induced AE emphasizes the importance of genetic evaluation of MGMT and chromosomal deletion of 1p36 that are not commonly performed in primary ependymal tumors. In addition, it is speculated that a GKS-induced tumor may have a different genetic background compared with the primary tumor because the pathogenesis of the tumors differed. PMID:26251808

  16. Redifferentiation and induction of tumor suppressors miR-122 and miR-375 by the PAX8/PPARγ fusion protein inhibits anaplastic thyroid cancer: a novel therapeutic strategy.

    Science.gov (United States)

    Reddi, H V; Driscoll, C B; Madde, P; Milosevic, D; Hurley, R M; McDonough, S J; Hallanger-Johnson, J; McIver, B; Eberhardt, N L

    2013-05-01

    Anaplastic thyroid cancer (ATC) is an aggressive, fatal disease unresponsive to traditional therapies, generating a need to develop effective therapies. The PAX8/PPARγ fusion protein (PPFP) has been shown to favorably modulate tumor growth in follicular thyroid cancer, prompting our evaluation of its efficacy to inhibit ATC cell and tumor growth in vitro and in vivo. PPFP was constitutively expressed in five ATC cell lines: BHT-101, FRO, C-643, KTC-2 and KTC-3, and inhibited cell growth in four of five cell lines and xenograft tumor growth in four of four cell lines. PPFP-mediated growth inhibition involved multiple mechanisms, including upregulation of miR-122 and miR-375, associated with decreased angiogenesis and AKT pathway inactivation, respectively. Also, PPFP expression resulted in marked increase of thyroid-specific marker transcripts, including PAX8, thyroid peroxidase (TPO), sodium iodide symporter (NIS) and thyroglobulin, to varying degrees by activating their respective promoters, suggesting that PPFP induced cellular redifferentiation. Functional studies demonstrate that increased NIS messenger RNA is not associated with increased 125I uptake. However, ectopic expression of wild-type NIS-induced perchlorate-sensitive iodine uptake, suggesting that endogenous NIS in ATC cell lines is defective. As current treatment for ATC is only palliative, overexpression of PPFP may offer a novel therapeutic strategy for the treatment of ATC. PMID:23598436

  17. Large bowel resection - slideshow

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/presentations/100089.htm Large bowel resection - Series To use the sharing features ... 6 out of 6 Normal anatomy Overview The large bowel [large intestine or the colon] is part ...

  18. Large bowel resection - discharge

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000151.htm Large bowel resection - discharge To use the sharing features ... surgery to remove all or part of your large intestine (large bowel). You may also have had ...

  19. Small & Large Intestine

    Science.gov (United States)

    ... the large intestine produces no digestive enzymes. Chemical digestion is completed in the small intestine before the chyme reaches the large intestine. Functions of the large intestine include the absorption of water and electrolytes and the elimination of ...

  20. The role of temozolomide in the management of patients with newly diagnosed anaplastic astrocytoma: a comparison of survival in the era prior to and following the availability of temozolomide

    Science.gov (United States)

    Abuali, Inas; Ye, Xiaobu; Lu, Yao; Grossman, Stuart A.

    2016-01-01

    Adding temozolomide (TMZ) to radiation for patients with newly-diagnosed anaplastic astrocytomas (AAs) is common clinical practice despite the lack of prospective studies demonstrating a survival advantage. Two retrospective studies, each with methodologic limitations, provide conflicting advice regarding treatment. This single-institution retrospective study was conducted to determine survival trends in patients with AA. All patients ≥18 years with newly-diagnosed AA treated at Johns Hopkins from 1995 to 2012 were included. As we incorporated TMZ into high-grade glioma treatment regimens in 2004, patients were divided into pre-2004 and post-2004 groups for analysis. Clinical, radiographic, and pathologic data were collected. Median overall survival (OS) was calculated using Kaplan–Meier estimates. A total of 196 patients were identified; 74 pre-2004 and 122 post-2004; mean age 47 ± 15 years; 57 % male; 87 % white, 69 % surgical debulking. Mean RT dose 5676 + 746 cGy; duration of concurrent chemoradiation 5.8 ± 0.8 weeks; and mean adjuvant chemotherapy 4.3 + 2.8 cycles. Baseline prognostic factors did not differ between groups. Chemotherapy was administered to 12 % of patients pre-2004 (TMZ = 1, procarbazine, lomustine and vincristine = 2, carmustine wafer = 6) and 94 % post-2004 (TMZ in all, p < 0.001). Median OS was 32 months (95 % CI 23–43). Survival was longer in the post-2004 cohort (37 mo, 24–64) than pre-2004 (27 mo, 19–40; HR 0.75, 0.53–1.06, p = 0.11). Multivariate analysis controlling for age, Karnofsky performance status, and extent of resection revealed a 36 % reduced risk of death (HR 0.64, 0.44–0.91, p = 0.015) in patients treated post-2004. This retrospective review found survival in newly diagnosed patients with AA improved with the addition of temozolomide to standard radiation. Until prospective randomized phase III data are available, these data support the practice of incorporating TMZ in the management of newly-diagnosed AA

  1. 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.

  2. Large Neighborhood Search

    DEFF Research Database (Denmark)

    Pisinger, David; Røpke, Stefan

    2010-01-01

    Heuristics based on large neighborhood search have recently shown outstanding results in solving various transportation and scheduling problems. Large neighborhood search methods explore a complex neighborhood by use of heuristics. Using large neighborhoods makes it possible to find better...... candidate solutions in each iteration and hence traverse a more promising search path. Starting from the large neighborhood search method,we give an overview of very large scale neighborhood search methods and discuss recent variants and extensions like variable depth search and adaptive large neighborhood...... search....

  3. Large Pelagics Intercept Survey

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Large Pelagics Intercept Survey (LPIS) is a dockside survey of private and charterboat captains who have just completed fishing trips directed at large pelagic...

  4. Fontanelles - excessively large

    Science.gov (United States)

    ... to Expect at Your Office Visit An enlarged large fontanelle is almost always found by the health ... head may be done. Alternative Names Soft spot - large; Newborn care - enlarged fontanelle; Neonatal care - enlarged fontanelle ...

  5. Large myelomeningocele repair

    OpenAIRE

    Farideh Nejat; Nima Baradaran; Mostafa El Khashab

    2011-01-01

    Background: Wound closure is accomplished in most cases of myelomeningocele (MMC) by undermining of the skin edges surrounding the defect. However, large defects cannot be closed reliably by this simple technique. Due to the technical challenge associated with large MMC, surgeons have devised different methods for repairing large defects. In this paper, we report our experience of managing large defects, which we believe bears a direct relationship to decrease the incidence of wound complicat...

  6. Intracranial metastasis of spinal intramedullary anaplastic astrocytoma

    OpenAIRE

    Kataria, Rashim; Bhasme, Vishal; Chopra, Sanjeev; V D Sinha; Singhvi, Shashi

    2011-01-01

    Meningeal spread of spinal intramedullary astrocytoma into the cranium is rare. Only few case reports are available so far in the literature. We report a case of intramedullary high grade astrocytoma of the conus, developing intracranial metastasis after three months of partial excision of the spinal mass. The need for radical surgery, entire neuroaxis radiation, and adjuvant chemotherapy is suggested in the management of malignant spinal cord astrocytoma to prevent dissemination.

  7. Incidence and patterns of ALK FISH abnormalities seen in a large unselected series of lung carcinomas

    Directory of Open Access Journals (Sweden)

    Dai Zunyan

    2012-12-01

    Full Text Available Abstract Background Anaplastic lymphoma receptor tyrosine kinase (ALK gene rearrangements have been reported in 2-13% of patients with non-small cell lung cancer (NSCLC. Patients with ALK rearrangements do not respond to EGFR-specific tyrosine kinase inhibitors (TKIs; however, they do benefit from small molecule inhibitors targeting ALK. Results In this study, fluorescence in situ hybridization (FISH using a break-apart probe for the ALK gene was performed on formalin fixed paraffin-embedded tissue to determine the incidence of ALK rearrangements and hybridization patterns in a large unselected cohort of 1387 patients with a referred diagnosis of non-small cell lung cancer (1011 of these patients had a histologic diagnosis of adenocarcinoma. The abnormal FISH signal patterns varied from a single split signal to complex patterns. Among 49 abnormal samples (49/1387, 3.5%, 32 had 1 to 3 split signals. Fifteen samples had deletions of the green 5′ end of the ALK signal, and 1 of these 15 samples showed amplification of the orange 3′ end of the ALK signal. Two patients showed a deletion of the 3′ALK signal. Thirty eight of these 49 samples (38/1011, 3.7% were among the 1011 patients with confirmed adenocarcinoma. Five of 8 patients with ALK rearrangements detected by FISH were confirmed to have EML4-ALK fusions by multiplex RT-PCR. Among the 45 ALK-rearranged samples tested, only 1 EGFR mutation (T790M was detected. Two KRAS mutations were detected among 24 ALK-rearranged samples tested. Conclusions In a large unselected series, the frequency of ALK gene rearrangement detected by FISH was approximately 3.5% of lung carcinoma, and 3.7% of patients with lung adenocarcinoma, with variant signal patterns frequently detected. Rare cases with coexisting KRAS and EGFR mutations were seen.

  8. LARGE BUILDING RADON MANUAL

    Science.gov (United States)

    The report summarizes information on how bilding systems -- especially the heating, ventilating, and air-conditioning (HVAC) system -- inclurence radon entry into large buildings and can be used to mitigate radon problems. It addresses the fundamentals of large building HVAC syst...

  9. Large N Scalars

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2016-01-01

    We construct effective Lagrangians, and corresponding counting schemes, valid to describe the dynamics of the lowest lying large N stable massive composite state emerging in strongly coupled theories. The large N counting rules can now be employed when computing quantum corrections via an effective...... at the electroweak scale. To illustrate the formalism we consider the possibility that the Higgs emerges as: the lightest glueball of a new composite theory; the large N scalar meson in models of dynamical electroweak symmetry breaking; the large N pseudodilaton useful also for models of near-conformal dynamics....... For each of these realisations we determine the leading N corrections to the electroweak precision parameters. The results nicely elucidate the underlying large N dynamics and can be used to confront first principle lattice results featuring composite scalars with a systematic effective approach....

  10. Adaptive Large Neighbourhood Search

    DEFF Research Database (Denmark)

    Røpke, Stefan

    Large neighborhood search is a metaheuristic that has gained popularity in recent years. The heuristic repeatedly moves from solution to solution by first partially destroying the solution and then repairing it. The best solution observed during this search is presented as the final solution....... This tutorial introduces the large neighborhood search metaheuristic and the variant adaptive large neighborhood search that dynamically tunes parameters of the heuristic while it is running. Both heuristics belong to a broader class of heuristics that are searching a solution space using very large...... neighborhoods. The tutorial also present applications of the adaptive large neighborhood search, mostly related to vehicle routing problems for which the heuristic has been extremely successful. We discuss how the heuristic can be parallelized and thereby take advantage of modern desktop computers...

  11. Large Pelagics Biological Survey

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Large Pelagics Biological Survey (LPBS) collects additional length and weight information and body parts such as otoliths, caudal vertebrae, dorsal spines, and...

  12. Large Customers (DR Sellers)

    Energy Technology Data Exchange (ETDEWEB)

    Kiliccot, Sila [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2011-10-25

    State of the large customers for demand response integration of solar and wind into electric grid; openADR; CAISO; DR as a pseudo generation; commercial and industrial DR strategies; California regulations

  13. Large whale incident database

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Large whale stranding, death, ship strike and entanglement incidents are all recorded to monitor the health of each population and track anthropogenic factors that...

  14. Large intestine (colon) (image)

    Science.gov (United States)

    ... portion of the digestive system most responsible for absorption of water from the indigestible residue of food. The ileocecal valve of the ileum (small intestine) passes material into the large intestine at the ...

  15. Large Pelagics Telephone Survey

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Large Pelagics Telephone Survey (LPTS) collects fishing effort information directly from captains holding Highly Migratory Species (HMS) permits (required by...

  16. Very large graphs

    OpenAIRE

    Lovasz, Laszlo

    2009-01-01

    In the last decade it became apparent that a large number of the most interesting structures and phenomena of the world can be described by networks: separable elements, with connections (or interactions) between certain pairs of them. These huge networks pose exciting challenges for the mathematician. Graph Theory (the mathematical theory of networks) faces novel, unconventional problems: these very large networks (like the Internet) are never completely known, in most cases they are not eve...

  17. 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

  18. 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

  19. Large electrostatic accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Jones, C.M.

    1984-01-01

    The increasing importance of energetic heavy ion beams in the study of atomic physics, nuclear physics, and materials science has partially or wholly motivated the construction of a new generation of large electrostatic accelerators designed to operate at terminal potentials of 20 MV or above. In this paper, the author briefly discusses the status of these new accelerators and also discusses several recent technological advances which may be expected to further improve their performance. The paper is divided into four parts: (1) a discussion of the motivation for the construction of large electrostatic accelerators, (2) a description and discussion of several large electrostatic accelerators which have been recently completed or are under construction, (3) a description of several recent innovations which may be expected to improve the performance of large electrostatic accelerators in the future, and (4) a description of an innovative new large electrostatic accelerator whose construction is scheduled to begin next year. Due to time and space constraints, discussion is restricted to consideration of only tandem accelerators.

  20. Large-Scale Disasters

    Science.gov (United States)

    Gad-El-Hak, Mohamed

    "Extreme" events - including climatic events, such as hurricanes, tornadoes, and drought - can cause massive disruption to society, including large death tolls and property damage in the billions of dollars. Events in recent years have shown the importance of being prepared and that countries need to work together to help alleviate the resulting pain and suffering. This volume presents a review of the broad research field of large-scale disasters. It establishes a common framework for predicting, controlling and managing both manmade and natural disasters. There is a particular focus on events caused by weather and climate change. Other topics include air pollution, tsunamis, disaster modeling, the use of remote sensing and the logistics of disaster management. It will appeal to scientists, engineers, first responders and health-care professionals, in addition to graduate students and researchers who have an interest in the prediction, prevention or mitigation of large-scale disasters.

  1. Dynamic of large reflectors

    Science.gov (United States)

    Picard, P.; Dauviau, C.; Lefebvre, J. D.; Garnier, C.; Truchi, C.

    1991-10-01

    Work in the field of the unfurlable mesh reflectors as part of the dynamic of large reflectors project is presented. These studies use the unfurlable reflector design developed since 1983: gilded molybdenum reflective mesh supported by a deployable truss. From this strong background two specific critical points are studied: the deployment phase, where, for a deployment test, the test measurements are correlated with dynamic software predictions and the deployment bench chosen uses a 0 g compensation device by helium balloons; the antenna deployed configuration, where the interaction between a large structure and the attitude and orbit control subsystem is analyzed.

  2. Developing Large Web Applications

    CERN Document Server

    Loudon, Kyle

    2010-01-01

    How do you create a mission-critical site that provides exceptional performance while remaining flexible, adaptable, and reliable 24/7? Written by the manager of a UI group at Yahoo!, Developing Large Web Applications offers practical steps for building rock-solid applications that remain effective even as you add features, functions, and users. You'll learn how to develop large web applications with the extreme precision required for other types of software. Avoid common coding and maintenance headaches as small websites add more pages, more code, and more programmersGet comprehensive soluti

  3. Large electromagnetic pumps. [LMFBR

    Energy Technology Data Exchange (ETDEWEB)

    Kilman, G.B.

    1976-01-01

    The development of large electromagnetic pumps for the liquid metal heat transfer systems of fission reactors has progressed for a number of years. Such pumps are now planned for fusion reactors and solar plants as well. The Einstein-Szilard (annular) pump has been selected as the preferred configuration. Some of the reasons that electromagnetic pumps may be preferred over mechanical pumps and why the annular configuration was selected are discussed. A detailed electromagnetic analysis of the annular pump, based on slug flow, is presented. The analysis is then used to explore the implications of large size and power on considerations of electromagnetic skin effect, geometric skin effect and the cylindrical geometry.

  4. LARGE SCALE GLAZED

    DEFF Research Database (Denmark)

    Bache, Anja Margrethe

    2010-01-01

    IN NEW TYPES OF LARGE SCALE AND VERY THIN, GLAZED CONCRETE FAÇADES IN BUILDING. IF SUCH ARE INTRODUCED IN AN ARCHITECTURAL CONTEXT THEY WILL HAVE A DISTINCTIVE IMPACT ON THE VISUAL EXPRESSION OF THE BUILDING. THE QUESTION IS WHAT KIND. THAT I WILL ATTEMPT TO ANSWER IN THIS ARTICLE THROUGH OBSERVATION......WORLD FAMOUS ARCHITECTS CHALLENGE TODAY THE EXPOSURE OF CONCRETE IN THEIR ARCHITECTURE. IT IS MY HOPE TO BE ABLE TO COMPLEMENT THESE. I TRY TO DEVELOP NEW AESTHETIC POTENTIALS FOR THE CONCRETE AND CERAMICS, IN LARGE SCALES THAT HAS NOT BEEN SEEN BEFORE IN THE CERAMIC AREA. IT IS EXPECTED TO RESULT...

  5. Teaching Large Evening Classes

    Science.gov (United States)

    Wambuguh, Oscar

    2008-01-01

    High enrollments, conflicting student work schedules, and the sheer convenience of once-a-week classes are pushing many colleges to schedule evening courses. Held from 6 to 9 pm or 7 to 10 pm, these classes are typically packed, sometimes with more than 150 students in a large lecture theater. How can faculty effectively teach, control, or even…

  6. Large Hadron Collider

    CERN Multimedia

    2007-01-01

    "In the spring 2008, the Large Hadron Collider (LHC) machine at CERN (the European Particle Physics laboratory) will be switched on for the first time. The huge machine is housed in a circular tunnel, 27 km long, excavated deep under the French-Swiss border near Geneva." (1,5 page)

  7. The large hadron computer

    CERN Multimedia

    Hirstius, Andreas

    2008-01-01

    Plans for dealing with the torrent of data from the Large Hadron Collider's detectors have made the CERN particle-phycis lab, yet again, a pioneer in computing as well as physics. The author describes the challenges of processing and storing data in the age of petabyt science. (4 pages)

  8. Teaching Very Large Classes

    Science.gov (United States)

    DeRogatis, Amy; Honerkamp, Kenneth; McDaniel, Justin; Medine, Carolyn; Nyitray, Vivian-Lee; Pearson, Thomas

    2014-01-01

    The editor of "Teaching Theology and Religion" facilitated this reflective conversation with five teachers who have extensive experience and success teaching extremely large classes (150 students or more). In the course of the conversation these professors exchange and analyze the effectiveness of several active learning strategies they…

  9. Estimating Large Numbers

    Science.gov (United States)

    Landy, David; Silbert, Noah; Goldin, Aleah

    2013-01-01

    Despite their importance in public discourse, numbers in the range of 1 million to 1 trillion are notoriously difficult to understand. We examine magnitude estimation by adult Americans when placing large numbers on a number line and when qualitatively evaluating descriptions of imaginary geopolitical scenarios. Prior theoretical conceptions…

  10. Large litter sizes

    DEFF Research Database (Denmark)

    Sandøe, Peter; Rutherford, K.M.D.; Berg, Peer

    2012-01-01

    This paper presents some key results and conclusions from a review (Rutherford et al. 2011) undertaken regarding the ethical and welfare implications of breeding for large litter size in the domestic pig and about different ways of dealing with these implications. Focus is primarily on the direct...

