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Sample records for alk-negative anaplastic large

  1. ALK-negative anaplastic large cell lymphoma with urinary bladder involvement diagnosed in urine cytology: A case report and literature review.

    PubMed

    Lobo, João; Henrique, Rui; Monteiro, Paula; Lobo, Cláudia

    2017-04-01

    Anaplastic large cell lymphoma is an aggressive T-cell neoplasm. It rarely involves the urinary bladder, with just twelve cases reported thus far and only one being ALK-negative. Immunophenotyping (particularly for ALK) is mandatory, both for prognostic and therapeutic reasons. Herein, we report the case of a patient with an ALK-negative anaplastic large cell lymphoma involving the bladder which was diagnosed and fully characterized by immunocytochemistry in urine cytology. The patient underwent a cystoscopy and the urine sample disclosed tumor diathesis background and aggregates of atypical cells, with evidence of multinucleation and mitotic figures. Immunocytochemistry revealed strong membrane/Golgi positivity for CD30 and negativity for ALK. The patient was submitted to transurethral resection for therapeutic purposes, which confirmed the diagnosis. To the best of our knowledge, this represents only the third case of anaplastic large cell lymphoma with bladder involvement diagnosed in urine cytology and the very first with diagnostic findings allowing for immunophenotyping of the disease in a bladder wash. The present report reinforces the role of urine cytology as a suitable method for establishing an earlier diagnosis and characterization of the disease, avoiding submitting patients to invasive procedures like transurethral resections. Diagn. Cytopathol. 2017;45:354-358. © 2016 Wiley Periodicals, Inc.

  2. Breast implant-associated ALK-negative anaplastic large cell lymphoma: a case report and discussion of possible pathogenesis.

    PubMed

    George, Eva V; Pharm, John; Houston, Courtney; Al-Quran, Semar; Brian, Grey; Dong, Huijia; Hai, Wang; Reeves, Westley; Yang, Li-Jun

    2013-01-01

    Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized clinical entity, with only 39 well-documented cases reported worldwide, including 3 fatalities. Because of its rarity, the clinical and pathologic features of this malignancy have yet to be fully defined. Moreover, the pathogenesis of ALCL in association with textured silicone gel breast implants is poorly understood. Here we report a case of BIA-ALCL arising in a 67-year-old woman with a mastectomy due to breast cancer followed by implantation of textured silicone gel breast prosthesis. The patient presented with breast enlargement and tenderness 8 years following reconstructive surgery. MRI revealed a fluid collection surrounding the affected breast implant. Pathologic examination confirmed the presence of malignant ALCL T cells that were CD30+, CD8+, CD15+, HLA-DR+, CD25+ ALK- and p53. A diagnosis of indolent BIA-ALCL was made since tumor cells were not found outside of the capsule. Interestingly, an extensive mixed lymphocytic infiltrate and ectopic lymphoid tissue (lymphoid neogenesis) adjacent to the fibrous implant capsule were present. The patient was treated with capsulectomy and implantation of new breast prostheses. Six months later, the patient was found to have BIA-ALCL involvement of an axillary lymph node with cytogenetic evolution of the tumor. To our knowledge, this is the sixth reported case of aggressive BIA-ALCL. Unique features of this case include the association with lymphoid neogenesis and the in vivo cytogenetic progression of the tumor. This case provides insight into the potential role of chronic inflammation and genetic instability in the pathogenesis of BIA-ALCL.

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

    PubMed

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

    2016-07-01

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

  4. Primary gastric anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma

    PubMed Central

    Tian, Chen; Zhang, Yizhuo

    2016-01-01

    Introduction Most primary stomach lymphomas are now recognized to originate from B-cell. Primary gastric anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) as shown in this case is very rare. Case report A 59-year-old man presented with a 1-month history of epigastric pain. Computed tomography showed a tumor in the stomach with perigastric lymphadenopathy. Biopsy of the tumor with gastroendoscopy showed ALCL. Bone marrow aspiration and trephine biopsy showed no infiltration. A diagnosis of primary gastric ALK-negative ALCL was made. The patient was first treated with four cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, but his condition did not show improvement. Then he was treated with two cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate and cytarabine (Hyper-CVAD/MA) regimen. In spite of these treatments, he still died of disease progression. Conclusion The prognosis of ALK-negative ALCLs is usually worse than ALK-positive ALCLs. In this case, the patient was not responsive to a multidrug chemotherapy with CHOP and Hyper-CVAD/MA. PMID:27695344

  5. Adult Systemic Anaplastic Large Cell Lymphoma: Recommendations for Diagnosis and Management

    PubMed Central

    Bennani-Baiti, Nabila; Ansell, Stephen

    2016-01-01

    Summary Systemic anaplastic large cell lymphomas (sALCLs) comprise a heterogeneous group of relatively rare T-cell non-Hodgkin lymphomas characterized by CD30 expression and other unifying pathologic features. ALK fusions are present in about 50% of cases. Pathological diagnosis can be challenging, particularly in ALK-negative cases. Though ALK-positive and ALK-negative sALCL are similar morphologically and immunophenotypically, they are separate entities with different genetics, clinical behavior, and outcomes. Evidence-based data evaluating treatment regimens are limited as randomized controlled trials are lacking and most prospective studies are too small to draw definitive conclusions. However, recent advances in molecular biology are bringing forth much needed knowledge in this field, and are likely to guide further targeted therapeutic development. PMID:26581318

  6. [Endobronchial anaplastic large cell lymphoma in childhood].

    PubMed

    Escobosa Sánchez, O M; Herrero Hernández, A; Acha García, T

    2009-05-01

    Anaplastic large cell lymphoma is a very rare disease in childhood. The most common location of this lymphoma is lymph node and skin, with endobronchial involvement being extremely rare. We report a case of a 10-year-old boy diagnosed by chance with an endobronchial anaplastic large cell lymphoma, while he was being investigated for a a benign bone disease, due to the initial absence of respiratory symptoms.

  7. ALK-positive anaplastic large cell lymphoma limited to the skin: clinical, histopathological and molecular analysis of 6 pediatric cases. A report from the ALCL99 study.

    PubMed

    Oschlies, Ilske; Lisfeld, Jasmin; Lamant, Laurence; Nakazawa, Atsuko; d'Amore, Emanuele S G; Hansson, Ulrika; Hebeda, Konnie; Simonitsch-Klupp, Ingrid; Maldyk, Jadwiga; Müllauer, Leonhard; Tinguely, Marianne; Stücker, Markus; Ledeley, Marie-Cecile; Siebert, Reiner; Reiter, Alfred; Brugières, Laurence; Klapper, Wolfram; Woessmann, Wilhelm

    2013-01-01

    Anaplastic large cell lymphomas are peripheral T-cell lymphomas that are characterized by a proliferation of large anaplastic blasts expressing CD30. In children, systemic anaplastic large cell lymphomas often present at advanced clinical stage and harbor translocations involving the anaplastic lymphoma kinase (ALK) gene leading to the expression of chimeric anaplastic lymphoma kinase (ALK)-fusion proteins. Primary cutaneous anaplastic large cell lymphoma is regarded as an ALK-negative variant confined to the skin and is part of the spectrum of primary cutaneous CD30-positive T-cell lymphoproliferative disorders. Thirty-three of 487 pediatric patients registered within the Anaplastic Large Cell Lymphoma-99 trial (1999 to 2006) presented with a skin limited CD30-positive lympho-proliferative disorder. In 23 of the 33 patients, material for international histopathological review was available, and the cases were studied for histopathological, immunophenotypical and clinical features as well as for breaks within the ALK gene. Five of 23 cases and one additional case (identified after closure of the trial) expressed ALK-protein. Complete staging excluded any other organ involvement in all children. Expression of ALK proteins was demonstrated by immunohistochemistry in all cases and the presence of breaks of the ALK gene was genetically confirmed in 5 evaluable cases. The histopathological and clinical picture of these skin-restricted ALK-positive lymphomas was indistinguishable from that of cutaneous anaplastic large cell lymphoma. Five children presented with a single skin lesion that was completely resected in 4 and incompletely resected in one. Three of these patients received no further therapy, 2 additional local radiotherapy, and one chemotherapy. All children remain in complete remission with a median follow up of seven years (range 1-8 years). We present 6 pediatric cases of ALK-positive primary cutaneous anaplastic large cell lymphomas. After thorough

  8. Expression of the Chemokine Receptor Gene, CCR8, is Associated with DUSP22 Rearrangements in Anaplastic Large Cell Lymphoma

    PubMed Central

    Xing, Xiaoming; Flotte, Thomas J.; Law, Mark E.; Blahnik, Anthony J.; Chng, Wee-Joo; Huang, Gaofeng; Knudson, Ryan A.; Ketterling, Rhett P.; Porcher, Julie C.; Ansell, Stephen M.; Sidhu, Jagmohan; Dogan, Ahmet; Feldman, Andrew L.

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is one of the most common T-cell non-Hodgkin lymphomas and has two main subtypes: an ALK-positive subtype characterized by ALK gene rearrangements and an ALK-negative subtype that is poorly understood. We recently identified recurrent rearrangements of the DUSP22 locus on 6p25.3 in both primary cutaneous and systemic ALK-negative ALCLs. This study aimed to determine the relationship between these rearrangements and expression of the chemokine receptor gene, CCR8. CCR8 has skin-homing properties, and has been suggested to play a role in limiting extracutaneous spread of primary cutaneous ALCLs. However, overexpression of CCR8 also has been reported in systemic ALK-negative ALCLs. As available antibodies for CCR8 have shown lack of specificity, we examined CCR8 expression using quantitative real-time PCR in frozen tissue and RNA in situ hybridization (ISH) in paraffin tissue. Both approaches showed higher CCR8 expression in ALCLs with DUSP22 rearrangements than in non-rearranged cases (PCR: 19.5-fold increase, p=0.01; ISH: 3.3-fold increase, p=0.0008). CCR8 expression was not associated with cutaneous presentation, cutaneous biopsy site, or cutaneous involvement during the disease course. These findings suggest that CCR8 expression in ALCL is more closely related to the presence of DUSP22 rearrangements than to cutaneous involvement, and that the function of CCR8 may extend beyond its skin-homing properties in this disease. This study also underscores the utility of RNA-ISH as a paraffin-based method for investigating gene expression when reliable antibodies for immunohistochemistry are not available. PMID:25390351

  9. Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma

    ClinicalTrials.gov

    2017-04-06

    Anaplastic Large Cell Lymphoma, ALK-Positive; CD30-Positive Neoplastic Cells Present; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma

  10. Primary anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma of the breast in a male patient.

    PubMed

    Ko, E S; Seol, H; Shin, J H; Ko, E Y

    2012-04-01

    Anaplastic large-cell lymphoma is an extremely rare lymphoma subtype. We describe the mammographic and ultrasonographic findings in a 51-year-old male patient who suffered from a palpable lump caused by this rare disease.

  11. ALK Signaling and Target Therapy in Anaplastic Large Cell Lymphoma

    PubMed Central

    Tabbó, Fabrizio; Barreca, Antonella; Piva, Roberto; Inghirami, Giorgio

    2012-01-01

    The discovery by Morris et al. (1994) of the genes contributing to the t(2;5)(p23;q35) translocation has laid the foundation for a molecular based recognition of anaplastic large cell lymphoma and highlighted the need for a further stratification of T-cell neoplasia. Likewise the detection of anaplastic lymphoma kinase (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. PMID:22649787

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

    PubMed Central

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

    2009-01-01

    Summary 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. PMID:18620733

  13. Fine-needle aspiration cytology yield as a basis for morphological, molecular, and cytogenetic diagnosis in alk-positive anaplastic large cell lymphoma with atypical clinical presentation.

    PubMed

    Bogdanic, Maja; Ostojic Kolonic, Slobodanka; Kaic, Gordana; Kardum Paro, Mirjana Mariana; Lasan Trcic, Ruzica; Kardum-Skelin, Ika

    2017-01-01

    ALK positive anaplastic large cell lymphoma is a T-cell lymphoma usually occurring in children and young adults. It frequently involves lymph nodes and extranodal sites and is associated with favorable prognosis. A 20-year old man was admitted for painful mass in the left axilla with overlying skin redness. Clinical presentation and US findings were highly suspicious for sarcoma. Definitive diagnosis was established cytolologically and using ancillary technologies from cytological samples. Fine needle aspiration cytology of tumor mass (lymph node conglomerate and surrounding tissue) show predominance of large, pleomorphic, atypical cells with large nuclei and vacuolised cytoplasm. Atypical cells immunocytochemically were positive for LCA, CD30, CD3, EMA, and ALK; negative for CD15 and CD56. NPM-ALK transcript was detected by reverse transcriptase-polymerase chain reaction (RT-PCT). Molecular analysis of TCRß and TCRγ genes demonstrated clonal TCR genes rearrangement. Complex karyotype with multiple numerical and structural changes was found on conventional cytogenetics. These findings excluded sarcoma and corroborated the diagnosis of ALK positive ALCL. Cutaneous involvement in ALCL can clinically mimic sarcoma, especially in cases with localized disease without B symptoms. In those cases, immunostaining, PCR, and conventional cytogenetics are helpful to exclude sarcoma. Diagn. Cytopathol. 2017;45:51-54. © 2016 Wiley Periodicals, Inc.

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

    PubMed

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

    2013-01-01

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

  15. Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes

    PubMed Central

    Vurchio, Valentina; Yang, Shao Ning; Moon, John; Kwee, Ivo; Rinaldi, Andrea; Pan, Heng; Crescenzo, Ramona; Cheng, Mangeng; Cerchietti, Leandro; Elemento, Olivier; Riveiro, Maria E.; Cvitkovic, Esteban; Bertoni, Francesco; Inghirami, Giorgio

    2016-01-01

    Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs. The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies. Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with bromodomain inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors (E2F2, NFKBIZ, FOS, JUNB, ID1, HOXA5 and HOXC6), members of multiple signaling pathways (ITK, PRKCH, and MKNK2), and histones (clusters 1-3). Combination of OTX015 with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 inhibitor, C1156Y-resistant ALK ALCL growth was impaired. These findings support OTX015 clinical trials in refractory ALCL in combination with inhibitors of interleukin-2-inducible kinase or SHH/GLI1. PMID:27793034

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

    PubMed

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

    2013-05-01

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

  17. Array-CGH analysis of cutaneous anaplastic large cell lymphoma.

    PubMed

    Szuhai, K; van Doorn, R; Tensen, C P; Van Kester

    2013-01-01

    This chapter describes a study in which the pattern of numerical chromosomal alterations in cutaneous anaplastic large cell lymphoma (C-ALCL) tumor samples was defined using array-based comparative genomic hybridization (CGH). First, the array-based CGH technique applied is outlined in detail. Next, its application in the analysis of C-ALCL tumor specimens is described. This approach resulted in the identification of highly recurrent chromosomal alterations in C-ALCL that include gain of 7q31 and loss on 6q16-6q21 and 13q34, each affecting 45% of the patients. The pattern characteristic of C-ALCL differs markedly from chromosomal alterations observed in other CTCL such as mycosis fungoides and Sézary syndrome and yielded several candidate genes with potential relevance in the pathogenesis of C-ALCL.