  11. The Large Hadron Collider

    CERN Multimedia

    Wright, Alison

    2007-01-01

    "We are on the threshold of a new era in particle-physics research. In 2008, the Large Hadron Collider (LHC) - the hightest-energy accelerator ever built - will come into operation at CERN, the European labortory that straddles the French-Swiss border near Geneva." (1/2 page)

  12. Large myelomeningocele repair

    Directory of Open Access Journals (Sweden)

    Farideh Nejat

    2011-01-01

    Full Text Available Background: Wound closure is accomplished in most cases of myelomeningocele (MMC by undermining of the skin edges surrounding the defect. However, large defects cannot be closed reliably by this simple technique. Due to the technical challenge associated with large MMC, surgeons have devised different methods for repairing large defects. In this paper, we report our experience of managing large defects, which we believe bears a direct relationship to decrease the incidence of wound complications. Materials and Methods: Forty children with large MMCs underwent surgical repair and represent our experience. We recommend using all hairy skin around the defect as a way to decrease the tension on the edges of the wound and the possible subsequent necrosis. It is our experience that vertical incision on one or two flanks parallel to the midline can decrease the tension of the wound. Moreover, ventriculo-peritoneal shunting for children who developed hydrocephalus was performed simultaneously, which constitutes another recommendation for preventing fluid collection and build up of pressure on the wound. Results: Patients in this study were in the age range of 2 days to 8 years. The most common location of MMC was in the thoracolumbar area. All but four patients had severe weakness in lower extremities. We used as much hairy skin around the MMC sac as possible in all cases. Vertical incisions on one or both flanks and simultaneous shunt procedure were performed in 36 patients. We treated children with large MMC defects with acceptable tension-free closure. Nonetheless, three patients developed superficial skin infection and partial wound dehiscence, and they were managed conservatively. Conclusions: We recommend using all hairy skin around the MMC defect for closure of large defects. In cases that were expected to be at a higher risk to develop dehiscence release incisions on one or two flanks towards the fascia were found to be useful. Simultaneous

  13. The Large Hadron Collider

    CERN Document Server

    Evans, Lyndon

    2012-01-01

    The construction of the Large Hadron Collider (LHC) has been a massive endeavour spanning almost 30 years from conception to commissioning. Building the machine with the highest possible energy (7 TeV) in the existing large electron–positron (LEP) collider tunnel of 27 km circumference and with a tunnel diameter of only 3.8 m has required considerable innovation. The first was the development of a two-in-one magnet, where the two rings are integrated into a single magnetic structure. This compact two-in-one structure was essential for the LHC owing to the limited space available in the existing LEP collider tunnel and the cost. The second was a bold move to the use of superfluid helium cooling on a massive scale, which was imposed by the need to achieve a high (8.3 T) magnetic field using an affordable Nb-Ti superconductor.

  14. The Large Hadron Collider

    CERN Document Server

    Juettner Fernandes, Bonnie

    2014-01-01

    What really happened during the Big Bang? Why did matter form? Why do particles have mass? To answer these questions, scientists and engineers have worked together to build the largest and most powerful particle accelerator in the world: the Large Hadron Collider. Includes glossary, websites, and bibliography for further reading. Perfect for STEM connections. Aligns to the Common Core State Standards for Language Arts. Teachers' Notes available online.

  15. Buyouts in Large Companies

    OpenAIRE

    Hermalin, Benjamin; SCHWARTZ, Alan

    1998-01-01

    We consider legal rules that determine the price at which minority shareholders can be excluded from the corporate enterprise after a change in control. These rules affect investment after such a change, as well as probability of the change itself. Our principal results are that minority shareholders should be given the value that their interest would have had were no later investment made and that this rule is best implemented in large companies by awarding the minority the preinvestment mar...

  16. Large Curved Surface Measurement

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The measurement principle of large curved surface through theodolite industry survey system is introduced. Two methods are suggested with respect to the distribution range of curved surface error. The experiments show that the measurement precision can be up to 0.15mm with relative precision of 3×10-5. Finally, something needed paying attention to and the application aspects on theodolite industry survey system are given.

  17. Large N_c

    OpenAIRE

    Jenkins, Elizabeth E.

    2009-01-01

    The 1/N_c expansion of QCD with N_c=3 has been successful in explaining a wide variety of QCD phenomenology. Here I focus on the contracted spin-flavor symmetry of baryons in the large-N_c limit and deviations from spin-flavor symmetry due to corrections suppressed by powers of 1/N_c. Baryon masses provide an important example of the 1/N_c expansion, and successful predictions of masses of heavy-quark baryons continue to be tested by experiment. The ground state charmed baryon masses have all...

  18. Large deviations from freeness

    CERN Document Server

    Kargin, Vladislav

    2010-01-01

    Let H=A+UBU* where A and B are two N-by-N Hermitian matrices and U is a Haar-distributed random unitary matrix, and let \\mu_H, \\mu_A, and \\mu_B be empirical measures of eigenvalues of matrices H, A, and B, respectively. Then, it is known (see, for example, Pastur-Vasilchuk, CMP, 2000, v.214, pp.249-286) that for large N, measure \\mu_H is close to the free convolution of measures \\mu_A and \\mu_B, where the free convolution is a non-linear operation on probability measures. The large deviations of the cumulative distribution function of \\mu_H from its expectation have been studied by Chatterjee in JFA, 2007, v. 245, pp.379-389. In this paper we improve Chatterjee's estimate and show that P {\\sup_x |F_H (x) -F_+ (x)| > \\delta} < exp [-f(\\delta) N^2], where F_H (x) and F_+ (x) denote the cumulative distribution functions of \\mu_H and the free convolution of \\mu_A and \\mu_B, respectively, and where f(\\delta) is a specific function.

  19. Large Particle Titanate Sorbents

    Energy Technology Data Exchange (ETDEWEB)

    Taylor-Pashow, K. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2015-10-08

    This research project was aimed at developing a synthesis technique for producing large particle size monosodium titanate (MST) to benefit high level waste (HLW) processing at the Savannah River Site (SRS). Two applications were targeted, first increasing the size of the powdered MST used in batch contact processing to improve the filtration performance of the material, and second preparing a form of MST suitable for deployment in a column configuration. Increasing the particle size should lead to improvements in filtration flux, and decreased frequency of filter cleaning leading to improved throughput. Deployment of MST in a column configuration would allow for movement from a batch process to a more continuous process. Modifications to the typical MST synthesis led to an increase in the average particle size. Filtration testing on dead-end filters showed improved filtration rates with the larger particle material; however, no improvement in filtration rate was realized on a crossflow filter. In order to produce materials suitable for column deployment several approaches were examined. First, attempts were made to coat zirconium oxide microspheres (196 µm) with a layer of MST. This proved largely unsuccessful. An alternate approach was then taken synthesizing a porous monolith of MST which could be used as a column. Several parameters were tested, and conditions were found that were able to produce a continuous structure versus an agglomeration of particles. This monolith material showed Sr uptake comparable to that of previously evaluated samples of engineered MST in batch contact testing.

  20. Silicic Large Igneous Provinces

    Institute of Scientific and Technical Information of China (English)

    Scott Bryan

    2007-01-01

    @@ Large Igneous Provinces (LIPs) are the end-product of huge additions of magma to the continental crust both at the surface and at depth. Since the first categorisation of LIPs by Coffin & Eldholm (1994), it has been recognised that LIPs are more varied inform, age and character, and this includes the recognition of Silicic LIPs. Silicic LIPs are the largest accumulations of primary volcaniclastic rocks at the Earth's surface with areal extents >0.1 Mkm2 and extrusive and subvolcanic intrusive volumes >0.25 Mkm3. The Late Palaeozoic to Cenozoic Silicic LIP events are the best recognised and are similar in terms of their dimension, crustal setting, volcanic architecture and geochemistry.

  1. Large Spin Perturbation Theory

    CERN Document Server

    Alday, Luis F

    2016-01-01

    We consider conformal field theories around points of large twist degeneracy. Examples of this are theories with weakly broken higher spin symmetry and perturbations around generalised free fields. At the degenerate point we introduce twist conformal blocks. These are eigenfunctions of certain quartic operators and encode the contribution, to a given four-point correlator, of the whole tower of intermediate operators with a given twist. As we perturb around the degenerate point, the twist degeneracy is lifted. In many situations this breaking is controlled by inverse powers of the spin. In such cases the twist conformal blocks can be decomposed into a sequence of functions which we systematically construct. Decomposing the four-point correlator in this basis turns crossing symmetry into an algebraic problem. Our method can be applied to a wide spectrum of conformal field theories in any number of dimensions and at any order in the breaking parameter. As an example, we compute the spectrum of various theories ...

  2. Large Scale Solar Heating

    DEFF Research Database (Denmark)

    Heller, Alfred

    2001-01-01

    model is designed and validated on the Marstal case. Applying the Danish Reference Year, a design tool is presented. The simulation tool is used for proposals for application of alternative designs, including high-performance solar collector types (trough solar collectors, vaccum pipe collectors......The main objective of the research was to evaluate large-scale solar heating connected to district heating (CSDHP), to build up a simulation tool and to demonstrate the application of the simulation tool for design studies and on a local energy planning case. The evaluation was mainly carried out......). Simulation programs are proposed as control supporting tool for daily operation and performance prediction of central solar heating plants. Finaly the CSHP technolgy is put into persepctive with respect to alternatives and a short discussion on the barries and breakthrough of the technology are given....

  3. The large binocular telescope.

    Science.gov (United States)

    Hill, John M

    2010-06-01

    The Large Binocular Telescope (LBT) Observatory is a collaboration among institutions in Arizona, Germany, Italy, Indiana, Minnesota, Ohio, and Virginia. The telescope on Mount Graham in Southeastern Arizona uses two 8.4 m diameter primary mirrors mounted side by side. A unique feature of the LBT is that the light from the two Gregorian telescope sides can be combined to produce phased-array imaging of an extended field. This cophased imaging along with adaptive optics gives the telescope the diffraction-limited resolution of a 22.65 m aperture and a collecting area equivalent to an 11.8 m circular aperture. This paper describes the design, construction, and commissioning of this unique telescope. We report some sample astronomical results with the prime focus cameras. We comment on some of the technical challenges and solutions. The telescope uses two F/15 adaptive secondaries to correct atmospheric turbulence. The first of these adaptive mirrors has completed final system testing in Firenze, Italy, and is planned to be at the telescope by Spring 2010.

  4. Large Size Telescope Report

    CERN Document Server

    Mazin, D; Teshima, M

    2016-01-01

    The Cherenkov Telescope Array (CTA) observatory will be deployed over two sites in the two hemispheres. Both sites will be equipped with four Large Size Telescopes (LSTs), which are crucial to achieve the science goals of CTA in the 20-200 GeV energy range. Each LST is equipped with a primary tessellated mirror dish of 23 m diameter, supported by a structure made mainly of carbon fibre reinforced plastic tubes and aluminum joints. This solution guarantees light weight (around 100 tons), essential for fast repositioning to any position in the sky in <20 seconds. The camera is composed of 1855 photomultiplier tubes and embeds the control, readout and trigger electronics. The detailed design is now complete and production of the first LST, which will serve as a prototype for the remaining seven, is ongoing. The installation of the first LST at the Roque de los Muchachos Observatory on the Canary island of La Palma (Spain) started in July 2016. In this paper we will outline the technical solutions adopted to f...

  5. Large Databases in Astronomy

    Science.gov (United States)

    Szalay, Alexander S.; Gray, Jim; Kunszt, Peter; Thakar, Anirudha; Slutz, Don

    The next-generation astronomy digital archives will cover most of the sky at fine resolution in many wavelengths, from X-rays through ultraviolet, optical, and infrared. The archives will be stored at diverse geographical locations. The intensive use of advanced data archives will enable astronomers to explore their data interactively. Data access will be aided by multidimensional spatial and attribute indices. The data will be partitioned in many ways. Small tag indices consisting of the most popular attributes will accelerate frequent searches. Splitting the data among multiple servers will allow parallel, scalable I/O and parallel data analysis. Hashing techniques will allow efficient clustering, and pair-wise comparison algorithms that should parallelize nicely. Randomly sampled subsets will allow debugging otherwise large queries at the desktop. Central servers will operate a data pump to support sweep searches touching most of the data. The anticipated queries will require special operators related to angular distances and complex similarity tests of object properties, like shapes, colors, velocity vectors, or temporal behaviors. These issues pose interesting data management challenges.

  6. Large scale tracking algorithms.

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, Ross L.; Love, Joshua Alan; Melgaard, David Kennett; Karelitz, David B.; Pitts, Todd Alan; Zollweg, Joshua David; Anderson, Dylan Z.; Nandy, Prabal; Whitlow, Gary L.; Bender, Daniel A.; Byrne, Raymond Harry

    2015-01-01

    Low signal-to-noise data processing algorithms for improved detection, tracking, discrimination and situational threat assessment are a key research challenge. As sensor technologies progress, the number of pixels will increase signi cantly. This will result in increased resolution, which could improve object discrimination, but unfortunately, will also result in a significant increase in the number of potential targets to track. Many tracking techniques, like multi-hypothesis trackers, suffer from a combinatorial explosion as the number of potential targets increase. As the resolution increases, the phenomenology applied towards detection algorithms also changes. For low resolution sensors, "blob" tracking is the norm. For higher resolution data, additional information may be employed in the detection and classfication steps. The most challenging scenarios are those where the targets cannot be fully resolved, yet must be tracked and distinguished for neighboring closely spaced objects. Tracking vehicles in an urban environment is an example of such a challenging scenario. This report evaluates several potential tracking algorithms for large-scale tracking in an urban environment.

  7. The large binocular telescope.

    Science.gov (United States)

    Hill, John M

    2010-06-01

    The Large Binocular Telescope (LBT) Observatory is a collaboration among institutions in Arizona, Germany, Italy, Indiana, Minnesota, Ohio, and Virginia. The telescope on Mount Graham in Southeastern Arizona uses two 8.4 m diameter primary mirrors mounted side by side. A unique feature of the LBT is that the light from the two Gregorian telescope sides can be combined to produce phased-array imaging of an extended field. This cophased imaging along with adaptive optics gives the telescope the diffraction-limited resolution of a 22.65 m aperture and a collecting area equivalent to an 11.8 m circular aperture. This paper describes the design, construction, and commissioning of this unique telescope. We report some sample astronomical results with the prime focus cameras. We comment on some of the technical challenges and solutions. The telescope uses two F/15 adaptive secondaries to correct atmospheric turbulence. The first of these adaptive mirrors has completed final system testing in Firenze, Italy, and is planned to be at the telescope by Spring 2010. PMID:20517352

  8. Large scale traffic simulations

    Energy Technology Data Exchange (ETDEWEB)

    Nagel, K.; Barrett, C.L. [Los Alamos National Lab., NM (United States)]|[Santa Fe Institute, NM (United States); Rickert, M. [Los Alamos National Lab., NM (United States)]|[Universitaet zu Koeln (Germany)

    1997-04-01

    Large scale microscopic (i.e. vehicle-based) traffic simulations pose high demands on computational speed in at least two application areas: (i) real-time traffic forecasting, and (ii) long-term planning applications (where repeated {open_quotes}looping{close_quotes} between the microsimulation and the simulated planning of individual person`s behavior is necessary). As a rough number, a real-time simulation of an area such as Los Angeles (ca. 1 million travellers) will need a computational speed of much higher than 1 million {open_quotes}particle{close_quotes} (= vehicle) updates per second. This paper reviews how this problem is approached in different projects and how these approaches are dependent both on the specific questions and on the prospective user community. The approaches reach from highly parallel and vectorizable, single-bit implementations on parallel supercomputers for Statistical Physics questions, via more realistic implementations on coupled workstations, to more complicated driving dynamics implemented again on parallel supercomputers. 45 refs., 9 figs., 1 tab.

  9. Stability of large systems

    Science.gov (United States)

    Hastings, Harold

    2007-03-01

    We address a long-standing dilemma concerning stability of large systems. MacArthur (1955) and Hutchinson (1959) argued that more ``complex'' natural systems tended to be more stable than less complex systems based upon energy flow. May (1972) argued the opposite, using random matrix models; see Cohen and Newman (1984, 1985), Bai and Yin (1986). We show that in some sense both are right: under reasonable scaling assumptions on interaction strength, Lyapunov stability increases but structural stability decreases as complexity is increased (c.f. Harrison, 1979; Hastings, 1984). We apply this result to a variety of network systems. References: Bai, Z.D. & Yin, Y.Q. 1986. Probab. Th. Rel. Fields 73, 555. Cohen, J.E., & Newman, C.M. 1984. Annals Probab. 12, 283; 1985. Theoret. Biol. 113, 153. Harrison, G.W. 1979. Amer. Natur. 113, 659. Hastings, H.M. 1984. BioSystems 17, 171. Hastings, H.M., Juhasz, F., & Schreiber, M. 1992. .Proc. Royal Soc., Ser. B. 249, 223. Hutchinson, G.E. 1959. Amer. Natur. 93, 145, MacArthur, R. H. 1955. Ecology 35, 533, May, R.M. 1972. Nature 238, 413.

  10. Applied large eddy simulation.

    Science.gov (United States)

    Tucker, Paul G; Lardeau, Sylvain

    2009-07-28

    Large eddy simulation (LES) is now seen more and more as a viable alternative to current industrial practice, usually based on problem-specific Reynolds-averaged Navier-Stokes (RANS) methods. Access to detailed flow physics is attractive to industry, especially in an environment in which computer modelling is bound to play an ever increasing role. However, the improvement in accuracy and flow detail has substantial cost. This has so far prevented wider industrial use of LES. The purpose of the applied LES discussion meeting was to address questions regarding what is achievable and what is not, given the current technology and knowledge, for an industrial practitioner who is interested in using LES. The use of LES was explored in an application-centred context between diverse fields. The general flow-governing equation form was explored along with various LES models. The errors occurring in LES were analysed. Also, the hybridization of RANS and LES was considered. The importance of modelling relative to boundary conditions, problem definition and other more mundane aspects were examined. It was to an extent concluded that for LES to make most rapid industrial impact, pragmatic hybrid use of LES, implicit LES and RANS elements will probably be needed. Added to this further, highly industrial sector model parametrizations will be required with clear thought on the key target design parameter(s). The combination of good numerical modelling expertise, a sound understanding of turbulence, along with artistry, pragmatism and the use of recent developments in computer science should dramatically add impetus to the industrial uptake of LES. In the light of the numerous technical challenges that remain it appears that for some time to come LES will have echoes of the high levels of technical knowledge required for safe use of RANS but with much greater fidelity. PMID:19531503

  11. A novel molecular variant of the chimeric NPM-ALK transcript in Ki-1 positive large cell lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Ladanyi, M. [Memorial Sloan-Kettering Cancer Center, New York, NY (United States)

    1994-09-01

    The breakpoints of the t(2;5)(p23;q35), reported to be present in 30-40% of Ki-1 positive large cell lymphoma (Ki-1 LCL), have recently been cloned. They involve a novel tyrosine kinase gene, ALK, at 2p23 and the nucleophosmin gene, NPM, at 5q35. Reverse transcriptase polymerase chain reaction (RT-PCR) using NPM and ALK primers detects a consistent fusion product in Ki-1 cases with the translocation. We performed NPM-ALK RT-PCR on 16 cases of Ki-1 LCL, of which 13 had informative cytogenetics. Amplifiable template was confirmed in all samples by RT-PCR using {beta}-actin primers. Ten cases showed the expected 177 base pair (bp) RT-PCR product indicative of the translocation, including all 6 cases with cytogenetic evidence of the t(2;5) and 3 cases without 5q35 abnormalities. One additional case, which had uninformative cytogenetics, showed only a novel 144 bp RT-PCR product. Sequencing of this PCR product showed an in-frame junction of NPM to ALK, 20 bp distal to the usual NPM junction site and 53 bp distal to usual ALK junction site. The predicted chimeric protein is thus shorter by 11 amino acids, but the putative ALK catalytic domain remains intact. This case was a histologically typical anaplastic Ki-1 LCL which showed a clonal rearrangement of the T-cell receptor {beta} gene. The functional significance of this molecular variant and its relation to the exon structure of both genes require further study. The overall incidence of the translocation in this series, about 70%, is higher than suspected from cytogenetic analysis alone.

  12. ALK+弥漫大B细胞淋巴瘤患者临床决策探讨%Clinical decision on a patient with ALK+diffuse large B cell lymphoma

    Institute of Scientific and Technical Information of China (English)

    董玲; 王先火; 王华庆; 付凯; 张会来; 孟斌; 张新伟; 宋秀宇; 张希梅; 翟琼莉; 刘霞; 侯芸; 李维

    2016-01-01

    Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare and distinct variant of DLBCL. It is classified as a unique subtype of DLBCL in the 2008 WHO classification of lymphomas. No standard and effective therapeutic regi-men is available for ALK+DLBCL because it shows a more aggressive clinical course and frequent relapse. Therefore, a standardized and individualized treatment is needed to benefit more patients diagnosed with ALK+DLBCL through a multiple disciplinary team. This arti-cle presents a case of an ALK+DLBCL patient who relapsed after transplantation and was successfully treated with the ALK kinase inhibi-tor Crizotinib.%ALK+弥漫大B细胞淋巴瘤(anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma,ALK+DLBCL)是淋巴瘤中一种罕见的和具有明显差异性的病理类型,2008年WHO将其归类为DLBCL一个独特的亚型,该病侵袭性高,容易复发,目前尚无规范有效的治疗方案。采取多学科协作体系(multidisciplinary treatment,MDT)有利于制定规范化、个体化的治疗方案,探索针对ALK+DLBCL患者更有效的治疗方法,从而让更多的患者获益。本研究分享1例2012年1月天津医科大学肿瘤医院收治的ALK+DLBCL高剂量化疗联合自体造血干细胞移植(autologous hematopoietic stem cell transplantation,AHSCT)后复发,采用ALK激酶抑制剂克唑替尼(Crizotinib)治疗成功的案例。

  13. MicroRNA 25, microRNA 145, and microRNA 210 as biomarkers for predicting the efficacy of maintenance treatment with pemetrexed in lung adenocarcinoma patients who are negative for epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations.