  18. AT13387 in Treating Patients With Relapsed or Refractory Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma, or Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2017-04-04

    Anaplastic Large Cell Lymphoma, ALK-Positive; BCL6 Positive; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma

  19. Primary Central Nervous System Anaplastic Large T-cell Lymphoma

    PubMed Central

    Splavski, Bruno; Muzevic, Dario; Ladenhauser-Palijan, Tatjana; Jr, Brano Splavski

    2016-01-01

    Introduction: Primary central nervous system lymphoma (PCNSL) of T-cell origin is an exceptionally rare, highly malignant intracranial neoplasm. Although such a tumor typically presents with a focal mass lesion. Case report: Past medical history of a 26-year-old male patient with a PCNS lymphoma of T-cell origin was not suggestive of intracranial pathology or any disorder of other organs and organic systems. To achieve a gross total tumor resection, surgery was performed via osteoplastic craniotomy using the left frontal transcortical transventricular approach. Histological and immunohistochemical analyses of the tissue removed described tumor as anaplastic large cell lymphoma of T-cells (T-ALCL). Postoperative and neurological recovery was complete, while control imaging of the brain showed no signs of residual tumor at a six-month follow-up. The patient, who did not appear immunocompromized, was referred to a hematologist and an oncologist where corticosteroids, the particular chemotherapeutic protocol and irradiation therapy were applied. Conclusion: Since PCNS lymphoma is a potentially curable brain tumor, we believe that proper selection of the management options, including early radical tumor resection for solitary PCNS lymphoma, may be proposed as a major treatment of such a tumor in selected patients, resulting in a satisfactory outcome. PMID:27703297

  20. ALK positive Anaplastic Large Cell Lymphoma of the Thoracic Spine

    PubMed Central

    Abrego, Gabriela; García, Julio; Gilbert, Bruce; Forseen, Scott; Toscano, Michael

    2016-01-01

    Primary bone lymphoma (PBL) is an uncommon extra nodal disease that represents about 1–3% of lymphoma cases. Imaging findings are variable and non-specific. Computed tomography may demonstrate lytic lesions with sequestra and periosteal reaction. On magnetic resonance imaging, lesions are T1WI hypointense and T2WI hyperintense, related to peritumoral edema or bone marrow replacement. Rarely lesions may have associated fibrosis and show a more hypointense signal pattern on T2WI. After administration of contrast, PBL tends to enhance avidly. We present a case of a 24 years old African American female patient with history of back pain. Initial imaging examinations showed lesions involving the T12 and T11 vertebral bodies with initial negative biopsy results. One month later, the patient returned with worsening back pain, and the follow up studies depicted collapse of the T12 vertebral body. A diagnosis of anaplastic large cell lymphoma in T12 was made. A brief review of the literature, imaging and pathological findings, and treatment options are also discussed. PMID:27761194

  1. ANALYSIS OF HUMAN T-CELL LYMPHOTROPIC VIRUS IN CD25-POSITIVE-ANAPLASTIC LARGE CELL LYMPHOMAS IN CHILDREN

    PubMed Central

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

    2009-01-01

    T-cell lymphomas are rare in children. Anaplastic large cell lymphoma (ALCL) is the most common pediatric mature T-cell lymphoma, accounting for about 10-20% of all pediatric non-Hodgkin lymphoma. ALCL is now recognized as two distinct diseases, i.e., ALCL-ALK-positive (ALCL- ALK+) and ALCL-ALK-negative (ALCL- ALK-); ALK-positive ALCL presents at a younger age and has a better prognosis. The human T-cell lymphotropic virus (HTLV-1) is a retrovirus that mainly infects helper T lymphocytes and is linked to the development of adult T-cell leukemia/lymphoma (ATLL). The other type of lymphoma related to this virus family is hairy cell leukemia (HCL). Both of these neoplasms frequently express CD25 (alpha chain-IL-2 receptor). Recently, it was demonstrated that CD25 is significantly expressed in childhood ALCL (75%). In Brazil, HTLV-1 infection is considered endemic, and vertical transmission is responsible for spread to children, and it is important to point out that 90% or more of the HTLV-1 carriers remain asymptomatic. Some cases of HTLV-1-related lymphomas in adults are described as having characteristics of ALCL, but are considered to be CD30-positive subtypes of ATLL based on the virologic findings. No similar cases have been described in children, therefore we analyzed 33 cases of pediatric ALCL, both CD25-positive and CD25-negative, looking for the presence of proviral HTLV-1 DNA, by PCR. All cases corresponded to the common histological type of ALCL and were CD30-positive in virtually all neoplastic cells. ALK expression was observed in all but two cases (93.9%), while CD25 was positive in 27 cases (82%), including one of the ALCL-ALK-. There was a strong positive correlation between ALK and CD25 expression. None of the cases showed proviral HTLV-1-DNA presence. Our study concludes that ALCL in children has no relationship with HTLV-1 and the high frequency of CD25 expression must be explained by a different mechanism than that described in ATLL. PMID:19864230

  2. A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma.

    PubMed

    Döring, Claudia; Hansmann, Martin-Leo; Agostinelli, Claudio; Piccaluga, Pier P; Facchetti, Fabio; Pileri, Stefano; Küppers, Ralf; Newrzela, Sebastian; Hartmann, Sylvia

    2014-10-01

    Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK(-) anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.

  3. Primary cutaneous anaplastic large cell lymphoma masquerading as large pyogenic granuloma

    PubMed Central

    Bains, Anupama; Vedant, Deepak; Shanker, Vinay; Tegta, G. R.

    2016-01-01

    Primary cutaneous anaplastic large cell lymphoma (pcALCL) forms 9% of the cutaneous T-cell lymphomas. It usually presents as solitary reddish brown ulcerating nodule or indurated plaque. Sometimes, it mimics other dermatological diseases such as eczema, pyoderma gangrenosum, pyogenic granuloma, morphea, and squamous cell carcinoma. Our case presented with large pyogenic granuloma like lesion with regional lymphadenopathy. Since pcALCL is rare, one can misdiagnose such cases and therefore high index of suspicion is necessary. PMID:27990392

  4. ALK Positive Anaplastic Large Cell Lymphoma Presenting as Extensive Bone Involvement

    PubMed Central

    Gajendra, Smeeta; Lipi, Lipika; Goel, Shalini; Misra, Ruchira

    2015-01-01

    Anaplastic lymphoma kinase (ALK) positive Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all Non-Hodgkin’s lymphomas that commonly involves nodal as well as a wide variety of extra nodal sites, as skin, soft tissue, bones and lungs, although primary or secondary involvement of bone is rare. Herein, we report a case of 14-year-old female child presented as extensive bony involvement with a clinical diagnosis of bone tumour/ small round cell tumour, which was proved to be ALK positive ALCL on histopathological examination. PMID:25738071

  5. Primary cutaneous CD 30 (+) ALK (−) anaplastic large cell lymphoma with dermoscopic findings: a case report

    PubMed Central

    Uzuncakmak, Tugba K.; Akdeniz, Necmettin; Karadag, Ayse S.; Taskin, Secil; Zemheri, Ebru I.; Argenziano, Giuseppe

    2017-01-01

    Primary cutaneous CD 30 (+) anaplastic large cell lymphoma (PCALCL) is a rare and indolent type of cutaneous T cell lymphoma, which usually presents as an asymptomatic solitary firm nodule that rapidly grows and often ulcerates without any systemic involvement. A 64-year-old female presented to our outpatient clinic with a one-year history of multiple pink nodular lesions on the chest, back and gluteal regions. Dermoscopic examination of the nodular lesions revealed pink-to-yellow structureless areas and arborizing-to-polymorphous vessels. Histopathologic examination was consistent with CD30 (+) anaplastic large cell lymphoma. Systemic involvement was not detected. Local radiotherapy for large nodules and surgical excision for small nodules were performed. The large nodules had totally regressed after 10 sessions of radiotherapy. PMID:28243498

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

    PubMed

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

    2016-03-26

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

  7. Hemophagocytic Lymphohistiocytosis in Association with Primary Cutaneous Anaplastic Large Cell Lymphoma

    PubMed Central

    Basheer, Aneesh; Padhi, Somanath; Nagarajan, Ramesh; Boopathy, Vinoth; Mookkappan, Sudhagar; Iqbal, Nayyar

    2014-01-01

    Hemophagocytic lymphohistiocytosis (HLH) has a well known association with lymphomas, especially of T cell origin. Prognosis of lymphoma associated HLH is very poor, especially in T cell lymphomas; and, therefore, early diagnosis might alter the outcome. Though association of HLH with systemic anaplastic large cell lymphoma (ALCL) is known, its occurrence in primary cutaneous ALCL (C-ALCL) is distinctly rare. We aim to describe a case of C-ALCL (anaplastic lymphoma kinase (ALK)−) in an elderly male who succumbed to the complication of associated HLH, which was possibly triggered by coexistent virus infection. We briefly present the literatures on lymphoma associated HLH and discuss the histopathological differentials of cutaneous CD30+ lymphoproliferative disorders. We do suggest that HLH may pose diagnostic challenges in the evaluation of an underlying lymphoma and hence warrants proper evaluation for the underlying etiologies and/or triggering factors. PMID:25405042