    Science.gov (United States)

    Shi, Sheng-Bin; Wang, Meng; Tian, Jing; Li, Rui; Chang, Chun-Xiao; Qi, Jie-Lin

    2016-04-01

    This study was conducted to evaluate microRNAs (miRNAs) as biomarkers for use in predicting the efficacy of maintenance therapy with pemetrexed in patients with stage IIIb or IV lung adenocarcinoma and who had already received first-line treatment with pemetrexed plus platinum. Patients who were negative for epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations were assigned to a pemetrexed group and an observation group. Patients in the pemetrexed group (n = 76) received maintenance treatment with pemetrexed (500 mg/m(2), once every 21 days) plus best supportive care. Patients in the observation group (n = 72) agreed to receive only best supportive care until disease progression. Blood samples were collected from all patients in both groups before treatment and were used to detect expression levels of various miRNAs in serum by the Reverse Transcription-Polymerase Chain Reaction (RT-PCR) method. The expression levels of miR-25, miR-145, and miR-210 were significantly different in the 2 groups of patients. Furthermore, the median progression-free survival (PFS) times for patients in the pemetrexed and observation groups were 4.5 and 2.9 months, respectively. The PFS times among patients in the pemetrexed group varied significantly and were related to patient expression levels of miR-25, miR-145, and miR-210, whereas patients in the observation group showed no differences in PFS time. Our data suggest miR-25, miR-145, and miR-210 as predictors for the efficacy of maintenance treatment with pemetrexed in lung adenocarcinoma patients who were negative for EGFR mutations or ALK translocations.

  14. Large for gestational age (LGA)

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/002248.htm Large for gestational age (LGA) To use the sharing features on this page, please enable JavaScript. Large for gestational age means that a fetus or ...

  15. Large-D gravity and low-D strings.

    Science.gov (United States)

    Emparan, Roberto; Grumiller, Daniel; Tanabe, Kentaro

    2013-06-21

    We show that in the limit of a large number of dimensions a wide class of nonextremal neutral black holes has a universal near-horizon limit. The limiting geometry is the two-dimensional black hole of string theory with a two-dimensional target space. Its conformal symmetry explains the properties of massless scalars found recently in the large-D limit. For black branes with string charges, the near-horizon geometry is that of the three-dimensional black strings of Horne and Horowitz. The analogies between the α' expansion in string theory and the large-D expansion in gravity suggest a possible effective string description of the large-D limit of black holes. We comment on applications to several subjects, in particular to the problem of critical collapse.

  16. Large-D gravity and low-D strings.

    Science.gov (United States)

    Emparan, Roberto; Grumiller, Daniel; Tanabe, Kentaro

    2013-06-21

    We show that in the limit of a large number of dimensions a wide class of nonextremal neutral black holes has a universal near-horizon limit. The limiting geometry is the two-dimensional black hole of string theory with a two-dimensional target space. Its conformal symmetry explains the properties of massless scalars found recently in the large-D limit. For black branes with string charges, the near-horizon geometry is that of the three-dimensional black strings of Horne and Horowitz. The analogies between the α' expansion in string theory and the large-D expansion in gravity suggest a possible effective string description of the large-D limit of black holes. We comment on applications to several subjects, in particular to the problem of critical collapse. PMID:23829726

  17. The association of pathological type、IDH-1 mutations and MGMT promoter methylation status on “pseudo-progress” of anaplastic gliomas%病理类型、IDH-1突变和MGMT启动子甲基化状态与间变性胶质瘤假性进展的相关性

    Institute of Scientific and Technical Information of China (English)

    李宏; 陆云涛; 漆松涛; 俞磊; 欧阳辉; 刘亚伟

    2013-01-01

    目的:明确间变性胶质瘤(Anaplastic glioma,AG)组织中病理类型、IDH-1基因突变以及MGMT启动子甲基化与患者综合治疗后发生假性进展(Pseudoprogression,PsPD)之间的相互关系.方法:对47例间变性胶质瘤标本采用基因片段测序的方法检测异柠檬酸脱氢酶(IDH-1)突变和MGMT启动子甲基化状态情况.对所有病例进行临床随访,结合肿瘤的病理类型,探讨其对术后PsPD发生的提示作用.结果:47例AG患者中有24例出现早期进展(6个月内).9例PsPD中IDH-1突变和MGMT启动子甲基化分别是6例和7例;另15例真性复发患者IDH-1突变和MGMT启动子甲基化分别是3例和5例,IDH-1突变对PsPD检出率与MGMT启动子甲基化相比,无明显差异(x2<0.02,P>0.9);PsPD中含少突胶质细胞病理成分的4例病例,包括3例间变性少突胶质细胞瘤(AO)和1例间变性少突显形细胞瘤(AOA),全部发生IDH-1突变,另5例间变性显形细胞瘤(AA)中有2例发生IDH-1突变,IDH-1突变对PsPD检出率与病理类型中含少突胶质细胞成分相比,无明显差异(x2=0.5,P>0.5).结论:病理类型中含有少突胶质细胞成分、存在IDH-1突变和MGMT启动子甲基化可以作为间变性胶质瘤中预测PsPD的可靠客观预计指标,有利于鉴别肿瘤PsPD和真性复发.%Aim:To identify the relationship between Pathological type,IDH mutation,MGMT promoter methylation in clinical samples of anaplastic gliomas (AG) with Pseudoprogression (PsPD) in patients received comprehensive treatment.Methods:DNA direct sequencing was used to detect IDH-1 mutation and MGMT promoter methylation status of the 47 clinical samples of AG.Clinical data of all patients with AG treated with surgery followed by radiotherapy plus (or not) concomitant temozolomide (TMZ) were followed up.IDH mutation and MGMT promoter methylation were analyzed statistically combined with pathological type of tumor to identify the predictive role of them on postoperative Ps

  18. Large deviations and idempotent probability

    CERN Document Server

    Puhalskii, Anatolii

    2001-01-01

    In the view of many probabilists, author Anatolii Puhalskii''s research results stand among the most significant achievements in the modern theory of large deviations. In fact, his work marked a turning point in the depth of our understanding of the connections between the large deviation principle (LDP) and well-known methods for establishing weak convergence results.Large Deviations and Idempotent Probability expounds upon the recent methodology of building large deviation theory along the lines of weak convergence theory. The author develops an idempotent (or maxitive) probability theory, introduces idempotent analogues of martingales (maxingales), Wiener and Poisson processes, and Ito differential equations, and studies their properties. The large deviation principle for stochastic processes is formulated as a certain type of convergence of stochastic processes to idempotent processes. The author calls this large deviation convergence.The approach to establishing large deviation convergence uses novel com...

  19. Large

    Directory of Open Access Journals (Sweden)

    Toufik Berri

    2014-11-01

    CL of the parotid gland in adults presents difficult challenges to the surgeon for both differential diagnosis of parotid masses and treatment. Surgery remains the treatment of choice despite its difficulty due to the infiltrating character of the lesion. Sclerotherapy is an alternative in macrocystic type when surgical management is not possible. Despite being benign tumors, CL are attended by a high rate of morbidity.

  20. Discreteness and Large Scale Surjections

    OpenAIRE

    Austin, Kyle

    2015-01-01

    We study the concept of coarse disjointness and large scale $n$-to-$1$ functions. As a byproduct, we obtain an Ostrand-type characterization of asymptotic dimension for coarse structures. It is shown that properties like finite asymptotic dimension, coarse finitism, large scale weak paracompactness, ect. are all invariants of coarsely $n$-to-$1$ functions. Metrizability of large scale structures is also investigated.

  1. Large deviations and rain showers

    OpenAIRE

    Wilkinson, Michael

    2015-01-01

    Rainfall from ice-free cumulus clouds requires collisions of large numbers of microscopic droplets to create every raindrop. The onset of rain showers can be surprisingly rapid, much faster than the mean time required for a single collision. Large-deviation theory is used to explain this observation.

  2. Querying Large Biological Network Datasets

    Science.gov (United States)

    Gulsoy, Gunhan

    2013-01-01

    New experimental methods has resulted in increasing amount of genetic interaction data to be generated every day. Biological networks are used to store genetic interaction data gathered. Increasing amount of data available requires fast large scale analysis methods. Therefore, we address the problem of querying large biological network datasets.…

  3. Large-scale data analytics

    CERN Document Server

    Gkoulalas-Divanis, Aris

    2014-01-01

    Provides cutting-edge research in large-scale data analytics from diverse scientific areas Surveys varied subject areas and reports on individual results of research in the field Shares many tips and insights into large-scale data analytics from authors and editors with long-term experience and specialization in the field

  4. Team Learning in Large Classes.

    Science.gov (United States)

    Roueche, Suanne D., Ed.

    1984-01-01

    Information and suggestions are provided on the use of team learning in large college classes. Introductory material discusses the negative cycle of student-teacher interaction that may be provoked by large classes, and the use of permanent, heterogeneous, six- or seven-member student learning groups as the central focus of class activity as a…

  5. Large shareholders and accounting research

    Institute of Scientific and Technical Information of China (English)

    Ole-Kristian; Hope

    2013-01-01

    Large shareholders are a potentially very important element of firms’ corporate governance system. Whereas analytical research is typically vague on who these large shareholders are, in practice there are important variations in the types of large owners(and the different types of large owners could play very different governance roles). After briefly reviewing the standard agency cost arguments, in this article I emphasize the heterogeneity of concentrated ownership and in particular focus on the roles of families, institutions, governments, and employee ownership. I also discuss the role of large shareholders in private(i.e., unlisted) firms, where ownership tends to be more concentrated than in publicly traded firms. Finally, I briefly discuss variations in ownership structures across selected countries.

  6. Measuring happiness in large population

    Science.gov (United States)

    Wenas, Annabelle; Sjahputri, Smita; Takwin, Bagus; Primaldhi, Alfindra; Muhamad, Roby

    2016-01-01

    The ability to know emotional states for large number of people is important, for example, to ensure the effectiveness of public policies. In this study, we propose a measure of happiness that can be used in large scale population that is based on the analysis of Indonesian language lexicons. Here, we incorporate human assessment of Indonesian words, then quantify happiness on large-scale of texts gathered from twitter conversations. We used two psychological constructs to measure happiness: valence and arousal. We found that Indonesian words have tendency towards positive emotions. We also identified several happiness patterns during days of the week, hours of the day, and selected conversation topics.

  7. Large Hadron Collider nears completion

    CERN Multimedia

    2008-01-01

    Installation of the final component of the Large Hadron Collider particle accelerator is under way along the Franco-Swiss border near Geneva, Switzerland. When completed this summer, the LHC will be the world's largest and most complex scientific instrument.

  8. Sustainability in Large Power Plants

    OpenAIRE

    Faria, Roberto Censi; Kniess, Cláudia Terezinha; Maccari, Emerson Antonio

    2012-01-01

    No business activity today can be implemented without take into account the aspects of sustainability. The concept of sustainable development that was born of the years 1970 and 1980 and was enshrined in the concept of the three pillars of John Elkington - economic, social and environmental issues, the "triple bottom line" is a constraint for all types of enterprises, especially for large hydropower plants. Large hydropower plants have been for a while the great enemy of development, because ...

  9. Large Fibroepithelial Polyp of Vulva

    OpenAIRE

    Sujaya V Rao; Nagarathna G.; Mahesha H Navada; Bhat, Poornima Ramachandra B.

    2011-01-01

    A rare case of a large fibroepithelial polyp (FEP) of the vulva is described. The polypoidal growth was 10 cm in its largest diameter, having a long pedicle with features of inflammation secondary to infection, and was found arising from the left labia majora. The patient did not manifest any signs of recurrence following excision. A large and infected FEP of the vulva is a rare occurrence and hence reported.

  10. Large-scale solar heat

    Energy Technology Data Exchange (ETDEWEB)

    Tolonen, J.; Konttinen, P.; Lund, P. [Helsinki Univ. of Technology, Otaniemi (Finland). Dept. of Engineering Physics and Mathematics

    1998-12-31

    In this project a large domestic solar heating system was built and a solar district heating system was modelled and simulated. Objectives were to improve the performance and reduce costs of a large-scale solar heating system. As a result of the project the benefit/cost ratio can be increased by 40 % through dimensioning and optimising the system at the designing stage. (orig.)

  11. Optimization theory for large systems

    CERN Document Server

    Lasdon, Leon S

    2011-01-01

    Important text examines most significant algorithms for optimizing large systems and clarifying relations between optimization procedures. Much data appear as charts and graphs and will be highly valuable to readers in selecting a method and estimating computer time and cost in problem-solving. Initial chapter on linear and nonlinear programming presents all necessary background for subjects covered in rest of book. Second chapter illustrates how large-scale mathematical programs arise from real-world problems. Appendixes. List of Symbols.

  12. Preparation of large monodisperse vesicles.

    Directory of Open Access Journals (Sweden)

    Ting F Zhu

    Full Text Available Preparation of monodisperse vesicles is important both for research purposes and for practical applications. While the extrusion of vesicles through small pores (approximately 100 nm in diameter results in relatively uniform populations of vesicles, extrusion to larger sizes results in very heterogeneous populations of vesicles. Here we report a simple method for preparing large monodisperse multilamellar vesicles through a combination of extrusion and large-pore dialysis. For example, extrusion of polydisperse vesicles through 5-microm-diameter pores eliminates vesicles larger than 5 microm in diameter. Dialysis of extruded vesicles against 3-microm-pore-size polycarbonate membranes eliminates vesicles smaller than 3 microm in diameter, leaving behind a population of monodisperse vesicles with a mean diameter of approximately 4 microm. The simplicity of this method makes it an effective tool for laboratory vesicle preparation with potential applications in preparing large monodisperse liposomes for drug delivery.

  13. Rindler force at large distances

    CERN Document Server

    Grumiller, Daniel

    2011-01-01

    Given some assumptions it is possible to derive the most general theory of gravity at large distances. The force law derived from this theory contains a Rindler term in addition to well-known contributions, a Schwarzschild mass and a cosmological constant. The same force law recently was confronted with solar system precision data. The Rindler force, if present in Nature, has intriguing consequences for gravity at large distances. In particular, the Rindler force is capable of explaining about 10% of the Pioneer anomaly and simultaneously ameliorates the shape of galactic rotation curves.

  14. Dijets at large rapidity intervals

    CERN Document Server

    Pope, B G

    2001-01-01

    Inclusive diet production at large pseudorapidity intervals ( Delta eta ) between the two jets has been suggested as a regime for observing BFKL dynamics. We have measured the dijet cross section for large Delta eta in pp collisions at square root s = 1800 and 630 GeV using the DOE detector. The partonic cross section increases strongly with the size of Delta eta . The observed growth is even stronger than expected on the basis of BFKL resummation in the leading logarithmic approximation. The growth of the partonic cross section can be accommodated with an effective BFKL intercept of alpha /sub BFKL/(20 GeV) = 1.65 +or- 0.07.

  15. The Limit of Large Vessels

    Institute of Scientific and Technical Information of China (English)

    Yang Peiju

    2011-01-01

    On Feb 21(st),the industry was shocked by the news that AP Moller-Maersk placed an order of 10 container ships of 18,000 TEU with the South Korean ship yards.The order brings the development of large vessels to a new climax and at the same time puts forward a series of research subjects to the industry,such as what is the limit for the development of large vessels,whether ship safety can be guaranteed,and etc.

  16. Ultrasonic large aperture imaging system

    International Nuclear Information System (INIS)

    A new ultrasonic large aperture imaging technique is described. This device combines a focussed transducer as a transmitter, producing a small ultrasonic beam, with N transducers as receivers. We show that is possible to considerably reduce the number of receivers if, on the one hand, we limit the reconstitution process to the emitter beam area and, on the other hand, we ensure that the artefacts, caused by the spatial sampling of the reception, are outside this area. Under these conditions, the result is a high resolution image which does not require large reconstitution processing times. Theoretical and experimental results are given

  17. Structuring very large domain models

    DEFF Research Database (Denmark)

    Störrle, Harald

    2010-01-01

    a lower level of detail have not been dealt with. This paper aims at filling this gap by reporting personal experiences from a very large scale industrial domain modeling project. There, structuring the logical view turned out to be a critical success factor. We explain the project and its setting......, analyze the role and repercussions of model structuring, and examine the implications model structuring decisions have on other parts of the project. We then explain the model structure abstracted from a very large scale industrial modeling project. Finally, we discuss lessons learned....

  18. Intracranial Large Artery Occlusive Disease

    Institute of Scientific and Technical Information of China (English)

    Wong KS; Li H; Kay R

    2000-01-01

    @@Intracranial large artery stenosis is the most commonly found vascular lesion in stroke patient of Chinese, Hispanic and African ancestry. There .have been few studies on the epidemiology, pathophysiology, treatment and prognosis of this important disease. Recent advances in technology provide safe and reliable investigation for studying large number of patients. Transcranial Doppler is an easily accessible, cheap and reliable method to diagnose intracranial stenosis. It is suitable for screening for and monitoring the progress of intracranial stenosis. Magnetic resonance angiography and CT angiography provide the morphology of lumenal stenosis but are less accessible.

  19. COOPERATIVE LEARNING IN LARGE CLASSES

    Institute of Scientific and Technical Information of China (English)

    GuoXiangju

    2004-01-01

    Teaching college English in large classes is a new challenge to teachers. To meet this challenge, the strategy of cooperative learning is practicable. This paper introduces cooperative learning and describes the experiment results, which prove the advantages of cooperative learning over competitive learning or individualistic learning.

  20. Large program implementation on minicomputers

    CERN Document Server

    Fonti, L

    1980-01-01

    A method is described to fit a very large program (usually executed on very big mainframes, like a CDC 7600 or IBM 370/168) on a 16-bit minicomputer with memory management support. The method outlined is fully general, even if references are made to a specific example: the implementation of the CERN program HYDRA on a PDP 11/70. (2 refs).

  1. Large angle measurement by interferometry

    Science.gov (United States)

    Apostol, Dan; Blanaru, Constantin; Damian, Victor S.; Logofatu, Petre-Catalin; Tumbar, R.; Dobroiu, Adrian

    1995-03-01

    An interferometric set-up able to measure angles as large as +180 degree(s) is presented. The principle of the method is to measure a linear displacement (translation) produced by a crank-gear mechanism which converts the angular movement of a rotating table. The optical scheme and consideration on the accuracy of the method are presented.

  2. Inconsistency in large pharmacogenomic studies

    DEFF Research Database (Denmark)

    Haibe-Kains, Benjamin; El-Hachem, Nehme; Birkbak, Nicolai Juul;

    2013-01-01

    Two large-scale pharmacogenomic studies were published recently in this journal. Genomic data are well correlated between studies; however, the measured drug response data are highly discordant. Although the source of inconsistencies remains uncertain, it has potential implications for using...

  3. Large deviations and portfolio optimization

    Science.gov (United States)

    Sornette, Didier

    Risk control and optimal diversification constitute a major focus in the finance and insurance industries as well as, more or less consciously, in our everyday life. We present a discussion of the characterization of risks and of the optimization of portfolios that starts from a simple illustrative model and ends by a general functional integral formulation. A major item is that risk, usually thought of as one-dimensional in the conventional mean-variance approach, has to be addressed by the full distribution of losses. Furthermore, the time-horizon of the investment is shown to play a major role. We show the importance of accounting for large fluctuations and use the theory of Cramér for large deviations in this context. We first treat a simple model with a single risky asset that exemplifies the distinction between the average return and the typical return and the role of large deviations in multiplicative processes, and the different optimal strategies for the investors depending on their size. We then analyze the case of assets whose price variations are distributed according to exponential laws, a situation that is found to describe daily price variations reasonably well. Several portfolio optimization strategies are presented that aim at controlling large risks. We end by extending the standard mean-variance portfolio optimization theory, first within the quasi-Gaussian approximation and then using a general formulation for non-Gaussian correlated assets in terms of the formalism of functional integrals developed in the field theory of critical phenomena.

  4. Large Hadron Collider nears completion

    CERN Multimedia

    2008-01-01

    Installation of the final component of the Large Hadron Collider particle accelerator is under way along the Franco-Swiss border near Geneva, Switzerland. When completed this summer, the LHC will be the world's largest and most complex scientific instrument. It is being constructed by the European Organization for Nuclear Research, one of the world's largest particle physics laboratories.

  5. The very large hadron collider

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-09-01

    This paper reviews the purposes to be served by a very large hadron collider and the organization and coordination of efforts to bring it about. There is some discussion of magnet requirements and R&D and the suitability of the Fermilab site.

  6. Large area CMOS image sensors

    International Nuclear Information System (INIS)

    CMOS image sensors, also known as CMOS Active Pixel Sensors (APS) or Monolithic Active Pixel Sensors (MAPS), are today the dominant imaging devices. They are omnipresent in our daily life, as image sensors in cellular phones, web cams, digital cameras, ... In these applications, the pixels can be very small, in the micron range, and the sensors themselves tend to be limited in size. However, many scientific applications, like particle or X-ray detection, require large format, often with large pixels, as well as other specific performance, like low noise, radiation hardness or very fast readout. The sensors are also required to be sensitive to a broad spectrum of radiation: photons from the silicon cut-off in the IR down to UV and X- and gamma-rays through the visible spectrum as well as charged particles. This requirement calls for modifications to the substrate to be introduced to provide optimized sensitivity. This paper will review existing CMOS image sensors, whose size can be as large as a single CMOS wafer, and analyse the technical requirements and specific challenges of large format CMOS image sensors.

  7. Strategic Management of Large Projects

    Institute of Scientific and Technical Information of China (English)

    WangYingluo; LiuYi; LiYuan

    2004-01-01

    The strategic management of large projects is both theoretically and practically important. Some scholars have advanced flexible strategy theory in China. The difference of strategic flexibility and flexible strategy is pointed out. The supporting system and characteristics of flexible strategy are analyzed. The changes of flexible strategy and integration of strategic management are discussed.

  8. Large area CMOS image sensors

    Science.gov (United States)

    Turchetta, R.; Guerrini, N.; Sedgwick, I.

    2011-01-01

    CMOS image sensors, also known as CMOS Active Pixel Sensors (APS) or Monolithic Active Pixel Sensors (MAPS), are today the dominant imaging devices. They are omnipresent in our daily life, as image sensors in cellular phones, web cams, digital cameras, ... In these applications, the pixels can be very small, in the micron range, and the sensors themselves tend to be limited in size. However, many scientific applications, like particle or X-ray detection, require large format, often with large pixels, as well as other specific performance, like low noise, radiation hardness or very fast readout. The sensors are also required to be sensitive to a broad spectrum of radiation: photons from the silicon cut-off in the IR down to UV and X- and gamma-rays through the visible spectrum as well as charged particles. This requirement calls for modifications to the substrate to be introduced to provide optimized sensitivity. This paper will review existing CMOS image sensors, whose size can be as large as a single CMOS wafer, and analyse the technical requirements and specific challenges of large format CMOS image sensors.

  9. Large molten pool heat transfer

    International Nuclear Information System (INIS)

    This workshop on large molten pool heat transfer is composed of 5 sessions which titles are: feasibility of in-vessel core debris cooling; experiments on molten pool heat transfer; calculational efforts on molten pool convection; heat transfer to the surrounding water, experimental techniques; future experiments and ex-vessel studies (RASPLAV, TOLBIAC, BALI, SULTAN, CORVIS, VULCANO, CORINE programs)

  10. Glioblastoma with oligodendroglial components: glioblastoma or anaplastic oligodendroglial tumors.

    Science.gov (United States)

    Takeuchi, Hiroaki; Hosoda, Tetsuya; Kitai, Ryuhei; Kodera, Toshiaki; Arishima, Hidetaka; Tsunetoshi, Kenzo; Neishi, Hiroyuki; Yamauchi, Takahiro; Sato, Kazufumi; Imamura, Yoshiyuki; Itoh, Hiroshi; Kubota, Toshihiko; Kikuta, Ken-ichiro

    2012-07-01

    There have been some recent reports about glioblastoma with oligodendroglial (OG) components and malignant glioma with primitive neuroectodermal tumor (PNET)-like components. We investigated whether the presence and extent of OG components and PNET-like components influenced the prognosis in patients with glioblastoma. Eighty-six patients with glioblastoma were divided into an OG group (28 %), which revealed areas with a honeycomb appearance, and a non-OG group (72 %) without a honeycomb appearance. Patients with glioblastoma were also divided into a PNET group (27 %), which revealed areas with PNET-like features defined as neoplastic cells with high N/C ratios and hyperchromatic oval-carrot-shaped nuclei, and lacked the typical honeycomb appearance, and a non-PNET group (73 %) without PNET features. There were no significant differences in overall survival among the OG, the non-OG, the PNET, and the non-PNET groups. Two patients who survived longer than 36 months had both OG and PNET components with 1p or 19q loss of heterozygosity. Perinuclear halo, which is a characteristic feature of oligodendrogliomas, is an artifact of tissue fixation. Therefore, we should not readily use the term glioblastoma with OG components. PNET-like components, which are considered rare in malignant gliomas, may be frequently identified in glioblastomas. PMID:22527749

  11. Psoriatic Arthritis during Treatment with Bevacizumab for Anaplastic Oligodendroglioma

    Directory of Open Access Journals (Sweden)

    D. Graceffa

    2012-01-01

    Full Text Available Bevacizumab is a recombinant humanised monoclonal antibody directed against the vascular endothelial growth factor (VEGF. The drug, alone or in combination with other anticancer agents, has been shown to be effective against several types of neoplasms. We report a case of a woman with a history of severe psoriasis who developed psoriatic arthritis during a course of bevacizumab, which was administered for a malignant glioma.

  12. Cutaneous CD30-positive lymphoproliferations : clinical and molecular aspects and differential diagnosis

    NARCIS (Netherlands)

    Benner, Marchina Frederika

    2012-01-01

    The studies presented in this thesis focused on cutaneous CD30-positive lymphoproliferations, particularly on primary cutaneous anaplastic large cell lymphoma (C-ALCL), a distinct type of cutaneous T-cell lymphoma (CTCL). In the initial staging of patients with an anaplastic large cell lymphoma firs

  13. Chunking of Large Multidimensional Arrays

    Energy Technology Data Exchange (ETDEWEB)

    Rotem, Doron; Otoo, Ekow J.; Seshadri, Sridhar

    2007-02-28

    Data intensive scientific computations as well on-lineanalytical processing applications as are done on very large datasetsthat are modeled as k-dimensional arrays. The storage organization ofsuch arrays on disks is done by partitioning the large global array intofixed size hyper-rectangular sub-arrays called chunks or tiles that formthe units of data transfer between disk and memory. Typical queriesinvolve the retrieval of sub-arrays in a manner that accesses all chunksthat overlap the query results. An important metric of the storageefficiency is the expected number of chunks retrieved over all suchqueries. The question that immediately arises is "what shapes of arraychunks give the minimum expected number of chunks over a query workload?"In this paper we develop two probabilistic mathematical models of theproblem and provide exact solutions using steepest descent and geometricprogramming methods. Experimental results, using synthetic workloads onreal life data sets, show that our chunking is much more efficient thanthe existing approximate solutions.

  14. Large Aspect Ratio Tokamak Study

    International Nuclear Information System (INIS)

    The Large Aspect Ratio Tokamak Study (LARTS) at Oak Ridge National Laboratory (ORNL) investigated the potential for producing a viable longburn tokamak reactor by enhancing the volt-second capability of the ohmic heating transformer through the use of high aspect ratio designs. The plasma physics, engineering, and economic implications of high aspect ratio tokamaks were assessed in the context of extended burn operation. Using a one-dimensional transport code plasma startup and burn parameters were addressed. The pulsed electrical power requirements for the poloidal field system, which have a major impact on reactor economics, were minimized by optimizing the startup and shutdown portions of the tokamak cycle. A representative large aspect ratio tokamak with an aspect ratio of 8 was found to achieve a burn time of 3.5 h at capital cost only approx. 25% greater than that of a moderate aspect ratio design tokamak

  15. Neutrinos Confronting Large Extra Dimensions

    CERN Document Server

    Maalampi, J; Vilja, I

    2001-01-01

    We study neutrino physics in a model with one large extra dimension. We assume the existence of two four-dimensional branes in the five-dimensional space-time, one for the ordinary particles and the other one for mirror particles, and we investigate neutrino masses and mixings in this scheme. Comparison of experimental neutrino data with the predictions of the model leads to various restrictions on the parameters of the model. For instance, the size of the extra dimension, R, turns out to be bounded from below. Cosmological considerations seem to favor a large R. The usual mixing schemes proposed as solutions to the solar and atmospheric neutrino anomalies are compatible with our model.

  16. Large floating structures technological advances

    CERN Document Server

    Wang, BT

    2015-01-01

    This book surveys key projects that have seen the construction of large floating structures or have attained detailed conceptual designs. This compilation of key floating structures in a single volume captures the innovative features that mark the technological advances made in this field of engineering, and will provide a useful reference for ideas, analysis, design, and construction of these unique and emerging urban projects to offshore and marine engineers, urban planners, architects and students.

  17. Very large solid angle spectrometers

    International Nuclear Information System (INIS)

    The basic conditions of coincidence experiments are discussed and some of the properties of specific detectors covering up to 90% of 4π steradian and presenting a very large momentum bite are shown. It will appear that such detectors, compared to classical iron dipole spectrometers, present larger acceptances, but a smaller resolving power and a rather low background rejection. The choice of which of these two solutions is to be used depends on the conditions of the specific experiments

  18. Quantum ergodicity on large graphs

    OpenAIRE

    Anantharaman, Nalini

    2015-01-01

    We give three different proofs of the main result of Anantharaman-Le Masson, establishing quantum ergodicity -- a form of delocalization --for eigenfunctions of the laplacian on large regular graphs of fixed degree. These three proofs are much shorter than the original one, quite different from one another, and we feelthat each of the four proofs sheds a different light on the problem. The goal of this exploration is to find a proof that could be adapted for othermodels of interest in mathema...

  19. Testing gravity on Large Scales

    OpenAIRE

    Raccanelli Alvise

    2013-01-01

    We show how it is possible to test general relativity and different models of gravity via Redshift-Space Distortions using forthcoming cosmological galaxy surveys. However, the theoretical models currently used to interpret the data often rely on simplifications that make them not accurate enough for precise measurements. We will discuss improvements to the theoretical modeling at very large scales, including wide-angle and general relativistic corrections; we then show that for wide and deep...

  20. Correlations between large prime numbers

    OpenAIRE

    Bershadskii, A.

    2011-01-01

    It is shown that short-range correlations between large prime numbers (~10^5 and larger) have a Poissonian nature. Correlation length \\zeta = 4.5 for the primes ~10^5 and it is increasing logarithmically according to the prime number theorem. For moderate prime numbers (~10^4) the Poissonian distribution is not applicable while the correlation length surprisingly continues to follow to the logarithmical law. A chaotic (deterministic) hypothesis has been suggested to explain the moderate prime...

  1. Additive Manufacturing for Large Products

    OpenAIRE

    Leirvåg, Roar Nelissen

    2013-01-01

    This thesis researches the possibility and feasibility of applying additive manufacturing technology in the manufacturing of propellers. The thesis concerns the production at the foundry Oshaug Metall AS. Their products consist of propellers and other large products cast in Nickel-Aluminium Bronze. This report looks at three approaches and applications for additive manufacturing at the foundry. These are additively manufactured pattern, sand mold and end metal parts. The available \\emph{State...

  2. Elliptic Flow at Large Viscosity

    OpenAIRE

    Koch, Volker

    2009-01-01

    In this contribution we present an alternative scenario for the large elliptic flow observed in relativistic heavy ion collisions. Motivated by recent results from Lattice QCD on flavor off-diagonal susceptibilities we argue that the matter right above $T_{c}$ can be described by single-particle dynamics in a repulsive single-particle potential, which in turn gives rise to elliptic flow. These ideas can be tested experimentally by measuring elliptic flow of heavy quarks, preferably via the me...

  3. A Large Area Timing RPC

    CERN Document Server

    Blanco, A; Finck, C; Fonte, Paulo J R; Gobbi, A; Policarpo, Armando; Rozas, M; Finck, Ch.

    2001-01-01

    A large area Resistive Plate Chamber (RPC) with a total active surface of 160x10 cm2 was built and tested. The surface was segmented in two 5 cm wide strips readout on both ends with custom, very high frequency, front end electronics. A timing resolution between 50 and 75 ps sigma with an efficiency for Minimum Ionizing Particles (MIPs) larger than 95% was attained over the whole active area, in addition with a position resolution along the strips of 1.2 cm. Despite the large active area per electronic channel, the observed timing resolution is remarkably close to the one previously obtained (50 ps sigma) with much smaller chambers of about 10 cm2 area. These results open perspectives of extending the application of timing RPCs to large area arrays exposed to moderate particle multiplicities, where the low cost, good time resolution, insensitivity to the magnetic field and compact mechanics may be attractive when compared with the standard scintillator-based Time-of-Flight (TOF) technology.

  4. Large wood recruitment and transport during large floods: A review

    Science.gov (United States)

    Comiti, F.; Lucía, A.; Rickenmann, D.

    2016-09-01

    Large wood (LW) elements transported during large floods are long known to have the capacity to induce dangerous obstructions along the channel network, mostly at bridges and at hydraulic structures such as weirs. However, our current knowledge of wood transport dynamics during high-magnitude flood events is still very scarce, mostly because these are (locally) rare and thus unlikely to be directly monitored. Therefore, post-event surveys are invaluable ways to get insights (although indirectly) on LW recruitment processes, transport distance, and factors inducing LW deposition - all aspects that are crucial for the proper management of river basins related to flood hazard mitigation. This paper presents a review of the (quite limited) literature available on LW transport during large floods, drawing extensively on the authors' own experience in mountain and piedmont rivers, published and unpublished. The overall picture emerging from these studies points to a high, catchment-specific variability in all the different processes affecting LW dynamics during floods. Specifically, in the LW recruitment phase, the relative floodplain (bank erosion) vs. hillslope (landslide and debris flows) contribution in mountain rivers varies substantially, as it relates to the extent of channel widening (which depends on many variables itself) but also to the hillslope-channel connectivity of LW mobilized on the slopes. As to the LW transport phase within the channel network, it appears to be widely characterized by supply-limited conditions; whereby LW transport rates (and thus volumes) are ultimately constrained by the amount of LW that is made available to the flow. Indeed, LW deposition during floods was mostly (in terms of volume) observed at artificial structures (bridges) in all the documented events. This implies that the estimation of LW recruitment and the assessment of clogging probabilities for each structure (for a flood event of given magnitude) are the most important

  5. Radiosurgery for Large Brain Metastases

    International Nuclear Information System (INIS)

    Purpose: To determine the efficacy and safety of radiosurgery in patients with large brain metastases treated with radiosurgery. Patients and Methods: Eighty patients with large brain metastases (>14 cm3) were treated with radiosurgery between 1998 and 2009. The mean age was 59 ± 11 years, and 49 (61.3%) were men. Neurologic symptoms were identified in 77 patients (96.3%), and 30 (37.5%) exhibited a dependent functional status. The primary disease was under control in 36 patients (45.0%), and 44 (55.0%) had a single lesion. The mean tumor volume was 22.4 ± 8.8 cm3, and the mean marginal dose prescribed was 13.8 ± 2.2 Gy. Results: The median survival time from radiosurgery was 7.9 months (95% confidence interval [CI], 5.343–10.46), and the 1-year survival rate was 39.2%. Functional improvement within 1–4 months or the maintenance of the initial independent status was observed in 48 (60.0%) and 20 (25.0%) patients after radiosurgery, respectively. Control of the primary disease, a marginal dose of ≥11 Gy, and a tumor volume ≥26 cm3 were significantly associated with overall survival (hazard ratio, 0.479; p = .018; 95% CI, 0.261–0.880; hazard ratio, 0.350; p = .004; 95% CI, 0.171–0.718; hazard ratio, 2.307; p = .006; 95% CI, 1.274–4.180, respectively). Unacceptable radiation-related toxicities (Radiation Toxicity Oncology Group central nervous system toxicity Grade 3, 4, and 5 in 7, 6, and 2 patients, respectively) developed in 15 patients (18.8%). Conclusion: Radiosurgery seems to have a comparable efficacy with surgery for large brain metastases. However, the rate of radiation-related toxicities after radiosurgery should be considered when deciding on a treatment modality.

  6. Large-bore pipe decontamination

    International Nuclear Information System (INIS)

    The decontamination and decommissioning (D and D) of 1200 buildings within the US Department of Energy-Office of Environmental Management (DOE-EM) Complex will require the disposition of miles of pipe. The disposition of large-bore pipe, in particular, presents difficulties in the area of decontamination and characterization. The pipe is potentially contaminated internally as well as externally. This situation requires a system capable of decontaminating and characterizing both the inside and outside of the pipe. Current decontamination and characterization systems are not designed for application to this geometry, making the direct disposal of piping systems necessary in many cases. The pipe often creates voids in the disposal cell, which requires the pipe to be cut in half or filled with a grout material. These methods are labor intensive and costly to perform on large volumes of pipe. Direct disposal does not take advantage of recycling, which could provide monetary dividends. To facilitate the decontamination and characterization of large-bore piping and thereby reduce the volume of piping required for disposal, a detailed analysis will be conducted to document the pipe remediation problem set; determine potential technologies to solve this remediation problem set; design and laboratory test potential decontamination and characterization technologies; fabricate a prototype system; provide a cost-benefit analysis of the proposed system; and transfer the technology to industry. This report summarizes the activities performed during fiscal year 1997 and describes the planned activities for fiscal year 1998. Accomplishments for FY97 include the development of the applicable and relevant and appropriate regulations, the screening of decontamination and characterization technologies, and the selection and initial design of the decontamination system

  7. Large number discrimination by mosquitofish.

    Directory of Open Access Journals (Sweden)

    Christian Agrillo

    Full Text Available BACKGROUND: Recent studies have demonstrated that fish display rudimentary numerical abilities similar to those observed in mammals and birds. The mechanisms underlying the discrimination of small quantities (<4 were recently investigated while, to date, no study has examined the discrimination of large numerosities in fish. METHODOLOGY/PRINCIPAL FINDINGS: Subjects were trained to discriminate between two sets of small geometric figures using social reinforcement. In the first experiment mosquitofish were required to discriminate 4 from 8 objects with or without experimental control of the continuous variables that co-vary with number (area, space, density, total luminance. Results showed that fish can use the sole numerical information to compare quantities but that they preferentially use cumulative surface area as a proxy of the number when this information is available. A second experiment investigated the influence of the total number of elements to discriminate large quantities. Fish proved to be able to discriminate up to 100 vs. 200 objects, without showing any significant decrease in accuracy compared with the 4 vs. 8 discrimination. The third experiment investigated the influence of the ratio between the numerosities. Performance was found to decrease when decreasing the numerical distance. Fish were able to discriminate numbers when ratios were 1:2 or 2:3 but not when the ratio was 3:4. The performance of a sample of undergraduate students, tested non-verbally using the same sets of stimuli, largely overlapped that of fish. CONCLUSIONS/SIGNIFICANCE: Fish are able to use pure numerical information when discriminating between quantities larger than 4 units. As observed in human and non-human primates, the numerical system of fish appears to have virtually no upper limit while the numerical ratio has a clear effect on performance. These similarities further reinforce the view of a common origin of non-verbal numerical systems in all

  8. Large-bore pipe decontamination

    Energy Technology Data Exchange (ETDEWEB)

    Ebadian, M.A.