  8. Breast implant-associated anaplastic large cell lymphoma: review of a distinct clinicopathologic entity.

    PubMed

    Xu, Jie; Wei, Shi

    2014-06-01

    Primary breast anaplastic large cell lymphoma (ALCL) is rare but is more commonly seen in patients with implants; fewer than 50 cases of breast implant-associated ALCL have been reported in the English language literature. Breast implant-associated ALCL is not a disease of the breast parenchyma, but instead is a disease of the fibrous capsule surrounding the implant. The patients usually present with an effusion around the implant and, rarely, with a solid mass. Morphologically, the neoplastic cells are large, epithelioid, and pleomorphic, with abundant cytoplasm, vesicular irregular nuclei, and frequent mitoses. Occasional "hallmark" cells may be present. The lesional cells typically show strong and diffuse immunoreactivity for CD30 and often express T-cell markers, cytotoxic-associated antigens, and epithelial membrane antigen. Almost all reported cases are negative for anaplastic lymphoma kinase. Molecular genetic analyses have demonstrated T-cell receptor gene rearrangements. The differential diagnosis essentially includes poorly differentiated carcinoma, other lymphomas, and chronic inflammation. Once a diagnosis of lymphoma is established, it is important to exclude systemic anaplastic lymphoma kinase-negative ALCL involving the breast, primary cutaneous ALCL, and other CD30(+) lymphoproliferative disorders. The patients with effusion-associated ALCL often have an indolent course and excellent prognosis, responding well to excision of the fibrous capsule around the implant (capsulectomy) and implant removal. In contrast, patients who present with a distinct mass may have a more aggressive course and poor prognosis, requiring chemotherapy and/or radiation therapy.

  9. Anaplastic large cell lymphoma in a reconstructed breast using a silicone implant: a UK case report.

    PubMed

    Sørensen, K; Murphy, J; Lennard, A; Wadehra, V; Menon, G K; Collis, N

    2014-04-01

    We present case of Anaplastic Large Cell Lymphoma discovered as an incidental finding whilst revising an implant based breast reconstruction in a 55 year old woman, whom previously had undergone risk reduction mastectomies and immediate reconstruction. During the procedure a presumed seroma was present but this was macroscopically atypical giving a 'milky' coloured appearance with a pink tinge to it. The atypical fluid was sent for analysis and the diagnosis of ALCL confirmed. Treatment consisted of unilateral capsulectomy on the affected side and bilateral removal of implants with staging scans suggesting the disease being confined to the capsule. She remains in remission 12 months following the original procedure.

  10. Coming of Age: Breast Implant-Associated Anaplastic Large Cell Lymphoma After 18 Years of Investigation.

    PubMed

    Clemens, Mark W; Miranda, Roberto N

    2015-10-01

    Breast implant associated anaplastic large cell lymphoma (BIALCL) is a distinct clinical entity that can present in patients receiving either reconstructive or cosmetic breast implants. Presenting symptoms include onset of a delayed (>1 year after implantation) fluid collection, mass of the capsule, or lymphadenopathy. Treatment has progressed in recent years and most commonly includes implant removal and total resection of the tumor, including capsule, mass, and involved lymph nodes. Further research is warranted to determine potential malignant drivers, disease progression, and optimal treatment strategies in advanced disease.

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

    PubMed Central

    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

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

    PubMed

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

    2013-01-01

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

  13. Skin involvement as the first manifestation of breast implant-associated anaplastic large cell lymphoma.

    PubMed

    Alcalá, Rebeca; Llombart, Beatriz; Lavernia, Javier; Traves, Víctor; Guillén, Carlos; Sanmartín, Onofre

    2016-07-01

    Breast implant-associated anaplastic large cell lymphoma (ALCL) is a newly described clinical and pathologic entity that typically presents as seroma in the fibrous scar around the implant. Less frequently, it presents as a solid peri-implant mass, and there have been no reports to date of cutaneous lesions as the presenting manifestation. We report the case of a 56-year-old woman with a history of bilateral breast reconstruction following breast cancer of the right breast who consulted with several papules on the right breast suggestive of metastasis. Histopathology showed a proliferation of large epithelioid lymphocytes with highly pleomorphic cells and nuclei. The neoplastic cells were CD15 and CD30 positive and ALK-1 negative. The epithelial markers were all negative except for epithelial membrane antigen (EMA), which was weakly positive. Molecular analysis showed monoclonal T-cell receptor γ gene rearrangement, confirming a diagnosis of breast implant-associated ALCL. The non-specific morphology of the skin lesions, the epithelioid nature of the neoplastic cells and the expression of EMA can lead to an erroneous diagnosis of skin metastases from a poorly differentiated adenocarcinoma of the breast. We recommend immunohistochemical staining for CD30 and ALK-1 for patients with breast implants who develop anaplastic lesions.

  14. A novel Patient Derived Tumorgraft model with TRAF1-ALK Anaplastic Large Cell Lymphoma translocation

    PubMed Central

    Abate, Francesco; Todaro, Maria; van der Krogt, Jo-Anne; Boi, Michela; Landra, Indira; Machiorlatti, Rodolfo; Tabbo’, Fabrizio; Messana, Katia; Barreca, Antonella; Novero, Domenico; Gaudiano, Marcello; Aliberti, Sabrina; Di Giacomo, Filomena; Tousseyn, Thomas; Lasorsa, Elena; Crescenzo, Ramona; Bessone, Luca; Ficarra, Elisa; Acquaviva, Andrea; Rinaldi, Andrea; Ponzoni, Maurilio; Longo, Dario Livio; Aime, Silvio; Cheng, Mangeng; Ruggeri, Bruce; Piccaluga, Pier Paolo; Pileri, Stefano; Tiacci, Enrico; Falini, Brunangelo; Pera-Gresely, Benet; Cerchietti, Leandro; Iqbal, Javeed; Chan, Wing C; Shultz, Leonard D.; Kwee, Ivo; Piva, Roberto; Wlodarska, Iwona; Rabadan, Raul; Bertoni, Francesco; Inghirami, Giorgio

    2016-01-01

    Although Anaplastic Large Cell Lymphomas (ALCL) carrying Anaplastic Lymphoma Kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human Patient Derived Tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and of NFkB pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells lacking PRDM1/Blimp-1 and with c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to down-regulation of p50/p52 and lymphoma growth inhibition. Moreover a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Moreover, a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, but the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable to validate the role of druggable molecules, predict therapeutic responses and are helpful tools for the implementation of patient specific therapies. PMID:25533804

  15. Primary central nervous system ALK-positive anaplastic large cell lymphoma in an adult

    PubMed Central

    Dong, Xiaoqin; Li, Jun; Huo, Na; Wang, Yan; Wu, Zhao; Lin, Xiaohong; Zhao, Hong

    2016-01-01

    Abstract Rationale: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin lymphoma. It mostly invades lymph nodes with extranodal involvement observed in the soft tissue, bone, and skin. Patient concerns: We report a 34-year-old Chinese male patient who presented with headache, diplopia, and vomit. Cerebrospinal fluid (CSF) analysis via lumbar puncture showed elevated CSF pressure, elevated CSF protein concentrations, decreased CSF glucose and chloride concentration significantly, and pleocytosis of 68 to 350 × 106/L, in which lymphocytes and monocytes were predominant. These changes could be suggestive of tuberculous (TB) meningitis. Enhanced magnetic resonance imaging of spinal cord delineated multiple enhancing nodules in spinal cord, cauda equina, and cristae membrane, and multiple abnormal enhancing lesions in bilateral lumbar intervertebral foramen. Diagnoses: Spinal dura mater biopsy and paraffin pathology examination revealed anaplastic lymphoma kinase positive ALCL. Interventions: High-dose methotrexate, cytosine arabinoside craniospinal, and radiotherapy. Outcomes: Last follow-up on September 22, 2015 showed no evidence of tumor recurrence and the lower extremity muscle strength recovered to 4/5. Lessons: ALCL of primary central nervous system is an exceedingly rare tumor, which is usually misdiagnosed as meningitis (especially TB meningitis) according to clinical manifestation and laboratory examination. Thus closely monitoring patient's conditions and timely adjusting therapeutic regimen during treatment are necessary. PMID:27930548

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2013-01-01

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

  18. Variant translocation partners of the anaplastic lymphoma kinase (ALK) gene in two cases of anaplastic large cell lymphoma, identified by inverse cDNA polymerase chain reaction.