    1998-01-01

    The decontamination and decommissioning (D and D) of 1200 buildings within the US Department of Energy-Office of Environmental Management (DOE-EM) Complex will require the disposition of miles of pipe. The disposition of large-bore pipe, in particular, presents difficulties in the area of decontamination and characterization. The pipe is potentially contaminated internally as well as externally. This situation requires a system capable of decontaminating and characterizing both the inside and outside of the pipe. Current decontamination and characterization systems are not designed for application to this geometry, making the direct disposal of piping systems necessary in many cases. The pipe often creates voids in the disposal cell, which requires the pipe to be cut in half or filled with a grout material. These methods are labor intensive and costly to perform on large volumes of pipe. Direct disposal does not take advantage of recycling, which could provide monetary dividends. To facilitate the decontamination and characterization of large-bore piping and thereby reduce the volume of piping required for disposal, a detailed analysis will be conducted to document the pipe remediation problem set; determine potential technologies to solve this remediation problem set; design and laboratory test potential decontamination and characterization technologies; fabricate a prototype system; provide a cost-benefit analysis of the proposed system; and transfer the technology to industry. This report summarizes the activities performed during fiscal year 1997 and describes the planned activities for fiscal year 1998. Accomplishments for FY97 include the development of the applicable and relevant and appropriate regulations, the screening of decontamination and characterization technologies, and the selection and initial design of the decontamination system.

  9. Active Learning in Large Classes

    DEFF Research Database (Denmark)

    Gørtz, Inge Li

    2011-01-01

    teaching large classes (more than 50 students), and describe how we successfully have in a second semester course in the Bachelor of Engineering (BEng) and Bachelor of Science Engineering (BSc Eng) program at the Technical University of Denmark (DTU). Approximately 200 students is attending...... the lectures in the course. The main idea is to use inductive, case-based learning, with many small exercises/ discussions during the lectures. We describe a framework for the lectures, that most lectures in the class were based on. The framework contains the conceive, design, and implement stage from the CDIO...

  10. Japanese large-scale interferometers

    International Nuclear Information System (INIS)

    The objective of the TAMA 300 interferometer was to develop advanced technologies for kilometre scale interferometers and to observe gravitational wave events in nearby galaxies. It was designed as a power-recycled Fabry-Perot-Michelson interferometer and was intended as a step towards a final interferometer in Japan. The present successful status of TAMA is presented. TAMA forms a basis for LCGT (large-scale cryogenic gravitational wave telescope), a 3 km scale cryogenic interferometer to be built in the Kamioka mine in Japan, implementing cryogenic mirror techniques. The plan of LCGT is schematically described along with its associated R and D

  11. Large volume cryogenic silicon detectors

    Energy Technology Data Exchange (ETDEWEB)

    Braggio, C. [Dipartimento di Fisica, Universita di Padova, via Marzolo 8, 35131 Padova (Italy); Boscardin, M. [Fondazione Bruno Kessler (FBK), via Sommarive 18, I-38100 Povo (Italy); Bressi, G. [INFN sez. di Pavia, via Bassi 6, 27100 Pavia (Italy); Carugno, G.; Corti, D. [INFN sez. di Padova, via Marzolo 8, 35131 Padova (Italy); Galeazzi, G. [INFN lab. naz. Legnaro, viale dell' Universita 2, 35020 Legnaro (Italy); Zorzi, N. [Fondazione Bruno Kessler (FBK), via Sommarive 18, I-38100 Povo (Italy)

    2009-12-15

    We present preliminary measurements for the development of a large volume silicon detector to detect low energy and low rate energy depositions. The tested detector is a one cm-thick silicon PIN diode with an active volume of 31 cm{sup 3}, cooled to the liquid helium temperature to obtain depletion from thermally-generated free carriers. A thorough study has been done to show that effects of charge trapping during drift disappears at a bias field value of the order of 100V/cm.

  12. Guam shaken by large quake

    Science.gov (United States)

    White, M. Catherine

    On August 8, an earthquake registering 8.1 on the Richter scale shook the Mariana Trench, which lies to the southeast of Guam, causing a rupture 55-60 km deep. Because large earthquakes are quite rare in the Mariana region, this significant thrust-type event offers a unique opportunity for study.The U.S. Geological Survey reports that seismic activity continued for several days after the earthquake. On August 11, an aftershock measuring 6.1 struck 40 miles southeast of Agana, Guam.

  13. The Large Aperture GRB Observatory

    CERN Document Server

    Allard, D; Asorey, H; Barros, H; Bertou, X; Castillo, M; Chirinos, J M; De Castro, A; Flores, S; González, J; Berisso, M Gomez; Grajales, J; Guada, C; Day, W R Guevara; Ishitsuka, J; López, J A; Martínez, O; Melfo, A; Meza, E; Loza, P Miranda; Barbosa, E Moreno; Murrugarra, C; Núñez, L A; Ormachea, L J Otiniano; Pérez, G; Perez, Y; Ponce, E; Quispe, J; Quintero, C; Rivera, H; Rosales, M; Rovero, A C; Saavedra, O; Salazar, H; Tello, J C; Peralda, R Ticona; Varela, E; Velarde, A; Villaseñor, L; Wahl, D; Zamalloa, M A

    2009-01-01

    The Large Aperture GRB Observatory (LAGO) is aiming at the detection of the high energy (around 100 GeV) component of Gamma Ray Bursts, using the single particle technique in arrays of Water Cherenkov Detectors (WCD) in high mountain sites (Chacaltaya, Bolivia, 5300 m a.s.l., Pico Espejo, Venezuela, 4750 m a.s.l., Sierra Negra, Mexico, 4650 m a.s.l). WCD at high altitude offer a unique possibility of detecting low gamma fluxes in the 10 GeV - 1 TeV range. The status of the Observatory and data collected from 2007 to date will be presented.

  14. Large area and flexible electronics

    CERN Document Server

    Caironi, Mario

    2015-01-01

    From materials to applications, this ready reference covers the entire value chain from fundamentals via processing right up to devices, presenting different approaches to large-area electronics, thus enabling readers to compare materials, properties and performance.Divided into two parts, the first focuses on the materials used for the electronic functionality, covering organic and inorganic semiconductors, including vacuum and solution-processed metal-oxide semiconductors, nanomembranes and nanocrystals, as well as conductors and insulators. The second part reviews the devices and applicatio

  15. Quick Mining of Isomorphic Exact Large Patterns from Large Graphs

    KAUST Repository

    Almasri, Islam

    2014-12-01

    The applications of the sub graph isomorphism search are growing with the growing number of areas that model their systems using graphs or networks. Specifically, many biological systems, such as protein interaction networks, molecular structures and protein contact maps, are modeled as graphs. The sub graph isomorphism search is concerned with finding all sub graphs that are isomorphic to a relevant query graph, the existence of such sub graphs can reflect on the characteristics of the modeled system. The most computationally expensive step in the search for isomorphic sub graphs is the backtracking algorithm that traverses the nodes of the target graph. In this paper, we propose a pruning approach that is inspired by the minimum remaining value heuristic that achieves greater scalability over large query and target graphs. Our testing on various biological networks shows that performance enhancement of our approach over existing state-of-the-art approaches varies between 6x and 53x. © 2014 IEEE.

  16. Large scale cluster computing workshop

    Energy Technology Data Exchange (ETDEWEB)

    Dane Skow; Alan Silverman

    2002-12-23

    Recent revolutions in computer hardware and software technologies have paved the way for the large-scale deployment of clusters of commodity computers to address problems heretofore the domain of tightly coupled SMP processors. Near term projects within High Energy Physics and other computing communities will deploy clusters of scale 1000s of processors and be used by 100s to 1000s of independent users. This will expand the reach in both dimensions by an order of magnitude from the current successful production facilities. The goals of this workshop were: (1) to determine what tools exist which can scale up to the cluster sizes foreseen for the next generation of HENP experiments (several thousand nodes) and by implication to identify areas where some investment of money or effort is likely to be needed. (2) To compare and record experimences gained with such tools. (3) To produce a practical guide to all stages of planning, installing, building and operating a large computing cluster in HENP. (4) To identify and connect groups with similar interest within HENP and the larger clustering community.

  17. Quantum chromodynamics at large distances

    International Nuclear Information System (INIS)

    The properties of quantum chromodynamics (QCD)at large distances are considered in the framework of traditional quantum field theory. The parameters that determine the infrared region are determined self-consistently by means of the renormalization-group method. Recent studies that confirm a singular infrared asymptotic behavior M2 /(k2 )2 of the gluon propagator are reviewed. Solutions of the Schwinger--Dyson equation for the quark propagator are found with the necessary properties: spontaneous breaking of the chiral invariance and a nonperturbative nature. The infrared behaviors of the lowest Green's functions are used to calculate the vacuum expectation values of the gluon and quark fields. Good agreement between the calculated vacuum expectation values and their phenomenological values is obtained. The study of the behavior of QCD at large distances leads to the conclusion that at the present level of development of the theory two possibilities can be discussed. The first is the well-known confinement hypothesis; the second has been called incomplete confinement and necessarily implies that open color can be observed. It is shown that the second possibility does not contradict existing experiments. Experimental data on anomalous nuclear fragments and ultra-high-energy radiation from the galactic source Cygnus X-3 are considered as evidence for incomplete confinement. The importance of searches for states with open color is emphasized

  18. Large-mode enhancement cavities.

    Science.gov (United States)

    Carstens, Henning; Holzberger, Simon; Kaster, Jan; Weitenberg, Johannes; Pervak, Volodymyr; Apolonski, Alexander; Fill, Ernst; Krausz, Ferenc; Pupeza, Ioachim

    2013-05-01

    In passive enhancement cavities the achievable power level is limited by mirror damage. Here, we address the design of robust optical resonators with large spot sizes on all mirrors, a measure that promises to mitigate this limitation by decreasing both the intensity and the thermal gradient on the mirror surfaces. We introduce a misalignment sensitivity metric to evaluate the robustness of resonator designs. We identify the standard bow-tie resonator operated close to the inner stability edge as the most robust large-mode cavity and implement this cavity with two spherical mirrors with 600 mm radius of curvature, two plane mirrors and a round trip length of 1.2 m, demonstrating a stable power enhancement of near-infrared laser light by a factor of 2000. Beam radii of 5.7 mm × 2.6 mm (sagittal × tangential 1/e(2) intensity radius) on all mirrors are obtained. We propose a simple all-reflective ellipticity compensation scheme. This will enable a significant increase of the attainable power and intensity levels in enhancement cavities. PMID:23670017

  19. Large-scale river regulation

    International Nuclear Information System (INIS)

    Recent concern over human impacts on the environment has tended to focus on climatic change, desertification, destruction of tropical rain forests, and pollution. Yet large-scale water projects such as dams, reservoirs, and inter-basin transfers are among the most dramatic and extensive ways in which our environment has been, and continues to be, transformed by human action. Water running to the sea is perceived as a lost resource, floods are viewed as major hazards, and wetlands are seen as wastelands. River regulation, involving the redistribution of water in time and space, is a key concept in socio-economic development. To achieve water and food security, to develop drylands, and to prevent desertification and drought are primary aims for many countries. A second key concept is ecological sustainability. Yet the ecology of rivers and their floodplains is dependent on the natural hydrological regime, and its related biochemical and geomorphological dynamics. (Author)

  20. Large errors and severe conditions

    CERN Document Server

    Smith, D L; Van Wormer, L A

    2002-01-01

    Physical parameters that can assume real-number values over a continuous range are generally represented by inherently positive random variables. However, if the uncertainties in these parameters are significant (large errors), conventional means of representing and manipulating the associated variables can lead to erroneous results. Instead, all analyses involving them must be conducted in a probabilistic framework. Several issues must be considered: First, non-linear functional relations between primary and derived variables may lead to significant 'error amplification' (severe conditions). Second, the commonly used normal (Gaussian) probability distribution must be replaced by a more appropriate function that avoids the occurrence of negative sampling results. Third, both primary random variables and those derived through well-defined functions must be dealt with entirely in terms of their probability distributions. Parameter 'values' and 'errors' should be interpreted as specific moments of these probabil...

  1. Analysis of large urban fires

    International Nuclear Information System (INIS)

    Fires in urban areas caused by a nuclear burst are analyzed as a first step towards determining their smoke-generation chacteristics, which may have grave implications for global-scale climatic consequences. A chain of events and their component processes which would follow a nuclear attack are described. A numerical code is currently being developed to calculate ultimately the smoke production rate for a given attack scenario. Available models for most of the processes are incorporated into the code. Sample calculations of urban fire-development history performed in the code for an idealized uniform city are presented. Preliminary results indicate the importance of the wind, thermal radiation transmission, fuel distributions, and ignition thresholds on the urban fire spread characteristics. Future plans are to improve the existing models and develop new ones to characterize smoke production from large urban fires. 21 references, 18 figures

  2. Author Clustering on Large Bibliographies

    CERN Document Server

    Sterz, Christoph

    2014-01-01

    We analyze and design an algorithm for clustering large sets of authors in Bibliographies. Not considering a distance function for a mutual comparison, but transforming the data into a multidimensional metric space, the algorithm described is similar to locally sensitive hashing. The task lies in the field of Record-Linkage. The algorithm was designed and performed based on the data of the CERN Document Server, consisting out of more than 1.7 million metadata entries and is part of the digital assets-managing-software invenio. Meant as a prototype, the algorithm performs efficiently, clustering all authors on CDS in under 30 minutes. We will discuss extensions improving the recall rate, wich still remains inferior to the currently used clustering-approach.

  3. Biotherapies in large vessel vasculitis.

    Science.gov (United States)

    Ferfar, Y; Mirault, T; Desbois, A C; Comarmond, C; Messas, E; Savey, L; Domont, F; Cacoub, P; Saadoun, D

    2016-06-01

    Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) and aortic involvement is not uncommon in Behcet's disease (BD) and relapsing polychondritis (RP). Glucocorticosteroids are the mainstay of therapy in LVV. However, a significant proportion of patients have glucocorticoid dependance, serious side effects or refractory disease to steroids and other immunosuppressive treatments such as cyclophosphamide, azathioprine, mycophenolate mofetil and methotrexate. Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with LVV. Anti-tumor necrosis factor-α drugs seem effective in patients with refractory Takayasu arteritis and vascular BD but have failed to do so in giant cell arteritis. Preliminary reports on the use of the anti-IL6-receptor antibody (tocilizumab), in LVV have been encouraging. The development of new biologic targeted therapies will probably open a promising future for patients with LVV. PMID:26883459

  4. Polarimetric calibration of large mirrors

    CERN Document Server

    Ariste, A Lopez

    2015-01-01

    Aims: To propose a method for the polarimetric calibration of large astronomical mirrors that does not require use of special optical devices nor knowledge of the exact polarization properties of the calibration target. Methods: We study the symmetries of the Mueller matrix of mirrors to exploit them for polarimetric calibration under the assumptions that only the orientation of the linear polarization plane of the calibration target is known with certainty. Results: A method is proposed to calibrate the polarization effects of single astronomical mirrors by the observation of calibration targets with known orientation of the linear polarization. We study the uncertainties of the method and the signal-to-noise ratios required for an acceptable calibration. We list astronomical targets ready for the method. We finally extend the method to the calibration of two or more mirrors, in particular to the case when they share the same incidence plane.

  5. Great expectations: large wind turbines

    International Nuclear Information System (INIS)

    This article focuses on wind turbine product development, and traces the background to wind turbines from the first generation 1.5 MW machines in 1995-6, plans for the second generation 3-5 MW class turbines to meet the expected boom in offshore wind projects, to the anticipated installation of a 4.5 MW turbine, and offshore wind projects planned for 2000-2002. The switch by the market leader Vestas to variable speed operation in 2000, the new product development and marketing strategy taken by the German Pro + Pro consultancy in their design of a 1.5 MW variable speed pitch control concept, the possible limiting of the size of turbines due to logistical difficulties, opportunities offered by air ships for large turbines, and the commissioning of offshore wind farms are discussed. Details of some 2-5 MW offshore wind turbine design specifications are tabulated

  6. Large-scale solar heating

    Energy Technology Data Exchange (ETDEWEB)

    Tolonen, J.; Konttinen, P.; Lund, P. [Helsinki Univ. of Technology, Otaniemi (Finland). Advanced Energy Systems

    1998-10-01

    Solar heating market is growing in many European countries and annually installed collector area has exceeded one million square meters. There are dozens of collector manufacturers and hundreds of firms making solar heating installations in Europe. One tendency in solar heating is towards larger systems. These can be roof integrated, consisting of some tens or hundreds of square meters of collectors, or they can be larger centralized solar district heating plants consisting of a few thousand square meters of collectors. The increase of size can reduce the specific investments of solar heating systems, because e.g. the costs of some components (controllers, pumps, and pipes), planning and installation can be smaller in larger systems. The solar heat output can also be higher in large systems, because more advanced technique is economically viable

  7. Multipole correction in large synchrotrons

    International Nuclear Information System (INIS)

    A new method of correcting dynamic nonlinearities due to the multipole content of a synchrotron such as the Superconducting Super Collider is discussed. The method uses lumped multipole elements placed at the center (C) of the accelerator half-cells as well as elements near the focusing (F) and defocusing (D) quads. In a first approximation, the corrector strengths follow Simpson's Rule. Correction of second-order sextupole nonlinearities may also be obtained with the F, C, and D octupoles. Correction of nonlinearities by about three orders of magnitude are obtained, and simple solutions to a fundamental problem in synchrotrons are demonstrated. Applications to the CERN Large Hadron Collider and lower energy machines, as well as extensions for quadrupole correction, are also discussed

  8. Adaptive Optics for Large Telescopes

    Energy Technology Data Exchange (ETDEWEB)

    Olivier, S

    2008-06-27

    The use of adaptive optics was originally conceived by astronomers seeking to correct the blurring of images made with large telescopes due to the effects of atmospheric turbulence. The basic idea is to use a device, a wave front corrector, to adjust the phase of light passing through an optical system, based on some measurement of the spatial variation of the phase transverse to the light propagation direction, using a wave front sensor. Although the original concept was intended for application to astronomical imaging, the technique can be more generally applied. For instance, adaptive optics systems have been used for several decades to correct for aberrations in high-power laser systems. At Lawrence Livermore National Laboratory (LLNL), the world's largest laser system, the National Ignition Facility, uses adaptive optics to correct for aberrations in each of the 192 beams, all of which must be precisely focused on a millimeter scale target in order to perform nuclear physics experiments.

  9. Large Eddy Simulations in Astrophysics

    CERN Document Server

    Schmidt, Wolfram

    2014-01-01

    In this review, the methodology of large eddy simulations (LES) is introduced and applications in astrophysics are discussed. As theoretical framework, the scale decomposition of the dynamical equations for neutral fluids by means of spatial filtering is explained. For cosmological applications, the filtered equations in comoving coordinates are also presented. To obtain a closed set of equations that can be evolved in LES, several subgrid scale models for the interactions between numerically resolved and unresolved scales are discussed, in particular the subgrid scale turbulence energy equation model. It is then shown how model coefficients can be calculated, either by dynamical procedures or, a priori, from high-resolution data. For astrophysical applications, adaptive mesh refinement is often indispensable. It is shown that the subgrid scale turbulence energy model allows for a particularly elegant and physically well motivated way of preserving momentum and energy conservation in AMR simulations. Moreover...

  10. Testing gravity on Large Scales

    Directory of Open Access Journals (Sweden)

    Raccanelli Alvise

    2013-09-01

    Full Text Available We show how it is possible to test general relativity and different models of gravity via Redshift-Space Distortions using forthcoming cosmological galaxy surveys. However, the theoretical models currently used to interpret the data often rely on simplifications that make them not accurate enough for precise measurements. We will discuss improvements to the theoretical modeling at very large scales, including wide-angle and general relativistic corrections; we then show that for wide and deep surveys those corrections need to be taken into account if we want to measure the growth of structures at a few percent level, and so perform tests on gravity, without introducing systematic errors. Finally, we report the results of some recent cosmological model tests carried out using those precise models.

  11. Conference on Large Scale Optimization

    CERN Document Server

    Hearn, D; Pardalos, P

    1994-01-01

    On February 15-17, 1993, a conference on Large Scale Optimization, hosted by the Center for Applied Optimization, was held at the University of Florida. The con­ ference was supported by the National Science Foundation, the U. S. Army Research Office, and the University of Florida, with endorsements from SIAM, MPS, ORSA and IMACS. Forty one invited speakers presented papers on mathematical program­ ming and optimal control topics with an emphasis on algorithm development, real world applications and numerical results. Participants from Canada, Japan, Sweden, The Netherlands, Germany, Belgium, Greece, and Denmark gave the meeting an important international component. At­ tendees also included representatives from IBM, American Airlines, US Air, United Parcel Serice, AT & T Bell Labs, Thinking Machines, Army High Performance Com­ puting Research Center, and Argonne National Laboratory. In addition, the NSF sponsored attendance of thirteen graduate students from universities in the United States and abro...

  12. Robust large dimension terahertz cloaking

    CERN Document Server

    Liang, Dachuan; Han, Jiaguang; Yang, Yuanmu; Zhang, Shuang; Zhang, Weili

    2011-01-01

    Invisibility cloaking not only catches the human imagination, but also promises fascinating applications in optics and photonics. By manipulating electromagnetic waves with metamaterials, researchers have been able to realize electromagnetic cloaking in the microwave, terahertz and optical regimes. Nevertheless, the complex design and fabrication process, narrow bandwidth, and high intrinsic losses in the metamaterial-based cloaks have imposed intractable limitations on their realistic applications. Seeking new approaches to overcome these perceived disadvantages is in progress. Here by using uniform sapphire crystal, we demonstrate the first homogenous invisibility cloak functioning at terahertz frequencies. The terahertz invisibility device features a large concealed volume, low loss, and broad bandwidth. In particular, it is capable of hiding objects with a dimension nearly an order of magnitude larger than that of its lithographic counterpart, but without involving complex and time-consuming cleanroom pro...

  13. Large-Scale Information Systems

    Energy Technology Data Exchange (ETDEWEB)

    D. M. Nicol; H. R. Ammerlahn; M. E. Goldsby; M. M. Johnson; D. E. Rhodes; A. S. Yoshimura

    2000-12-01

    Large enterprises are ever more dependent on their Large-Scale Information Systems (LSLS), computer systems that are distinguished architecturally by distributed components--data sources, networks, computing engines, simulations, human-in-the-loop control and remote access stations. These systems provide such capabilities as workflow, data fusion and distributed database access. The Nuclear Weapons Complex (NWC) contains many examples of LSIS components, a fact that motivates this research. However, most LSIS in use grew up from collections of separate subsystems that were not designed to be components of an integrated system. For this reason, they are often difficult to analyze and control. The problem is made more difficult by the size of a typical system, its diversity of information sources, and the institutional complexities associated with its geographic distribution across the enterprise. Moreover, there is no integrated approach for analyzing or managing such systems. Indeed, integrated development of LSIS is an active area of academic research. This work developed such an approach by simulating the various components of the LSIS and allowing the simulated components to interact with real LSIS subsystems. This research demonstrated two benefits. First, applying it to a particular LSIS provided a thorough understanding of the interfaces between the system's components. Second, it demonstrated how more rapid and detailed answers could be obtained to questions significant to the enterprise by interacting with the relevant LSIS subsystems through simulated components designed with those questions in mind. In a final, added phase of the project, investigations were made on extending this research to wireless communication networks in support of telemetry applications.

  14. Sweetwater, Texas Large N Experiment

    Science.gov (United States)

    Sumy, D. F.; Woodward, R.; Barklage, M.; Hollis, D.; Spriggs, N.; Gridley, J. M.; Parker, T.

    2015-12-01

    From 7 March to 30 April 2014, NodalSeismic, Nanometrics, and IRIS PASSCAL conducted a collaborative, spatially-dense seismic survey with several thousand nodal short-period geophones complemented by a backbone array of broadband sensors near Sweetwater, Texas. This pilot project demonstrates the efficacy of industry and academic partnerships, and leveraged a larger, commercial 3D survey to collect passive source seismic recordings to image the subsurface. This innovative deployment of a large-N mixed-mode array allows industry to explore array geometries and investigate the value of broadband recordings, while affording academics a dense wavefield imaging capability and an operational model for high volume instrument deployment. The broadband array consists of 25 continuously-recording stations from IRIS PASSCAL and Nanometrics, with an array design that maximized recording of horizontal-traveling seismic energy for surface wave analysis over the primary target area with sufficient offset for imaging objectives at depth. In addition, 2639 FairfieldNodal Zland nodes from NodalSeismic were deployed in three sub-arrays: the outlier, backbone, and active source arrays. The backbone array consisted of 292 nodes that covered the entire survey area, while the outlier array consisted of 25 continuously-recording nodes distributed at a ~3 km distance away from the survey perimeter. Both the backbone and outlier array provide valuable constraints for the passive source portion of the analysis. This project serves as a learning platform to develop best practices in the support of large-N arrays with joint industry and academic expertise. Here we investigate lessons learned from a facility perspective, and present examples of data from the various sensors and array geometries. We will explore first-order results from local and teleseismic earthquakes, and show visualizations of the data across the array. Data are archived at the IRIS DMC under stations codes XB and 1B.

  15. Large and small photovoltaic powerplants

    Science.gov (United States)

    Cormode, Daniel

    The installed base of photovoltaic power plants in the United States has roughly doubled every 1 to 2 years between 2008 and 2015. The primary economic drivers of this are government mandates for renewable power, falling prices for all PV system components, 3rd party ownership models, and a generous tariff scheme known as net-metering. Other drivers include a desire for decreasing the environmental impact of electricity generation and a desire for some degree of independence from the local electric utility. The result is that in coming years, PV power will move from being a minor niche to a mainstream source of energy. As additional PV power comes online this will create challenges for the electric grid operators. We examine some problems related to large scale adoption of PV power in the United States. We do this by first discussing questions of reliability and efficiency at the PV system level. We measure the output of a fleet of small PV systems installed at Tucson Electric Power, and we characterize the degradation of those PV systems over several years. We develop methods to predict energy output from PV systems and quantify the impact of negatives such as partial shading, inverter inefficiency and malfunction of bypass diodes. Later we characterize the variability from large PV systems, including fleets of geographically diverse utility scale power plants. We also consider the power and energy requirements needed to smooth those systems, both from the perspective of an individual system and as a fleet. Finally we report on experiments from a utility scale PV plus battery hybrid system deployed near Tucson, Arizona where we characterize the ability of this system to produce smoothly ramping power as well as production of ancillary energy services such as frequency response.

  16. Global large carnivore conservation and international law

    NARCIS (Netherlands)

    Trouwborst, A.

    2015-01-01

    International cooperation, including through international legal instruments, appears important for the conservation of large carnivores worldwide. This is due to, inter alia, the worrying conservation status and population trends of many large carnivore species; the importance of large carnivores f

  17. Gastric Large Cell Neuroendocrine Carcinoma

    Science.gov (United States)

    Rustagi, Tarun; Alekshun, Todd J.

    2010-01-01

    Case: A 63-year-old male presented with unintentional weight loss of 20 pounds over a 4-month duration. He reported loss of appetite, intermittent post-prandial nausea, bloating and early satiety. He also complained of dyspepsia and had been treated for reflux during the previous 2 years. He denied vomiting, dysphagia, odynophagia, abdominal pain, melena, hematochezia, or alterations in bowel habits. Additionally, he denied fevers, night sweats, cough, or dyspnea. He quit smoking 25 years ago, and denied alcohol use. His past medical history was significant for basal cell carcinoma treated with local curative therapy and he was without recurrence on surveillance. Pertinent family history included a paternal uncle with lung cancer at the age of 74. Physical examination was unremarkable except for occult heme-positive stools. Laboratory evaluation revealed elevated liver enzymes (ALT-112, AST-81, AlkPhos-364). CT scan of the chest, abdomen and pelvis showed diffuse heterogeneous liver with extensive nodularity, raising the concern for metastases. Serum tumor-markers: PSA, CEA, CA 19-9, and AFP were all within normal limits. Screening colonoscopy was normal, but esophagogastroduodenoscopy revealed a malignant-appearing ulcerative lesion involving the gastro-esophageal junction and gastric cardia. Pathology confirmed an invasive gastric large cell neuroendocrine carcinoma. Ultrasound-guided fine needle aspiration of a hepatic lesion revealed malignant cells with cytologic features consistent with large-cell type carcinoma and positive immunostaining for synaptophysin favoring neuroendocrine differentiation. A PET-CT demonstrated intense diffuse FDG uptake of the liver, suggesting diffuse hepatic parenchymal infiltration by tumor. There were multiple foci of intense osseous FDG uptake with corresponding osteolytic lesions seen on CT scan. The remaining intra-abdominal and intra-thoracic structures were unremarkable. The patient will receive palliative systemic therapy

  18. Large Block Test Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Lin, W

    2001-12-01

    This report documents the Large-Block Test (LBT) conducted at Fran Ridge near Yucca Mountain, Nevada. The LBT was a thermal test conducted on an exposed block of middle non-lithophysal Topopah Spring tuff (Tptpmn) and was designed to assist in understanding the thermal-hydrological-mechanical-chemical (THMC) processes associated with heating and then cooling a partially saturated fractured rock mass. The LBT was unique in that it was a large (3 x 3 x 4.5 m) block with top and sides exposed. Because the block was exposed at the surface, boundary conditions on five of the six sides of the block were relatively well known and controlled, making this test both easier to model and easier to monitor. This report presents a detailed description of the test as well as analyses of the data and conclusions drawn from the test. The rock block that was tested during the LBT was exposed by excavation and removal of the surrounding rock. The block was characterized and instrumented, and the sides were sealed and insulated to inhibit moisture and heat loss. Temperature on the top of the block was also controlled. The block was heated for 13 months, during which time temperature, moisture distribution, and deformation were monitored. After the test was completed and the block cooled down, a series of boreholes were drilled, and one of the heater holes was over-cored to collect samples for post-test characterization of mineralogy and mechanical properties. Section 2 provides background on the test. Section 3 lists the test objectives and describes the block site, the site configuration, and measurements made during the test. Section 3 also presents a chronology of events associated with the LBT, characterization of the block, and the pre-heat analyses of the test. Section 4 describes the fracture network contained in the block. Section 5 describes the heating/cooling system used to control the temperature in the block and presents the thermal history of the block during the test

  19. Joint studies on large CANDU

    International Nuclear Information System (INIS)

    from economic, safety and strategic viewpoints. A large number of research and development programs are now in place at AECL and KAERI that will permit substantial improvements to be realized in the next generation of CANDU okabts, Furthermore, opportunities exist for engineered improvements based on the research and development in advancing the generic CANDU Technology. Final Large CANDU joint study report with technical deliverables will be issued 1994 October. Phase 2 R and D program of the joint studies will be determined this year and implemented in next year. CANDU neutron economy permits versatility in choices of fuel cycles. This allows a utility to choose fuel cycle options for lower fuelling cost, better security of supply, and ultimately for much lower spent-fuel volume, than with PWR's alone. To meet Korea's strategic requirements, CANDU should be an integral part of the electricity supply mix.

  20. Large errors and severe conditions

    International Nuclear Information System (INIS)

    Physical parameters that can assume real-number values over a continuous range are generally represented by inherently positive random variables. However, if the uncertainties in these parameters are significant (large errors), conventional means of representing and manipulating the associated variables can lead to erroneous results. Instead, all analyses involving them must be conducted in a probabilistic framework. Several issues must be considered: First, non-linear functional relations between primary and derived variables may lead to significant 'error amplification' (severe conditions). Second, the commonly used normal (Gaussian) probability distribution must be replaced by a more appropriate function that avoids the occurrence of negative sampling results. Third, both primary random variables and those derived through well-defined functions must be dealt with entirely in terms of their probability distributions. Parameter 'values' and 'errors' should be interpreted as specific moments of these probability distributions. Fourth, there are pragmatic reasons for seeking convenient analytical formulas to approximate the 'true' probability distributions of derived parameters generated by Monte Carlo simulation. This paper discusses each of these issues and illustrates the main concepts with realistic examples involving radioactivity decay and nuclear astrophysics

  1. Anthropogenic Triggering of Large Earthquakes

    Science.gov (United States)

    Mulargia, Francesco; Bizzarri, Andrea

    2014-08-01

    The physical mechanism of the anthropogenic triggering of large earthquakes on active faults is studied on the basis of experimental phenomenology, i.e., that earthquakes occur on active tectonic faults, that crustal stress values are those measured in situ and, on active faults, comply to the values of the stress drop measured for real earthquakes, that the static friction coefficients are those inferred on faults, and that the effective triggering stresses are those inferred for real earthquakes. Deriving the conditions for earthquake nucleation as a time-dependent solution of the Tresca-Von Mises criterion applied in the framework of poroelasticity yields that active faults can be triggered by fluid overpressures < 0.1 MPa. Comparing this with the deviatoric stresses at the depth of crustal hypocenters, which are of the order of 1-10 MPa, we find that injecting in the subsoil fluids at the pressures typical of oil and gas production and storage may trigger destructive earthquakes on active faults at a few tens of kilometers. Fluid pressure propagates as slow stress waves along geometric paths operating in a drained condition and can advance the natural occurrence of earthquakes by a substantial amount of time. Furthermore, it is illusory to control earthquake triggering by close monitoring of minor ``foreshocks'', since the induction may occur with a delay up to several years.

  2. Large Scale Magnetostrictive Valve Actuator

    Science.gov (United States)

    Richard, James A.; Holleman, Elizabeth; Eddleman, David

    2008-01-01

    Marshall Space Flight Center's Valves, Actuators and Ducts Design and Development Branch developed a large scale magnetostrictive valve actuator. The potential advantages of this technology are faster, more efficient valve actuators that consume less power and provide precise position control and deliver higher flow rates than conventional solenoid valves. Magnetostrictive materials change dimensions when a magnetic field is applied; this property is referred to as magnetostriction. Magnetostriction is caused by the alignment of the magnetic domains in the material s crystalline structure and the applied magnetic field lines. Typically, the material changes shape by elongating in the axial direction and constricting in the radial direction, resulting in no net change in volume. All hardware and testing is complete. This paper will discuss: the potential applications of the technology; overview of the as built actuator design; discuss problems that were uncovered during the development testing; review test data and evaluate weaknesses of the design; and discuss areas for improvement for future work. This actuator holds promises of a low power, high load, proportionally controlled actuator for valves requiring 440 to 1500 newtons load.

  3. MALIGNANCY IN LARGE COLORECTAL LESIONS

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Oliveira dos SANTOS

    2014-09-01

    Full Text Available Context The size of colorectal lesions, besides a risk factor for malignancy, is a predictor for deeper invasion Objectives To evaluate the malignancy of colorectal lesions ≥20 mm. Methods Between 2007 and 2011, 76 neoplasms ≥20 mm in 70 patients were analyzed Results The mean age of the patients was 67.4 years, and 41 were women. Mean lesion size was 24.7 mm ± 6.2 mm (range: 20 to 50 mm. Half of the neoplasms were polypoid and the other half were non-polypoid. Forty-two (55.3% lesions were located in the left colon, and 34 in the right colon. There was a high prevalence of III L (39.5% and IV (53.9% pit patterns. There were 72 adenomas and 4 adenocarcinomas. Malignancy was observed in 5.3% of the lesions. Thirty-three lesions presented advanced histology (adenomas with high-grade dysplasia or early adenocarcinoma, with no difference in morphology and site. Only one lesion (1.3% invaded the submucosa. Lesions larger than 30 mm had advanced histology (P = 0.001. The primary treatment was endoscopic resection, and invasive carcinoma was referred to surgery. Recurrence rate was 10.6%. Conclusions Large colorectal neoplasms showed a low rate of malignancy. Endoscopic treatment is an effective therapy for these lesions.

  4. Computing issues for large detectors

    International Nuclear Information System (INIS)

    The computing issues which will affect planning for experiments at RHIC is reviewed. It is traditional in workshops on new facilities to discuss the computing requirements for the experiments. Usually this discussion will focus on the number of MIPS (Million Instructions Per Second) needed to analyze the data tapes and, perhaps, the number of Terabytes of data storage. These are important parameters for planning new facilities. They are, however, only two of the features that define the computing requirements for new experiments. In this paper, the author discusses a broader range of computing issues and indicates how the problems of large experiments might be addressed on the time-scale of RHIC. In this discussion, he draws on the experiences of high energy physics groups working at colliding beam facilities, especially the Tevatron and LEP. In the colliding beam experiments, it has become increasingly important to consider the computing system as a component of the full detector system. The computing system includes online and offline computers, workstations, networks and mass-storage. It also includes software, both commercial and experiment-specific. In the next section, he reviews recent developments in computing equipment as well as mass storage and networks. In the following section, he turns to the problems of software development, testing and maintenance

  5. Large cities are less green

    CERN Document Server

    Oliveira, E A; Makse, H A

    2014-01-01

    We study how urban quality evolves as a result of carbon dioxide emissions as urban agglomerations grow. We employ a bottom-up approach combining two unprecedented microscopic data on population and carbon dioxide emissions in the continental US. We first aggregate settlements that are close to each other into cities using the City Clustering Algorithm (CCA) defining cities beyond the administrative boundaries. Then, we use data on $\\rm{CO}_2$ emissions at a fine geographic scale to determine the total emissions of each city. We find a superlinear scaling behavior, expressed by a power-law, between $\\rm{CO}_2$ emissions and city population with average allometric exponent $\\beta = 1.46$ across all cities in the US. This result suggests that the high productivity of large cities is done at the expense of a proportionally larger amount of emissions compared to small cities. Furthermore, our results are substantially different from those obtained by the standard administrative definition of cities, i.e. Metropol...

  6. Control of large space structures

    Science.gov (United States)

    Gran, R.; Rossi, M.; Moyer, H. G.; Austin, F.

    1979-01-01

    The control of large space structures was studied to determine what, if any, limitations are imposed on the size of spacecraft which may be controlled using current control system design technology. Using a typical structure in the 35 to 70 meter size category, a control system design that used actuators that are currently available was designed. The amount of control power required to maintain the vehicle in a stabilized gravity gradient pointing orientation that also damped various structural motions was determined. The moment of inertia and mass properties of this structure were varied to verify that stability and performance were maintained. The study concludes that the structure's size is required to change by at least a factor of two before any stability problems arise. The stability margin that is lost is due to the scaling of the gravity gradient torques (the rigid body control) and as such can easily be corrected by changing the control gains associated with the rigid body control. A secondary conclusion from the study is that the control design that accommodates the structural motions (to damp them) is a little more sensitive than the design that works on attitude control of the rigid body only.

  7. How large should whales be?

    Directory of Open Access Journals (Sweden)

    Aaron Clauset

    Full Text Available The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2 g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000 g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000 g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.

  8. How large should whales be?

    Science.gov (United States)

    Clauset, Aaron

    2013-01-01

    The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2 g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000 g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000 g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.

  9. Mapping change in large networks.

    Directory of Open Access Journals (Sweden)

    Martin Rosvall

    Full Text Available Change is a fundamental ingredient of interaction patterns in biology, technology, the economy, and science itself: Interactions within and between organisms change; transportation patterns by air, land, and sea all change; the global financial flow changes; and the frontiers of scientific research change. Networks and clustering methods have become important tools to comprehend instances of these large-scale structures, but without methods to distinguish between real trends and noisy data, these approaches are not useful for studying how networks change. Only if we can assign significance to the partitioning of single networks can we distinguish meaningful structural changes from random fluctuations. Here we show that bootstrap resampling accompanied by significance clustering provides a solution to this problem. To connect changing structures with the changing function of networks, we highlight and summarize the significant structural changes with alluvial diagrams and realize de Solla Price's vision of mapping change in science: studying the citation pattern between about 7000 scientific journals over the past decade, we find that neuroscience has transformed from an interdisciplinary specialty to a mature and stand-alone discipline.

  10. Large optics inspection, tilting, and washing stand

    Science.gov (United States)

    Ayers, Marion Jay; Ayers, Shannon Lee

    2010-08-24

    A large optics stand provides a risk free means of safely tilting large optics with ease and a method of safely tilting large optics with ease. The optics are supported in the horizontal position by pads. In the vertical plane the optics are supported by saddles that evenly distribute the optics weight over a large area.

  11. India's National Large Solar Telescope

    Science.gov (United States)

    Hasan, S. S.

    2012-12-01

    India's 2-m National Large Solar Telescope (NLST) is aimed primarily at carrying out observations of the solar atmosphere with high spatial and spectral resolution. A comprehensive site characterization program, that commenced in 2007, has identified two superb sites in the Himalayan region at altitudes greater than 4000-m that have extremely low water vapor content and are unaffected by monsoons. With an innovative optical design, the NLST is an on-axis Gregorian telescope with a low number of optical elements to reduce the number of reflections and yield a high throughput with low polarization. In addition, it is equipped with a high-order adaptive optics to produce close to diffraction limited performance. To control atmospheric and thermal perturbations of the observations, the telescope will function with a fully open dome, to achieve its full potential atop a 25 m tower. Given its design, NLST can also operate at night, without compromising its solar performance. The post-focus instruments include broad-band and tunable Fabry-Pérot narrow-band imaging instruments; a high resolution spectropolarimeter and an Echelle spectrograph for night time astronomy. This project is led by the Indian Institute of Astrophysics and has national and international partners. Its geographical location will fill the longitudinal gap between Japan and Europe and is expected to be the largest solar telescope with an aperture larger than 1.5 m till the ATST and EST come into operation. An international consortium has been identified to build the NLST. The facility is expected to be commissioned by 2016.