    PubMed

    Takeoka, Kayo; Okumura, Atsuko; Honjo, Gen; Ohno, Hitoshi

    2014-01-01

    In anaplastic large cell lymphoma (ALCL), the anaplastic lymphoma kinase (ALK) gene is rearranged with diverse partners due to variant translocations/inversions. Case 1 was a 39-year-old man who developed multiple tumors in the mediastinum, psoas muscle, lung, and lymph nodes. A biopsy specimen of the inguinal node was effaced by large tumor cells expressing CD30, epithelial membrane antigen, and cytoplasmic ALK, which led to a diagnosis of ALK(+) ALCL. Case 2 was a 51-year-old man who was initially diagnosed with undifferentiated carcinoma. He developed multiple skin tumors eight years after his initial presentation, and was finally diagnosed with ALK(+) ALCL. He died of therapy-related acute myeloid leukemia. G-banding and fluorescence in situ hybridization using an ALK break-apart probe revealed the rearrangement of ALK and suggested variant translocation in both cases. We applied an inverse cDNA polymerase chain reaction (PCR) strategy to identify the partner of ALK. Nucleotide sequencing of the PCR products and a database search revealed that the sequences of ATIC in case 1 and TRAF1 in case 2 appeared to follow those of ALK. We subsequently confirmed ATIC-ALK and TRAF1-ALK fusions by reverse transcriptase PCR and nucleotide sequencing. We successfully determined the partner gene of ALK in two cases of ALK(+) ALCL. ATIC is the second most common partner of variant ALK rearrangements, while the TRAF1-ALK fusion gene was first reported in 2013, and this is the second reported case of ALK(+) ALCL carrying TRAF1-ALK.

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

    PubMed

    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. Intracranial large vessel vasculopathy and anaplastic meningioma 19 years after cranial irradiation for acute lymphoblastic leukaemia.

    PubMed

    Foreman, N K; Laitt, R D; Chambers, E J; Duncan, A W; Cummins, B H

    1995-04-01

    A child was diagnosed in 1969 as having acute lymphoblastic leukaemia (ALL) and received chemotherapy. On bone marrow relapse in 1973, he was treated with cranial irradiation (20 Gy) in addition to chemotherapy. He continues in complete remission 19 years after his relapse. At age 25 years, he presented with headaches and left hemiparesis. Computerised tomograph demonstrated a large, enhancing right-sided intracranial tumour. Angiography was performed and showed the right internal carotid artery was occluded. Most of the right hemisphere was supplied from the external carotid via the middle meningeal artery. The left posterior cerebral artery and the left anterior cerebral artery were absent presumably as a result of radiation-induced arteritis. A resection of an anaplastic meningioma arising from the right sphenoidal ridge was achieved. There was a rapid improvement in function and he returned to work. Vasculopathy of the large intracranial arteries has been described after high dose radiation. It may occur as in this case after moderate dose radiation. There is a correlation with meningioma. There is a possibility that large artery vasculopathy will be present in a proportion of patients irradiated for ALL. The long lag time between irradiation and the development of meningioma may mean that, as survivors of childhood ALL enter their third decade since cure, this tumour may be seen increasingly.

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

    PubMed Central

    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

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

    PubMed

    Hsu, Hsiang-Hao; Huang, Chiu-Ching

    2004-01-01

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

  3. Anaplastic lymphoma kinase status in rhabdomyosarcomas.

    PubMed

    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

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

    PubMed Central

    Chen, Xueyan; Soma, Lorinda A; Fromm, Jonathan R

    2014-01-01

    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 (CD)30 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. PMID:24379682

  5. Silicone implant and primary breast ALK1-negative anaplastic large cell lymphoma, fact or fiction?

    PubMed Central

    Li, Shiyong; Lee, Andrew K

    2010-01-01

    The safety of silicone-based implant for mammoplasty has been debated for decades. A series of anecdotal case reports and a recent epidemiological case-control study have suggested a possible association between silicone implant and the development of primary breast ALK1-negative anaplastic large cell lymphoma (ALCL), a rare type of peripheral T-cell lymphoma. In this report, we describe an additional case of primary breast ALK1-negative ALCL in the fibrous capsule and cystic fluid of silicone breast implant in a 58 year old woman who underwent breast reconstructive surgery after lumpectomy for her infiltrating breast adenocarcinoma. Morphologically and immunohistochemically, the lymphoma cells may be confused with recurrent infiltrating breast adenocarcinoma or other non-hematolymphoid malignancies. Molecular studies were needed to determine T-lineage differentiation of the malignant lymphoma cells. We will also review the case reports and case series published in the English literature and discuss our current understanding of silicone implant in primary breast ALK1-negative ALCL. PMID:19918336

  6. Breast Implant Informed Consent Should Include the Risk of Anaplastic Large Cell Lymphoma.

    PubMed

    Clemens, Mark W; Miranda, Roberto N; Butler, Charles E

    2016-04-01

    Breast implant-associated anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma arising around breast implants. Public awareness has increased following a safety communication warning of the association of breast implant-associated ALCL by the U.S. Food and Drug Administration in 2011. Difficulty with determining an accurate assessment of risk, including diagnosis, or standardized treatment regimen has led surgeons to commonly omit preoperative discussion of this rare and frequently misunderstood cancer. Risk disclosure is a form of respect for patient autonomy, and informed consent has positive practical and moral consequences for the practice of plastic surgery. A model of breast implant-associated ALCL informed consent implementation and health care provider education are reviewed with 1-year process follow-up at a tertiary cancer center. Breast implant-associated ALCL should be included during preoperative counseling on the risks of breast implantation when obtaining informed consent. Pertinent aspects of decision-making include disease awareness, presenting symptoms, and resources for concerned patients. Education of health care professionals and provision of patient-focused materials ensures effectiveness of the informed consent process.

  7. Anaplastic T large cell lymphoma diagnosed by exfoliative cytology in a post renal transplant patient.

    PubMed

    Treaba, Diana; Assad, Lina; Goldberg, Cathryn; Loew, Jerome; Reddy, Vijaya B; Kluskens, Larry; Gattuso, Paolo

    2002-07-01

    In the last two decades posttransplant lymphoproliferative disorders (PTLDs) have been recognized as a complication of organ transplantation with immunosuppression. The reported incidence of PTLDs in renal transplant patients ranges between 0.3-3% (Birkeland et al., Transplantation 1999;67:876-881). In contrast to the reported incidence of PTLDs in post bone marrow transplant, it is 1% in HLA-matched recipients and up to 20% in HLA mismatched T-cell depleted bone marrow recipients (Curtis et al., Blood 1996;94:2208-2216). In cardiac transplant recipients the reported incidence of PTLDs is between 1.8-9.8 (Mihalov et al., Clin Transplant 1996;10:248-255). PTLDs are predominately extranodal. They have varied morphologic patterns and clonality, but almost all are associated with Epstein-Barr virus (EBV). The vast majority are of B cell lineage; only about 10% are of T-cell origin. We report a T-cell anaplastic large cell lymphoma (ALCL) presenting with bilateral pleural effusion and liver involvement in a renal transplant recipient.