  12. Fronts in Large Marine Ecosystems

    Science.gov (United States)

    Belkin, Igor M.; Cornillon, Peter C.; Sherman, Kenneth

    2009-04-01

    Oceanic fronts shape marine ecosystems; therefore front mapping and characterization are among the most important aspects of physical oceanography. Here we report on the first global remote sensing survey of fronts in the Large Marine Ecosystems (LME). This survey is based on a unique frontal data archive assembled at the University of Rhode Island. Thermal fronts were automatically derived with the edge detection algorithm of Cayula and Cornillon (1992, 1995, 1996) from 12 years of twice-daily, global, 9-km resolution satellite sea surface temperature (SST) fields to produce synoptic (nearly instantaneous) frontal maps, and to compute the long-term mean frequency of occurrence of SST fronts and their gradients. These synoptic and long-term maps were used to identify major quasi-stationary fronts and to derive provisional frontal distribution maps for all LMEs. Since SST fronts are typically collocated with fronts in other water properties such as salinity, density and chlorophyll, digital frontal paths from SST frontal maps can be used in studies of physical-biological correlations at fronts. Frontal patterns in several exemplary LMEs are described and compared, including those for: the East and West Bering Sea LMEs, Sea of Okhotsk LME, East China Sea LME, Yellow Sea LME, North Sea LME, East and West Greenland Shelf LMEs, Newfoundland-Labrador Shelf LME, Northeast and Southeast US Continental Shelf LMEs, Gulf of Mexico LME, and Patagonian Shelf LME. Seasonal evolution of frontal patterns in major upwelling zones reveals an order-of-magnitude growth of frontal scales from summer to winter. A classification of LMEs with regard to the origin and physics of their respective dominant fronts is presented. The proposed classification lends itself to comparative studies of frontal ecosystems.

  13. 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

  14. Phase II Pediatric Study With Dabrafenib in HGG Patients

    Science.gov (United States)

    2016-03-09

    Anaplastic Astrocytoma; Glioblastoma; Giant Cell Glioblastoma; Gliosarcoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma; Anaplastic Ependymoma; Choroid Plexus Carcinoma; Anaplastic Ganglioglioma; Pineal Parenchymal Tumor; Pineoblastoma; Medulloblastoma; PNET; Rhabdoid Tumor; Perineurioma; MPNST; Malignant Meningloma; Anaplastic Hemangiopericytoma

  15. Handbook of Large-Scale Random Networks

    CERN Document Server

    Bollobas, Bela; Miklos, Dezso

    2008-01-01

    Covers various aspects of large-scale networks, including mathematical foundations and rigorous results of random graph theory, modeling and computational aspects of large-scale networks, as well as areas in physics, biology, neuroscience, sociology and technical areas

  16. Architecture of Large-Scale Systems

    OpenAIRE

    Koschel, Arne; Astrova, Irina; Deutschkämer, Elena; Ester, Jacob; Feldmann, Johannes

    2013-01-01

    In this paper various techniques in relation to large-scale systems are presented. At first, explanation of large-scale systems and differences from traditional systems are given. Next, possible specifications and requirements on hardware and software are listed. Finally, examples of large-scale systems are presented.

  17. 27 CFR 19.915 - Large plants.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Large plants. 19.915... OF THE TREASURY LIQUORS DISTILLED SPIRITS PLANTS Distilled Spirits For Fuel Use Permits § 19.915 Large plants. Any person wishing to establish a large plant shall make application for and obtain...

  18. Large Devaluations and the Real Exchange Rate

    Science.gov (United States)

    Burstein, Ariel; Eichenbaum, Martin; Rebelo, Sergio

    2005-01-01

    In this paper we argue that the primary force behind the large drop in real exchange rates that occurs after large devaluations is the slow adjustment in the prices of nontradable goods and services. Our empirical analysis uses data from five large devaluation episodes: Argentina (2002), Brazil (1999), Korea (1997), Mexico (1994), and Thailand…

  19. Conundrum of the Large Scale Streaming

    CERN Document Server

    Malm, T M

    1999-01-01

    The etiology of the large scale peculiar velocity (large scale streaming motion) of clusters would increasingly seem more tenuous, within the context of the gravitational instability hypothesis. Are there any alternative testable models possibly accounting for such large scale streaming of clusters?

  20. Shape control of large space structures

    Science.gov (United States)

    Hagan, M. T.

    1982-01-01

    A survey has been conducted to determine the types of control strategies which have been proposed for controlling the vibrations in large space structures. From this survey several representative control strategies were singled out for detailed analyses. The application of these strategies to a simplified model of a large space structure has been simulated. These simulations demonstrate the implementation of the control algorithms and provide a basis for a preliminary comparison of their suitability for large space structure control.

  1. Reliability of large and complex systems

    CERN Document Server

    Kolowrocki, Krzysztof

    2014-01-01

    Reliability of Large and Complex Systems, previously titled Reliability of Large Systems, is an innovative guide to the current state and reliability of large and complex systems. In addition to revised and updated content on the complexity and safety of large and complex mechanisms, this new edition looks at the reliability of nanosystems, a key research topic in nanotechnology science. The author discusses the importance of safety investigation of critical infrastructures that have aged or have been exposed to varying operational conditions. This reference provides an asympt

  2. Large Format Uncooled Focal Plane Array Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Black Forest Engineering has identified innovative modifications in uncooled focal plane array (UFPA) architecture and processing that allows development of large...

  3. ELID Grinding of Large Aspheric Optics Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Large aperture aspheric optics are among the most susceptible optical surfaces to the accumulation of periodic surface artifacts during fabrication. Periodic...

  4. The large deviation approach to statistical mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Touchette, Hugo [School of Mathematical Sciences, Queen Mary University of London, London E1 4NS (United Kingdom)], E-mail: h.touchette@qmul.ac.uk

    2009-07-15

    The theory of large deviations is concerned with the exponential decay of probabilities of large fluctuations in random systems. These probabilities are important in many fields of study, including statistics, finance, and engineering, as they often yield valuable information about the large fluctuations of a random system around its most probable state or trajectory. In the context of equilibrium statistical mechanics, the theory of large deviations provides exponential-order estimates of probabilities that refine and generalize Einstein's theory of fluctuations. This review explores this and other connections between large deviation theory and statistical mechanics, in an effort to show that the mathematical language of statistical mechanics is the language of large deviation theory. The first part of the review presents the basics of large deviation theory, and works out many of its classical applications related to sums of random variables and Markov processes. The second part goes through many problems and results of statistical mechanics, and shows how these can be formulated and derived within the context of large deviation theory. The problems and results treated cover a wide range of physical systems, including equilibrium many-particle systems, noise-perturbed dynamics, nonequilibrium systems, as well as multifractals, disordered systems, and chaotic systems. This review also covers many fundamental aspects of statistical mechanics, such as the derivation of variational principles characterizing equilibrium and nonequilibrium states, the breaking of the Legendre transform for nonconcave entropies, and the characterization of nonequilibrium fluctuations through fluctuation relations.

  5. Large-scale perspective as a challenge

    NARCIS (Netherlands)

    Plomp, M.G.A.

    2012-01-01

    1. Scale forms a challenge for chain researchers: when exactly is something ‘large-scale’? What are the underlying factors (e.g. number of parties, data, objects in the chain, complexity) that determine this? It appears to be a continuum between small- and large-scale, where positioning on that cont

  6. Computing in Large-Scale Dynamic Systems

    NARCIS (Netherlands)

    Pruteanu, A.S.

    2013-01-01

    Software applications developed for large-scale systems have always been difficult to de- velop due to problems caused by the large number of computing devices involved. Above a certain network size (roughly one hundred), necessary services such as code updating, topol- ogy discovery and data dissem

  7. 75 FR 73983 - Assessments, Large Bank Pricing

    Science.gov (United States)

    2010-11-30

    ... Kapoor, Counsel, Legal Division, (202) 898-3960. Correction In proposed rule FR Doc. 2010-29138...; ] FEDERAL DEPOSIT INSURANCE CORPORATION 12 CFR Part 327 RIN 3064-AD66 Assessments, Large Bank Pricing AGENCY..., 2010, regarding Assessments, Large Bank Pricing. This correction clarifies that the comment period...

  8. 76 FR 17521 - Assessments, Large Bank Pricing

    Science.gov (United States)

    2011-03-30

    ... Register of February 25, 2011 (76 FR 10672), regarding Assessments, Large Bank Pricing. This correction... 17th Street, NW., Washington, DC 20429. SUPPLEMENTARY INFORMATION: In FR Doc. 2011-3086, appearing on... 327 RIN 3064-AD66 Assessments, Large Bank Pricing AGENCY: Federal Deposit Insurance Corporation...

  9. Comb-drive actuators for large displacements

    NARCIS (Netherlands)

    Legtenberg, Rob; Groeneveld, A.W.; Elwenspoek, M.

    1996-01-01

    The design, fabrication and experimental results of lateral-comb-drive actuators for large displacements at low driving voltages is presented. A comparison of several suspension designs is given, and the lateral large deflection behaviour of clamped - clamped beams and a folded flexure design is mod

  10. Hierarchies of Alarms for Large Distributed Systems

    CERN Document Server

    Boccioli, M; Martos, V; Holme, O

    2014-01-01

    The control systems of most of the infrastructure at CERN make use of the SCADA package WinCC Open Architecture by ETM*, including successful projects to control large scale systems such as the Large Hadron Collider (LHC) accelerator and associated experiments.).

  11. Implementing Large Projects in Software Engineering Courses

    Science.gov (United States)

    Coppit, David

    2006-01-01

    In software engineering education, large projects are widely recognized as a useful way of exposing students to the real-world difficulties of team software development. But large projects are difficult to put into practice. First, educators rarely have additional time to manage software projects. Second, classrooms have inherent limitations that…

  12. Large 1 behaviour of the phase shifts

    International Nuclear Information System (INIS)

    We investigate the large l behaviour of the phase-shifts, using their W.K.B. expressions, which are good in this case. A recurrence relation for the phase-shifts is deduced when the potentials fall off as 1/sub(r)m, while a potentially useful inequality is obtained for potentials which decrease monotonically for large r. (author)

  13. Large Scale Computations in Air Pollution Modelling

    DEFF Research Database (Denmark)

    Zlatev, Z.; Brandt, J.; Builtjes, P. J. H.;

    Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998......Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998...

  14. Integration of large scale wind power

    Energy Technology Data Exchange (ETDEWEB)

    Davidsen, Troels [Inopower A/S (Denmark)

    2011-07-01

    Since 2006, the Danish TSO Energinet.dk, has got large power consumption systems available for balancing the power grid during large Wind Power in feed situations. In 2011 a total of 250 MW electro boilers are installed. The power for the electro boilers is traded on the Nordpool power exchange in the day a head market and the ancillary services markets. (orig.)

  15. Perception for a large deployable reflector telescope

    Science.gov (United States)

    Breckinridge, J. M.; Swanson, P. N.; Meinel, A. B.; Meinel, M. P.

    1984-01-01

    Optical science and technology concepts for a large deployable reflector for far-infrared and submillimeter astronomy from above the earth's atmosphere are discussed. Requirements given at the Asilomar Conference are reviewed. The technical challenges of this large-aperture (about 20-meter) telescope, which will be diffraction limited in the infrared, are highlighted in a brief discussion of one particular configuration.

  16. Large Nonferrous Metals Deposits Found in Yunnan

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    <正>According to the Department of Land and Resources of Yunnan, Yunnan has made great achievements since implementation of the geological prospecting action plan. 5 ultra-large deposits and several large deposits have been found, and a group of key areas with favorable ore-forming prospect have been pinpointed.

  17. The algebras of large N matrix mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Halpern, M.B.; Schwartz, C.

    1999-09-16

    Extending early work, we formulate the large N matrix mechanics of general bosonic, fermionic and supersymmetric matrix models, including Matrix theory: The Hamiltonian framework of large N matrix mechanics provides a natural setting in which to study the algebras of the large N limit, including (reduced) Lie algebras, (reduced) supersymmetry algebras and free algebras. We find in particular a broad array of new free algebras which we call symmetric Cuntz algebras, interacting symmetric Cuntz algebras, symmetric Bose/Fermi/Cuntz algebras and symmetric Cuntz superalgebras, and we discuss the role of these algebras in solving the large N theory. Most important, the interacting Cuntz algebras are associated to a set of new (hidden!) local quantities which are generically conserved only at large N. A number of other new large N phenomena are also observed, including the intrinsic nonlocality of the (reduced) trace class operators of the theory and a closely related large N field identification phenomenon which is associated to another set (this time nonlocal) of new conserved quantities at large N.

  18. Fast large-scale reionization simulations

    NARCIS (Netherlands)

    Thomas, Rajat M.; Zaroubi, Saleem; Ciardi, Benedetta; Pawlik, Andreas H.; Labropoulos, Panagiotis; Jelic, Vibor; Bernardi, Gianni; Brentjens, Michiel A.; de Bruyn, A. G.; Harker, Geraint J. A.; Koopmans, Leon V. E.; Pandey, V. N.; Schaye, Joop; Yatawatta, Sarod; Mellema, G.

    2009-01-01

    We present an efficient method to generate large simulations of the epoch of reionization without the need for a full three-dimensional radiative transfer code. Large dark-matter-only simulations are post-processed to produce maps of the redshifted 21-cm emission from neutral hydrogen. Dark matter h

  19. Large- quantum chromodynamics and harmonic sums

    Indian Academy of Sciences (India)

    Eduardo De Rafael

    2012-06-01

    In the large- limit of QCD, two-point functions of local operators become harmonic sums. I review some properties which follow from this fact and which are relevant for phenomenological applications. This has led us to consider a class of analytic number theory functions as toy models of large- QCD which also is discussed.

  20. Trust Dynamics in a Large System Implementation

    DEFF Research Database (Denmark)

    Schlichter, Bjarne Rerup; Rose, Jeremy

    2013-01-01

    A large information systems implementation (such as ERP systems) relies on the trust of its stakeholders to suc-ceed. Such projects impact diverse groups of stakeholders, each with their legitimate interests and expectations. Levels of stakeholder trust can be expected to vary in large scale...... the dynamics of trust relations. Giddens, as part of his study of modernity, theorises trust dynamics in relation to abstract social systems, though without focusing on information systems. We use Gid-dens’ concepts to investigate evolving trust relationships in a longitudinal case analysis of a large...... implementations (which can take several years), and cannot be taken for granted. Previous studies have largely focused on the taxonomic deconstruction of the trust construct, through point-in-time variance studies. They have identified the relationship between trust and project outcomes, but largely ignored...

  1. Generically large nongaussianity in small multifield inflation

    Energy Technology Data Exchange (ETDEWEB)

    Bramante, Joseph [Department of Physics, University of Notre Dame,Notre Dame, IN, 46556 (United States)

    2015-07-07

    If forthcoming measurements of cosmic photon polarization restrict the primordial tensor-to-scalar ratio to r<0.01, small field inflation will be a principal candidate for the origin of the universe. Here we show that small multifield inflation, without the hybrid mechanism, typically results in large squeezed nongaussianity. Small multifield potentials contain multiple flat field directions, often identified with the gauge invariant field directions in supersymmetric potentials. We find that unless these field directions have equal slopes, large nongaussianity arises. After identifying relevant differences between large and small two-field potentials, we demonstrate that the latter naturally fulfill the Byrnes-Choi-Hall large nongaussianity conditions. Computations of the primordial power spectrum, spectral index, and squeezed bispectrum, reveal that small two-field models which otherwise match observed primordial perturbations, produce excludably large nongaussianity if the inflatons’ field directions have unequal slopes.

  2. Virion Proteomics of Large DNA Viruses

    Institute of Scientific and Technical Information of China (English)

    Ran-ran WANG; Zhi-hong HU; Hua-lin WANG; Fei DENG

    2009-01-01

    Large DNA viruses normally have complex structures with many of protein components derived from both viral and host origins. The development in proteomics, especially mass spectrometry identification techniques provide powerful tools for analyzing large viruses. In this review, we have summarized the recent achievements on proteomic studies of large DNA viruses, such as herpesvirus, poxvirus, nimavirus and baculoviruse. The proteomics of baculovirus occlusion-derived virions (ODV) were emphasized. Different mass spectrometry techniques used on ,carious baculoviruses were introduced, and the identified structurally associated proteins of baculoviruses are summarized.

  3. Large scale network-centric distributed systems

    CERN Document Server

    Sarbazi-Azad, Hamid

    2014-01-01

    A highly accessible reference offering a broad range of topics and insights on large scale network-centric distributed systems Evolving from the fields of high-performance computing and networking, large scale network-centric distributed systems continues to grow as one of the most important topics in computing and communication and many interdisciplinary areas. Dealing with both wired and wireless networks, this book focuses on the design and performance issues of such systems. Large Scale Network-Centric Distributed Systems provides in-depth coverage ranging from ground-level hardware issu

  4. Has Job Security Vanished in Large Corporations?

    OpenAIRE

    Steven G. Allen; Clark, Robert L.; Sylvester J. Schieber

    1999-01-01

    The prevailing wisdom in media accounts is that job stability has vanished, especially for those in large corporations. Academic studies of job stability have found little difference between the 1990s and earlier decades, but these studies have not been able to focus on large firms. This paper provides the first detailed analysis of job stability in large corporations in the 1990s using a sample of 51 firms that are clients of Watson Wyatt Worldwide. We find that mean tenure and the percentag...

  5. The ESO Large Programme First Stars

    CERN Document Server

    Bonifacio, P; Andrievsky, S; Barbuy, B; Beers, T C; Caffau, E; Cayrel, R; Depagne, E; François, P; Hernandez, J I Gonzalez; Hansen, C J; Herwig, F; Hill, V; Korotin, S A; Ludwig, H -G; Molaro, P; Nordström, B; Plez, B; Primas, F; Sivarani, T; Spite, F; Spite, M

    2008-01-01

    In ESO period 65 (April-September 2000) the large programme 165.N-0276, led by Roger Cayrel, began making use of UVES at the Kueyen VLT telescope. Known within the Team and outside as ``First Stars'', it was aimed at obtaining high resolution, high signal-to-noise ratio spectra in the range 320 nm -- 1000 nm for a large sample of extremely metal-poor (EMP) stars identified from the HK objective prism survey.In this contribution we highlight the main results of the large programme.

  6. Very Large System Dynamics Models - Lessons Learned

    Energy Technology Data Exchange (ETDEWEB)

    Jacob J. Jacobson; Leonard Malczynski

    2008-10-01

    This paper provides lessons learned from developing several large system dynamics (SD) models. System dynamics modeling practice emphasize the need to keep models small so that they are manageable and understandable. This practice is generally reasonable and prudent; however, there are times that large SD models are necessary. This paper outlines two large SD projects that were done at two Department of Energy National Laboratories, the Idaho National Laboratory and Sandia National Laboratories. This paper summarizes the models and then discusses some of the valuable lessons learned during these two modeling efforts.

  7. Distributed Simulation of Large Computer Systems

    Institute of Scientific and Technical Information of China (English)

    MorenoMarzolla

    2001-01-01

    Sequential simulation of large complex physical systems is often regarded as a computationally expensive task.In order to speed-up complex discrete-event simulations,the paradigm of Parallel and Distributed Discrete Event Simulation (PDES) has been introduced since the late 70s.In this paper we'll analyze the applicability of PDES to the modeling and analysis of large computer system;such systems are increasingly common in the area of High Energy and Nuclear Physics,because many modern experiments make use of large"compute farms",Some feasibility tests have been performed on a prototype distributed siumulator.

  8. Synthesis of Small and Large scale Dynamos

    CERN Document Server

    Subramanian, K

    2000-01-01

    Using a closure model for the evolution of magnetic correlations, we uncover an interesting plausible saturated state of the small-scale fluctuation dynamo (SSD) and a novel anology between quantum mechanical tunneling and the generation of large-scale fields. Large scale fields develop via the $\\alpha$-effect, but as magnetic helicity can only change on a resistive timescale, the time it takes to organize the field into large scales increases with magnetic Reynolds number. This is very similar to the results which obtain from simulations using full MHD.

  9. Large scale dynamos with ambipolar diffusion nonlinearity

    CERN Document Server

    Brandenburg, A; Brandenburg, Axel; Subramanian, Kandaswamy

    2000-01-01

    It is shown that ambipolar diffusion as a toy nonlinearity leads to very similar behaviour of large scale turbulent dynamos as full MHD. This is demonstrated using both direct simulations in a periodic box and a closure model for the magnetic correlation functions applicable to infinite space. Large scale fields develop via a nonlocal inverse cascade as described by the alpha-effect. However, because magnetic helicity can only change on a resistive timescale, the time it takes to organize the field into large scales increases with magnetic Reynolds number.

  10. Large Numbers and Calculators: A Classroom Activity.

    Science.gov (United States)

    Arcavi, Abraham; Hadas, Nurit

    1989-01-01

    Described is an activity demonstrating how a scientific calculator can be used in a mathematics classroom to introduce new content while studying a conventional topic. Examples of reading and writing large numbers, and reading hidden results are provided. (YP)

  11. Hawaii Large Capacity Cesspools (LCC) Compliant

    Data.gov (United States)

    U.S. Environmental Protection Agency — LCC Compliant: Large Capacity Cesspools that have been properly abandoned or converted to a seepage pit that is associated with a State approved IWS. These LCCs are...

  12. Cosmogenic Nuclides Study of Large Iron Meteorites

    Science.gov (United States)

    Hutzler, A.; Smith, T.; Rochette, P.; Bourles, D. L.; Leya, I.; Gattacceca, J.

    2014-09-01

    Six large iron meteorites were selected (Saint-Aubin, Mont-Dieu, Caille, Morasko, Agoudal, and Gebel Kamil). We measured stable and radiogenic cosmogenic nuclides, to study pre-atmospheric size, cosmic-ray exposure ages and terrestrial ages.

  13. Enhanced performance large volume dissolution-DNP

    DEFF Research Database (Denmark)

    Bowen, Sean; Ardenkjær-Larsen, Jan Henrik

    2014-01-01

    A systematic study of the performance of the dissolution process in dissolution-DNP is presented. A relatively simple set of modifications is made to the standard Hypersense dissolution system to enable polarization of large volume samples. These consist of a large volume sample cup along...... with supporting modifications to the dissolution head and related components. Additional modifications were made to support the mapping of the temperature/pressure space of the dissolution process as well as enabling the use of large volumes of solvent and improving the robustness of the system. No loss...... of polarization was observed as sample size was increased to the 1g capacity of the large volume cup and for a dilution factor as low as 1:10....

  14. Preparing for the Large Hadron Collider

    CERN Document Server

    Appleton, Owen

    2007-01-01

    "Processing data for the Large Hadron Collider, the next-generation particle accelerator under construction at CERN, Switzerland, is one of the driving forces for development of Grid technology." (1 page)

  15. Trust dynamics in a large system implementation

    DEFF Research Database (Denmark)

    Schlichter, Bjarne Rerup; Rose, Jeremy

    2013-01-01

    A large information systems implementation (such as Enterprise Resource Planning systems) relies on the trust of its stakeholders to succeed. Such projects impact diverse groups of stakeholders, each with their legitimate interests and expectations. Levels of stakeholder trust can be expected...... outcomes, but largely ignored the dynamics of trust relations. Giddens, as part of his study of modernity, theorises trust dynamics in relation to abstract social systems, though without focusing on information systems. We use Giddens’ concepts to investigate evolving trust relationships in a longitudinal...... to vary in large-scale implementations (which can take several years), and cannot be taken for granted. Previous studies have largely focused on the taxonomic deconstruction of the trust construct, through point-in-time variance studies. They have identified the relationship between trust and project...

  16. Large eddy simulation of turbulent swirling jets

    OpenAIRE

    García-Villalba Navaridas, Manual

    2006-01-01

    Annulare und co-annulare Drallstrahlen werden oft bei Verbrennungsmaschinen wie z.B. von Gasturbinen eingesetzt. In der vorliegenden Arbeit wurden annulare und co-annulare Drallstrahlen mit Hilfe der Large-Eddy Simulation untersucht.

  17. HI Imaging of the Large Magellanic Cloud

    OpenAIRE

    Kim, S.; Staveley-Smith, L; Sault, R. J.

    2000-01-01

    We present results from the combined Australia Telescope Compact Array (ATCA) aperture synthesis mosaic survey of HI emission in the Large Magellanic Cloud with 64m Parkes single dish telescope observations.

  18. Large-bandwidth planar photonic crystal waveguides

    DEFF Research Database (Denmark)

    Søndergaard, Thomas; Lavrinenko, Andrei

    2002-01-01

    A general design principle is presented for making finite-height photonic crystal waveguides that support leakage-free guidance of light over large frequency intervals. The large bandwidth waveguides are designed by introducing line defects in photonic crystal slabs, where the material in the line...... defect has appropriate dispersion properties relative to the photonic crystal slab material surrounding the line defect. A three-dimensional theoretical analysis is given for large-bandwidth waveguide designs based on a silicon-air photonic crystal slab suspended in air. In one example, the leakage......-free single-mode guidance is found for a large frequency interval covering 60% of the photonic band-gap....

  19. Large Deviations in Quantum Spin Chain

    CERN Document Server

    Ogata, Yoshiko

    2008-01-01

    We show the full large deviation principle for KMS-states and $C^*$-finitely correlated states on a quantum spin chain. We cover general local observables. Our main tool is Ruelle's transfer operator method.

  20. Large Field Inflation and Gravitational Entropy

    DEFF Research Database (Denmark)

    Kaloper, Nemanja; Kleban, Matthew; Lawrence, Albion;

    2016-01-01

    Large field inflation can be sensitive to perturbative and nonperturbative quantum corrections that spoil slow roll. A large number $N$ of light species in the theory, which occur in many string constructions, can amplify these problems. One might even worry that in a de Sitter background, light...... species will lead to a violation of the covariant entropy bound at large $N$. If so, requiring the validity of the covariant entropy bound could limit the number of light species and their couplings, which in turn could severely constrain axion-driven inflation. Here we show that there is no such problem...... in this light, and show that they are perfectly consistent with the covariant entropy bound. Thus, while quantum gravity might yet spoil large field inflation, holographic considerations in the semiclassical theory do not obstruct it....

  1. Interference Mitigation in Large Random Wireless Networks

    CERN Document Server

    Aldridge, Matthew

    2011-01-01

    A central problem in the operation of large wireless networks is how to deal with interference -- the unwanted signals being sent by transmitters that a receiver is not interested in. This thesis looks at ways of combating such interference. In Chapters 1 and 2, we outline the necessary information and communication theory background, including the concept of capacity. We also include an overview of a new set of schemes for dealing with interference known as interference alignment, paying special attention to a channel-state-based strategy called ergodic interference alignment. In Chapter 3, we consider the operation of large regular and random networks by treating interference as background noise. We consider the local performance of a single node, and the global performance of a very large network. In Chapter 4, we use ergodic interference alignment to derive the asymptotic sum-capacity of large random dense networks. These networks are derived from a physical model of node placement where signal strength d...

  2. Generalized parton distributions at large momentum transfer

    OpenAIRE

    Kroll, P.

    2001-01-01

    The role of generalized parton distributions in wide-angle exclusive reactions will be discussed. In contrast to deep virtual exclusive reactions the wide angle processes offer the possibility of investigating the generalized parton distributions at large momentum transfer.

  3. Teaching a Large Physics Class at Cornell.

    Science.gov (United States)

    Orear, Jay

    1979-01-01

    A professor discusses the advantages and disadvantages of teaching a physics class in a large research-oriented university. Various innovative teaching techniques and the ways in which they benefit the students, are presented. (SA)

  4. Gravitational Wilson Loop and Large Scale Curvature

    OpenAIRE

    Hamber, H.; Williams, R.

    2007-01-01

    In a quantum theory of gravity the gravitational Wilson loop, defined as a suitable quantum average of a parallel transport operator around a large near-planar loop, provides important information about the large-scale curvature properties of the geometry. Here we shows that such properties can be systematically computed in the strong coupling limit of lattice regularized quantum gravity, by performing local averages over loop bivectors, and over lattice rotations, using an assumed near-unifo...

  5. A very large multigap resistive plate chamber

    CERN Document Server

    Cerron-Zeballos, E; Hatzifotiadou, D; Kim, D W; Lamas-Valverde, J; Lee, S C; Platner, E D; Roberts, J; Williams, M C S; Zichichi, A

    1999-01-01

    We have built and tested a very large multigap resistive plate chamber (MRPC). We discuss the suitability of the multigap RPC for the construction of large area modules. We give details of the construction technique and results from a scan across the surface of the chamber. We also report on the implementation of `half-strip resolution', where we improve the spatial resolution by a factor 2 without increasing the number of read-out channels. (9 refs).

  6. Effective Language Teaching in Large Classes

    Institute of Scientific and Technical Information of China (English)

    张丽丽

    2010-01-01

    <正>With more and more people who are jumping into the line of learning the second language (especially English),and also due to the limited resources in language teaching,many foreign language teachers are nowadays confronting the large classes when teaching.So how to teach foreign language effectively in large classes has become an issue as well as a special field to make researches in.

  7. On asymmetric collisions with large disruption parameters

    International Nuclear Information System (INIS)

    Collisions between a weak electron bunch and a strong positron bunch are studied within a flat model. Electrons are tracked through the transverse space charge field of the positron bunch, and it is shown that positrons in a storage ring may remain stable after asymmetric collisions with a weak electron bunch in spite of large values of the electron disruption parameter. The plasma oscillations that affect collisions with large disruption parameters may be suppressed by properly matching the electrons. 8 refs., 5 figs

  8. Large deviations for fractional Poisson processes

    CERN Document Server

    Beghin, Luisa

    2012-01-01

    We present large deviation results for two versions of fractional Poisson processes: the main version which is a renewal process, and the alternative version where all the random variables are weighted Poisson distributed. We also present a sample path large deviation result for suitably normalized counting processes; finally we show how this result can be applied to the two versions of fractional Poisson processes considered in this paper.

  9. Model for gravity at large distances

    OpenAIRE

    Grumiller, Daniel(Institute for Theoretical Physics, Vienna University of Technology, Wiedner Hauptstrasse 8-10/136, A-1040, Vienna, Austria)

    2010-01-01

    We construct an effective model for gravity of a central object at large scales. To leading order in the large radius expansion we find a cosmological constant, a Rindler acceleration, a term that sets the physical scales and subleading terms. All these terms are expected from general relativity, except for the Rindler term. The latter leads to an anomalous acceleration in geodesics of test-particles.

  10. Chemical Vapour Deposition of Large Area Graphene

    OpenAIRE

    Larsen, Martin Benjamin Barbour Spanget; Bøggild, Peter; Booth, Tim; Jørgensen, Anders Michael

    2015-01-01

    Chemical Vapor Deposition (CVD) is a viable technique for fabrication of large areas of graphene. CVD fabrication is the most prominent and common way of fabricating graphene in industry. In this thesis I have attempted to optimize a growth recipe and catalyst layer for CVD fabrication of uniform, single layer, and high carrier mobility large area graphene. The main goals of this work are; (1) explore the graphene growth mechanics in a low pressure cold-wall CVD system on a copper substrate, ...

  11. Large generalized books are p-good

    OpenAIRE

    Nikiforov, Vladimir; Rousseau, Cecil

    2004-01-01

    An r-book of size q is a union of q (r+1)-cliques sharing a common r-clique. We find exactly the Ramsey number of a p-clique versus r-books of sufficiently large size. Furthermore, we find asymptotically the Ramsey number of any fixed p-chromatic graph versus r-books of sufficiently large size. The key element in our proofs is Szemeredi's Regularity Lemma.

  12. Large Format Detector Arrays for Astrophysics

    Science.gov (United States)

    Moseley, Harvey

    2006-01-01

    Improvements in detector design and advances in fabrication techniques has resulted in devices which can reach fundamental sensitivity limits in many cases. Many pressing astrophysical questions require large arrays of such sensitive detectors. I will describe the state of far infrared through millimeter detector development at NASA/GSFC, the design and production of large format arrays, and the initial deployment of these powerful new tools.

  13. Achieving business model innovation in large corporations

    OpenAIRE

    Winterhalter, Stephan; Weiblen, Tobias; Wecht, Christoph; Gassmann, Oliver

    2014-01-01

    Despite the fact that business model innovation (BMI) has attracted intense scholarly attention, there is a paucity of insights concerning the organizational implementation of BMI efforts in large corporations. This paper investigates how business model innovation is managed in the complex environment of the chemical industry and derives consequences for the establishment of a systematic BMI process in large corporations. Based on a multiple case study design, we identify three different type...

  14. Spatial Indexing of Large Multidimensional Databases

    OpenAIRE

    Csabai, István; Trencséni, Márton; Herczegh, Géza; Dobos, László; Józsa, Péter; Purger, Norbert; Budavári, Tamás; Szalay, Alexander

    2012-01-01

    Scientific endeavors such as large astronomical surveys generate databases on the terabyte scale. These, usually multidimensional databases must be visualized and mined in order to find interesting objects or to extract meaningful and qualitatively new relationships. Many statistical algorithms required for these tasks run reasonably fast when operating on small sets of in-memory data, but take noticeable performance hits when operating on large databases that do not fit into memory. We utili...

  15. Irradiation injuries of the large intestine

    International Nuclear Information System (INIS)

    A series of 15 patients suffering from irradiation injuries to the large bowel is reviewed. Ten patients required surgical intervention; intestinal continuity was re-established in three patients. As only three of the patients developed recurrent carcinoma, the initial operation for irradiation injury to the large bowel should be carefully planned so that the patient is not ultimately cured of carcinoma but left with a permanent stoma

  16. Large Payload Ground Transportation and Test Considerations

    Science.gov (United States)

    Rucker, Michelle A.

    2016-01-01

    Many spacecraft concepts under consideration by the National Aeronautics and Space Administration’s (NASA’s) Evolvable Mars Campaign take advantage of a Space Launch System payload shroud that may be 8 to 10 meters in diameter. Large payloads can theoretically save cost by reducing the number of launches needed--but only if it is possible to build, test, and transport a large payload to the launch site in the first place. Analysis performed previously for the Altair project identified several transportation and test issues with an 8.973 meters diameter payload. Although the entire Constellation Program—including Altair—has since been canceled, these issues serve as important lessons learned for spacecraft designers and program managers considering large payloads for future programs. A transportation feasibility study found that, even broken up into an Ascent and Descent Module, the Altair spacecraft would not fit inside available aircraft. Ground transportation of such large payloads over extended distances is not generally permitted, so overland transportation alone would not be an option. Limited ground transportation to the nearest waterway may be possible, but water transportation could take as long as 67 days per production unit, depending on point of origin and acceptance test facility; transportation from the western United States would require transit through the Panama Canal to access the Kennedy Space Center launch site. Large payloads also pose acceptance test and ground processing challenges. Although propulsion, mechanical vibration, and reverberant acoustic test facilities at NASA’s Plum Brook Station have been designed to accommodate large spacecraft, special handling and test work-arounds may be necessary, which could increase cost, schedule, and technical risk. Once at the launch site, there are no facilities currently capable of accommodating the combination of large payload size and hazardous processing such as hypergolic fuels

  17. Geological characteristics of large gas provinces and large gas fields in China

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Based on the examination of the global researches on oil and gas provinces and large gas fields and the analysis of the features,attributes and distribution of large gas provinces and gas fields,this paper puts forward three indicators of determining large oil and gas provinces:spatial indicator,reservoir-forming indicator and resource indicator.It classifies the gas accumulated areas and large gas provinces in China and analyzes the controlling factors on the distribution of large gas provinces and large gas fields:the lateral distribution is mainly controlled by high-energy sedimentary facies and constructive diagenetic facies,palaeo-highs and their periclinal zones,deep faults,etc,and the vertical distribution is mainly controlled by unconformities,series of evaporates and deep low-velocity highly-conductive beds,etc.It also reveals the main geological characteristics of large gas provinces and large gas fields in China.Large gas fields in four-type basins have their own characteristics and onland large gas fields are dominantly developed in foreland basins and craton basins;there are three types of gas sources,of which,coal is the main source with high gas generating intensity and varying origins;reservoir rocks of the large gas fields(provinces)are of various types and dominated generally by low-middle permeability and porosity pore-type reservoirs;structural traps and litho-stratigraphic traps coexist in Chinese large gas fields and form dense high abundance and large-area low and middle-abundance large gas fields;most of the large gas fields have late hydrocarbon-generation peaks and reservoir formation,and experienced the process of multiple-stage charging and late finalization; large gas provinces(fields)have good sealing and preservation conditions,and evaporates seals are largely developed in large and extra-large gas fields.This paper intends to shed light on the exploration and development of large gas fields(provinces)through analyzing their

  18. Metrology of Large Parts. Chapter 5

    Science.gov (United States)

    Stahl, H. Philip

    2012-01-01

    As discussed in the first chapter of this book, there are many different methods to measure a part using optical technology. Chapter 2 discussed the use of machine vision to measure macroscopic features such as length and position, which was extended to the use of interferometry as a linear measurement tool in chapter 3, and laser or other trackers to find the relation of key points on large parts in chapter 4. This chapter looks at measuring large parts to optical tolerances in the sub-micron range using interferometry, ranging, and optical tools discussed in the previous chapters. The purpose of this chapter is not to discuss specific metrology tools (such as interferometers or gauges), but to describe a systems engineering approach to testing large parts. Issues such as material warpage and temperature drifts that may be insignificant when measuring a part to micron levels under a microscope, as will be discussed in later chapters, can prove to be very important when making the same measurement over a larger part. In this chapter, we will define a set of guiding principles for successfully overcoming these challenges and illustrate the application of these principles with real world examples. While these examples are drawn from specific large optical testing applications, they inform the problems associated with testing any large part to optical tolerances. Manufacturing today relies on micrometer level part performance. Fields such as energy and transportation are demanding higher tolerances to provide increased efficiencies and fuel savings. By looking at how the optics industry approaches sub-micrometer metrology, one can gain a better understanding of the metrology challenges for any larger part specified to micrometer tolerances. Testing large parts, whether optical components or precision structures, to optical tolerances is just like testing small parts, only harder. Identical with what one does for small parts, a metrologist tests large parts and optics

  19. Hierarchical Control for Large-Scale Systems

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    A class of large-seale systems, where the overall objective function is a nonlinear function of performance index of each subsystem, is investigated in this paper. This type of large-scale control problem is non-separable in the sense of conventional hierarchical control. Hierarchical control is extended in the paper to large-scale non-separable control problems, where multiobjective optimization is used as separation strategy. The large-scale non-separable control problem is embedded, under ;ertain conditions, into a family of the weighted Lagrangian formulation. The weighted Lagrangian formulation is separable with respect to subsystems and can be effectively solved using the interaction balance approach at the two lower levels in the proposed three-level solution structure. At the third level, the weighting vector for the weighted Lagrangian formulation is adjusted iteratively to search the optimal weighting vector with which the optimal of the original large-scale non-separable control problem is obtained. Theoretical base of the algorithm is established. Simulation shows that the algorithm is effective.

  20. Astronomy Outreach for Large and Unique Audiences

    Science.gov (United States)

    Lubowich, D.; Sparks, R. T.; Pompea, S. M.; Kendall, J. S.; Dugan, C.

    2013-04-01

    In this session, we discuss different approaches to reaching large audiences. In addition to star parties and astronomy events, the audiences for some of the events include music concerts or festivals, sick children and their families, minority communities, American Indian reservations, and tourist sites such as the National Mall. The goal is to bring science directly to the public—to people who attend astronomy events and to people who do not come to star parties, science museums, or science festivals. These programs allow the entire community to participate in astronomy activities to enhance the public appreciation of science. These programs attract large enthusiastic crowds often with young children participating in these family learning experiences. The public will become more informed, educated, and inspired about astronomy and will also be provided with information that will allow them to continue to learn after this outreach activity. Large and unique audiences often have common problems, and their solutions and the lessons learned will be presented. Interaction with the participants in this session will provide important community feedback used to improve astronomy outreach for large and unique audiences. New ways to expand astronomy outreach to new large audiences will be discussed.