  8. Anaplastic large cell lymphoma associated with breast implants: a report of 13 cases.

    PubMed

    Aladily, Tariq N; Medeiros, L Jeffrey; Amin, Mitual B; Haideri, Nisreen; Ye, Dongjiu; Azevedo, Sergio J; Jorgensen, Jeffrey L; de Peralta-Venturina, Mariza; Mustafa, Eid B; Young, Ken H; You, M James; Fayad, Luis E; Blenc, Ann Marie; Miranda, Roberto N

    2012-07-01

    We report 13 cases of anaplastic large cell lymphoma (ALCL) associated with breast implants. Patient age ranged from 39 to 68 years, and the interval from implant to ALCL was 4 to 29 years. All tumors were composed of large, pleomorphic cells that were CD30 and ALK1, and all 7 cases assessed had monoclonal T-cell receptor γ-chain rearrangements. Two patient subgroups were identified. Ten patients presented with effusion surrounded by fibrous capsule without a grossly identifiable tumor mass. Nine patients had stage I and 1 had stage II disease. Eight patients underwent implant removal and capsulectomy. Four patients received chemotherapy and 4 radiation therapy. All patients were alive without disease at last follow-up. A second subgroup of 3 patients had effusion and a distinct mass adjacent to the implant. One patient had stage I and 2 stage II disease. One patient had a 3-year history of lymphomatoid papulosis, and 1 patient had a 1-year history of CD30 T-cell lymphoma adjacent to the breast before the diagnosis of ALCL associated with breast implant. Two patients received chemotherapy and 1 radiation therapy. Two patients died 2 and 12 years after diagnosis, respectively. We conclude that the clinical behavior of ALCL associated with breast implants is heterogeneous. Patients who present with effusion without a distinct mass have an indolent disease course, similar to CD30 lymphoproliferative disorder of skin. In contrast, patients who present with a distinct mass may have advanced stage or possibly systemic disease and have a poorer prognosis.

  9. Treatment of Primary Cutaneous CD30+ Anaplastic Large-Cell Lymphoma With Radiation Therapy

    SciTech Connect

    Yu, James B.; McNiff, Jennifer M.; Lund, Molly W.; Wilson, Lynn D.

    2008-04-01

    Purpose: Primary cutaneous CD30+ anaplastic large-cell lymphoma (CALCL) is a relatively rare and indolent variant of cutaneous T-cell lymphoma (CTCL). This report examines the response of localized disease to radiation alone. Methods: The Yale Cancer Center records were examined, and all patients with CTCL from January 1, 2001, to September 1, 2006, evaluated in the Department of Therapeutic Radiology were identified. Only those patients with localized or single CALCL lesions, no clinical evidence or history of lymphomatoid papulosis, no history of other CTCLs, no history of other skin disorders, lack of lymph node involvement, unambiguous pathology reports, and treatment with radiation alone were included. Results: Eight patients were identified. Median age was 67 years, and gender was split evenly. Patients received radiation ranging from 34 to 44 Gy in 2-Gy fractions. Most patients (5 of 8) received 40 Gy, using 6 to 9 MeV electrons with 0.5 to 2 cm of bolus. All patients had a complete response. All patients were without evidence of disease at the most recent follow-up (median follow-up, 12 months). Radiation therapy was well tolerated, and the only recorded toxicity was Grade I to II dermatitis. Conclusions: Radiation therapy alone for localized CALCL is very well tolerated and clinical response is excellent. A dose of 40 Gy in 2-Gy fractions seems to be well tolerated and effective in inducing a complete response. Lower doses may be effective in achieving the same result, but data are not available. Longer follow-up is necessary before conclusions regarding durable disease-free survival can be made.

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

    PubMed

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

    2000-12-01

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

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

    PubMed Central

    Buetti-Dinh, Antoine; O’Hare, Thomas

    2016-01-01

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

  12. Bone involvement and abcess formation by neutrophil-rich CD30+ anaplastic large-cell lymphoma mimicking skeletal infection in an AIDS patient.

    PubMed

    Mira, José A; Fernández-Alonso, Jorge; Macías, Juan; Sáez, Carmen; Japón, Miguel A; Pereda, Teresa; Pineda, Juan A

    2003-07-01

    Neutrophil-rich CD30+ anaplastic large-cell lymphoma (ALCL) is a rare pathological entity without distinct clinical behavior. Twelve cases of neutrophil-rich CD30+ anaplastic large-cell lymphoma (ALCL) have been reported, three of them were HIV-infected patients. All these reports stressed the presence of neutrophil infiltration as a new morphologic feature of CD30+ ALCL. Only one case of cutaneous involvement presented with microabscess formation. We describe a case of neutrophil-rich CD30+ ALCL in an AIDS patient with a clinical picture determined by the massive neutrophil infiltration of the tumor without necrosis nor local infection, but with the formation of abscesses.

  13. Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma

    PubMed Central

    Desquesnes, Aurore; Le Gonidec, Sophie; AlSaati, Talal; Beau, Isabelle; Lamant, Laurence; Meggetto, Fabienne; Espinos, Estelle; Codogno, Patrice; Brousset, Pierre; Giuriato, Sylvie

    2015-01-01

    Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients. PMID:26338968

  14. Breast Implant-Associated Anaplastic Large Cell Lymphoma: Report of 2 Cases and Review of the Literature.

    PubMed

    Hart, Alexandra M; Lechowicz, Mary Jo; Peters, Kendall K; Holden, Jeannine; Carlson, Grant W

    2014-08-01

    Although primary breast lymphomas are exceedingly rare, cases of breast implant-associated anaplastic large cell lymphoma (iALCL) continue to be reported. The authors describe their experience with 2 patients and review the literature. Both patients presented with periprosthetic fluid collection. Neither had evidence of systemic disease nor received systemic therapy. Both were disease free after bilateral capsulectomies and implant removal without implant replacement, and disease did not recur. During the literature review, 63 cases of iALCL (including our 2 patients) were identified. The median time from implant placement to diagnosis was 9 years. Both saline and silicone implants were associated with iALCL. Of the 26 cases for which implant surface was reported, the surface was textured in 24. Of the 58 patients with an identifiable presentation, 39 had periprosthetic fluid collection, including 7 with an associated mass; 13 had an isolated mass at presentation, including 1 with axillary adenopathy. Forty patients had capsulectomy, 7 of whom underwent implant replacement. Of the 44 patients with known treatment, 33 received chemotherapy and 23 received radiation. Of the 49 patients with known anaplastic large cell lymphoma, 15 had disease recurrence, and 4 patient deaths were reported. Of the 18 patients presenting with a mass, 11 had disease recurrence, including all 4 patients who died. This study represents the largest review of patients with iALCL described to date. Although most cases have an indolent clinical course, the variety of presentations defined as "seroma" vs "capsular involvement" emphasizes the importance of investigating a definitive method of diagnosis, management, and treatment of this disease. LEVEL OF EVIDENCE 5.

  15. Apatinib as post second-line therapy in EGFR wild-type and ALK-negative advanced lung adenocarcinoma

    PubMed Central

    Fang, Shen-Cun; Zhang, Hai-Tao; Zhang, Ying-Ming; Xie, Wei-Ping

    2017-01-01

    In the absence of a driver mutation, chemotherapy is the standard treatment option as first- and second-line therapy for advanced non-small-cell lung cancer (NSCLC). Though a large number of patients are suitable for post second-line therapies, the quality and quantity of the available drugs in this setting is poor. Apatinib, a small molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, is a first-generation oral antiangiogenesis drug approved in the People’s Republic of China for use as a subsequent line of treatment for advanced gastric cancer. Herein, we report three cases of advanced NSCLC with epidermal growth factor receptor wild-type and anaplastic lymphoma kinase-negative status, wherein the patients showed partial response to apatinib. Moreover, the three patients have achieved a progression-free survival of 2.8, 5.8, and 6 months, respectively. The main toxicities were hypertension, proteinuria, and hand–foot syndrome. Apatinib may provide an additional option for the treatment of advanced NSCLC, especially for advanced lung adenocarcinoma without a driver mutation. PMID:28176910

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

    PubMed

    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.

  17. Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: a study of children and adolescents in Japan.

    PubMed

    Fukano, Reiji; Mori, Tetsuya; Kobayashi, Ryoji; Mitsui, Tetsuo; Fujita, Naoto; Iwasaki, Fuminori; Suzumiya, Junji; Chin, Motoaki; Goto, Hiroaki; Takahashi, Yoshiyuki; Hara, Junichi; Park, Yong-Dong; Inoue, Masami; Koga, Yuhki; Inagaki, Jiro; Sakamaki, Hisashi; Adachi, Souichi; Kawa, Keisei; Kato, Koji; Suzuki, Ritsuro

    2015-02-01

    To evaluate haematopoietic stem cell transplantation (HSCT) in children and adolescents, we reviewed the records of 47 patients who were ≤18 years, had relapsed or refractory anaplastic large cell lymphoma, and received HSCT between 1990 and 2010. At HSCT, complete remission (CR) was less common in allogeneic HSCT recipients (n = 24) than in autologous HSCT recipients (n = 23) (P = 0·01). The autologous and allogeneic HSCT groups differed in terms of 5-year event-free survival (EFS) (38% vs. 50%, P = 0·63), cumulative incidence of progress or relapse (49% vs. 28%, P = 0·25), and treatment-related mortality (12% vs. 25%, P = 0·40). However, these differences were not significant. Patients with non-CR at autologous HSCT had a significantly lower EFS rate (14% vs. 48%, P = 0·03). Conversely, although those with non-CR at allogeneic HSCT had a lower EFS rate, this was not significant (44% vs. 63%, P = 0·26). Reduced-intensity conditioning regimens were used for three of the 16 allogeneic HSCTs received by patients with non-CR. These three patients achieved CR, surviving 32-65 months after HSCT. These results demonstrated that allogeneic HSCT might be a treatment option for patients who do not achieve CR through conventional chemotherapy.

  18. CCL11-CCR3 interactions promote survival of anaplastic large cell lymphoma cells via ERK1/2 activation.

    PubMed

    Miyagaki, Tomomitsu; Sugaya, Makoto; Murakami, Takashi; Asano, Yoshihide; Tada, Yayoi; Kadono, Takafumi; Okochi, Hitoshi; Tamaki, Kunihiko; Sato, Shinichi

    2011-03-15

    CCR3 is a specific marker of anaplastic large cell lymphoma (ALCL) cells. ALCL cells also express CCL11, a ligand for CCR3, leading to the hypothesis that CCL11 may play an autocrine role in ALCL progression. In this study, we investigated a role of CCL11 in cell survival and growth of human Ki-JK cells, established from an ALCL patient, and murine EL-4 lymphoma cells. Both Ki-JK and EL-4 cells expressed cell surface CCR3. CCL11 increased cell survival rates of Ki-JK cells in a dose-dependent manner, whereas it promoted EL-4 cell proliferation. Furthermore, CCL11 induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in both Ki-JK cells and EL-4 cells. Cell survival and tumor proliferation promoted by CCL11 was completely blocked by inhibition of ERK phosphorylation. CCL11 induced expression of antiapoptotic proteins, Bcl-xL and survivin, in Ki-JK cells. CCL11 also enhanced tumor growth of EL-4 and Ki-JK cells in vivo. Consistent with these results, tumor cells of cutaneous ALCL expressed CCR3 and increased levels of phosphorylated ERK1/2, Bcl-xL, and survivin in situ. Thus, our findings prompt a novel therapeutic approach to treat relapses of an aggressive form of lymphoma based on the discovery that a cell surface marker of disease functions as a critical autocrine growth receptor.

  19. The long non-coding RNA LINC01013 enhances invasion of human anaplastic large-cell lymphoma.

    PubMed

    Chung, I-Hsiao; Lu, Pei-Hsuan; Lin, Yang-Hsiang; Tsai, Ming-Ming; Lin, Yun-Wen; Yeh, Chau-Ting; Lin, Kwang-Huei

    2017-03-22

    Anaplastic large-cell lymphoma (ALCL) is a rare type of highly malignant, non-Hodgkin lymphoma (NHL). Currently, only studies on the chimeric oncogene NPM-ALK have reported a link to ALCL progression. However, the specific molecular mechanisms underlying the invasion of ALCL are still unclear. Here, we sought to investigate differentially expressed, long non-coding RNAs (lncRNAs) in ALCL and their potential biological function. Our microarray analyses revealed that LINC01013, a novel non-coding RNA gene, was highly expressed in clinical specimens of ALCL and was significantly upregulated in invasive ALCL cell lines. Knockdown of LINC01013 suppressed tumor cell invasion; conversely, its overexpression enhanced tumor cell invasion. LINC01013-induced invasion was mediated by activation of the epithelial-to-mesenchymal transition (EMT)-associated proteins, snail and fibronectin. Specifically, LINC01013 induced snail, resulting in activation of fibronectin and enhanced ALCL cell invasion. Collectively, these findings support a potential role for LINC01013 in cancer cell invasion through the snail-fibronectin activation cascade and suggest that LINC01013 could potentially be utilized as a metastasis marker in ALCL.

  20. Posttransplant Lymphoproliferative Disorder Manifesting as Intestinal Epstein-Barr Virus-Positive Anaplastic Large-Cell Lymphoma in an Adult Renal Transplant Recipient.

    PubMed

    Börcek, Pelin; Özdemir, B Handan; Özgün, Gonca; Haberal, Mehmet

    2016-11-01

    Posttransplant lymphoproliferative disorder is a relatively common posttransplant malignancy affecting as many as 10% of all solid-organ recipients. Most cases of posttransplant lymphoproliferative disorder are of B-cell origin, with common Epstein-Barr virus association. Posttransplant lymphoproliferative disorders of T-cell origin are much rarer and less frequently associated with Epstein-Barr virus. Here, we report an unusual case of Epstein-Barr virus-positive anaplastic large-cell lymphoma causing an intestinal perforation in an adult renal transplant recipient. A 52-year-old male patient with renal allograft developed cryptogenic end-stage liver failure and was accepted as a candidate for liver transplant. Before transplant, he was admitted with severe abdominal pain, which turned out to result from ileal perforation. Pathologic evaluation of the intestinal resection showed diffuse malignant lymphoid infiltration of the ileum, consistent with anaplastic large-cell lymphoma. The tumor was positive for Epstein-Barr virus genome. Anaplastic large-cell lymphoma is a rare form of T-cell posttransplant lymphoproliferative disorder that is infrequently associated with Epstein-Barr virus. The occurrence of this extraordinary form of post transplant lymphoproliferative disorder, its late onset, intestinal localization, and Epstein-Barr virus as sociation represent a unique clinical rarity.

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

    PubMed

    La Fortune, Kristin; Zhang, Dahua; Raca, Gordana; Ranheim, Erik A

    2013-01-01

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

  2. Anaplastic large-cell lymphoma associated with breast implants: a unique entity within the spectrum of peri-implant effusions.

    PubMed

    Chai, Siaw Ming; Kavangh, Simon; Ooi, Sin Sin; Sterrett, Gregory F; Cull, Gavin; Plunkett, Myfanwy; Spagnolo, Dominic; Amanuel, Benhur; Joske, David; Leslie, Connull; Barham, Tony; Frost, Felicity

    2014-11-01

    Anaplastic large-cell lymphoma (ALCL) is a rare and newly described complication associated with breast implants. Patients often present with a peri-implant effusion, which is amenable to fine-needle aspiration. The laboratory handling of peri-implant effusions for cytology and ancillary studies is as crucial as recognizing the characteristic cytology of ALCL. All cases of peri-implant effusions were retrieved from the PathWest database between January 2003 and May 2013, yielding four cases of breast implant-associated ALCL and six benign samples. The cytological features were evaluated and information from ancillary studies collated. Clinical and follow-up histology was available in all cases. All ALCL cases contained highly atypical lymphoid cells including 'hallmark' cells. In contrast, benign peri-implant effusions showed a mixture of inflammatory cells, being either neutrophil-rich (three cases) or lymphocyte-rich (three cases). A CD30 positive, ALK1 negative immunophenotype was demonstrated in all cases on cell block immunohistochemistry. Flow cytometry and T-cell receptor clonality studies confirmed aberrant T-cell immunophenotype in four of four and clonally rearranged T-cell receptor antigens in three of three cases. ALCL was identified in three of four subsequent capsulectomies. Staging confirmed disease limited to the capsular tissue or peri-implant effusion in all cases. None of the six patients with benign peri-implant effusions developed lymphoma during follow-up. Cases of ALCL accounted for 40% of peri-implant effusions received over a 10-year period, indicating the rarity of these samples and the high likelihood of malignancy. Awareness of this entity and its presentation should allow for appropriate triage of these specimens and definitive diagnosis on effusion specimens.

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

    PubMed Central

    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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed Central

    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

  6. Anaplastic thyroid cancer

    MedlinePlus

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

  7. EXTRINSIC APOPTOTIC PATHWAYS: A NEW POTENTIAL “TARGET” FOR MORE SUFFICIENT THERAPY IN A CASE OF CUTANEOUS ANAPLASTIC LARGE CD30+ ALK–T-CELL LYMPHOMA

    PubMed Central

    Georgi, Tchernev; Carlos, Cardoso José; Lubomir, Arseniev; Hiroyuki, Okamoto

    2011-01-01

    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(lo)n). 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. PMID:21572802

  8. Anaplastic Large Cell Lymphoma

    MedlinePlus

    ... and support programs: • Lymphoma Helpline • Clinical Trials Information Service • Lymphoma Support Network • Publications • Teleconferences • Webcasts & podcasts • In-person conferences Medical ...

  9. Nodal anaplastic large-cell lymphoma ALK-1- with CD30+ cutaneous lymphoproliferation treated with mistletoe: spontaneous remission or treatment response?

    PubMed

    Kameda, G; Kempf, W; Oschlies, I; Michael, K; Seifert, G; Längler, A

    2011-11-01

    A 12-year old girl presented with general weakness and weight loss, a localised cervical lymph node enlargement and cutaneous lesions compatible with lymphomatoid papulosis (LyP). Biopsies from lymph node and skin revealed a histological diagnosis of nodal large cell ALK-1- anaplastic lymphoma (ALCL) with a synchronous CD30+ cutaneous lymphoproliferation consistent with lymphomatoid papulosis (LyP). The girl was treated with mistletoe (MT) as monotherapy. Within 1 week after initiation of MT-treatment the skin lesions and lymph node enlargement improved. Under continuing MT-therapy 30 months after diagnosis the patient is still in complete remission. It is not possible to know whether this was a rare case of spontaneous remission of the nodal and skin-manifestations of this CD30+ T-cell lymphoproliferation or whether the observed effect was a specific therapeutic response to MT-treatment.

  10. Consequences of heat shock protein 72 (Hsp72) expression and activity on stress-induced apoptosis in CD30+ NPM-ALK+ anaplastic large-cell lymphomas.

    PubMed

    Bonvini, P; Zorzi, E; Mussolin, L; Pillon, M; Romualdi, C; Peron, M; d'Amore, E S G; Lamant, L; Rosolen, A

    2012-06-01

    Understanding the mechanisms that control stress-induced apoptosis is critical to explain how tumours respond to treatment, as cancer cells frequently escape drug toxicity by regulating stress response through heat shock protein (HSP) expression. The overexpression of Hsp72, in particular, results in increased incidence of cell transformation, and correlates with poor prognosis in a wide range of cancers. We have shown that Hsp72 assists folding of oncogenic NPM-ALK kinase in anaplastic large-cell lymphomas (ALCLs), but its role in the maintenance of the malignant phenotype remains uncertain. Therefore, we assessed Hsp72 expression in ALCLs, investigating more in detail the mechanisms that regulate its status and activity. We found that Hsp72 is unique among the HSPs involved in tumourigenesis to be overexpressed in ALK(+) tumours and cell lines and to be induced by stress. Different from other HSPs, Hsp72 prevents cell injury, Bax activation and death by apoptosis in ALK(+) cells, acting both upstream and downstream of mitochondria. Conversely, Hsp72 is underexpressed in ALK(-) ALCL cells, and it is unable to protect cells from apoptosis under stress. Moreover, when Hsp72 expression is reduced following NPM-ALK inhibition, lymphoma cells undergo apoptosis, demonstrating the importance of Hsp72 in regulating ALCL stress response and drug sensitivity.

  11. Combination of the human anti-CD30 antibody 5F11 with cytostatic drugs enhances its antitumor activity against Hodgkin and anaplastic large cell lymphoma cell lines.

    PubMed

    Heuck, Friederike; Ellermann, Julia; Borchmann, Peter; Rothe, Achim; Hansen, Hinrich; Engert, Andreas; von Strandmann, Elke Pogge

    2004-01-01

    Due to its selective overexpression on the malignant cells of Hodgkin's lymphoma (HL) and large cell anaplastic lymphoma (ALCL), CD30 is an excellent target for immunotherapy of these diseases. The fully human monoclonal anti-CD30-antibody 5F11 has been shown to be effective against CD30-expressing cell lines both in vitro and in vivo. In addition, 5F11 shows promising antitumor activity in phase 1/2 clinical trials. To extend these promising results, the authors evaluated combinations of 5F11 with conventional cytostatic drugs against a variety of lymphoma cell lines in vitro. Most combinations tested showed at least additive cytotoxic effects on the HL-derived cell lines L428, L540, and L1236 and the ALCL-derived cell line Karpas 299 as measured by proliferation assays (XTT) and the induction of apoptosis (annexin-V FACS analysis). The most impressive results were detected with the combination of 5F11 and gemcitabine or etoposide. The data suggest that the combination of the human antibody 5F11 with conventional chemotherapy might be beneficial in the combined chemo-immunotherapy of CD30-positive lymphomas.

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

    PubMed Central

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

    2017-01-01

    Primary breast lymphoma is a rare disease and accounts for 0.5% of cases of breast cancer. Most primary breast lymphomas develop from B cells, and the involvement of T cells is rare. Anaplastic large cell lymphoma (ALCL) is a recently discovered T-cell lymphoma associated with breast implants. Only a few cases have been reported to date. It is believed that the incidence of ALCL is increasing because of the increasing number of breast implants. The clinical presentation is variable and can manifest as a palpable mass in the breast or armpit, breast pain, or capsular contracture. Because of the rarity of the disease and the lack of knowledge to date, clinical diagnosis is often delayed, with consequent delays in treatment. The cause and pathogenesis have not been fully elucidated, and there are no evidence-based guidelines for diagnosis, treatment, or follow-up of this disease. We present a review of cases of patients with silicone breast implants, including ALCL, a rare type of breast cancer that is still under study, and silicone-induced granuloma of breast implant capsule and its differential diagnosis, and discuss if a silicone-induced granuloma of breast implant capsule could be the precursor of the disease. PMID:28331364

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

    PubMed

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

    2017-01-01

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

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

    ClinicalTrials.gov

    2013-11-24

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

  15. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project.

    PubMed

    Savage, Kerry J; Harris, Nancy Lee; Vose, Julie M; Ullrich, Fred; Jaffe, Elaine S; Connors, Joseph M; Rimsza, Lisa; Pileri, Stefano A; Chhanabhai, Mukesh; Gascoyne, Randy D; Armitage, James O; Weisenburger, Dennis D

    2008-06-15

    The International Peripheral T-Cell Lymphoma Project is a collaborative effort designed to gain better understanding of peripheral T-cell and natural killer (NK)/T-cell lymphomas (PTCLs). A total of 22 institutions in North America, Europe, and Asia submitted clinical and pathologic information on PTCLs diagnosed and treated at their respective centers. Of the 1314 eligible patients, 181 had anaplastic large-cell lymphoma (ALCL; 13.8%) on consensus review: One hundred fifty-nine had systemic ALCL (12.1%) and 22 had primary cutaneous ALCL (1.7%). Patients with anaplastic lymphoma kinase-positive (ALK(+)) ALCL had a superior outcome compared with those with ALK(-) ALCL (5-year failure-free survival [FFS], 60% vs 36%; P = .015; 5-year overall survival [OS], 70% vs 49%; P = .016). However, contrary to prior reports, the 5-year FFS (36% vs 20%; P = .012) and OS (49% vs 32%; P = .032) were superior for ALK(-) ALCL compared with PTCL, not otherwise specified (PTCL-NOS). Patients with primary cutaneous ALCL had a very favorable 5-year OS (90%), but with a propensity to relapse (5-year FFS, 55%). In summary, ALK(-) ALCL should continue to be separated from both ALK(+) ALCL and PTCL-NOS. Although the prognosis of ALK(-) ALCL appears to be better than that for PTCL-NOS, it is still unsatisfactory and better therapies are needed. Primary cutaneous ALCL is associated with an indolent course.

  16. Anaplastic ependymoma simulating glioblastoma in the cerebrum of an adult.

    PubMed

    Shintaku, Masayuki; Hashimoto, Kenji

    2012-01-01

    A case of anaplastic ependymoma of the cerebral hemisphere in which the histopathological features closely simulated those of glioblastoma is reported. The patient was a 72-year-old woman with a large, well-demarcated tumor in the left temporal lobe. The tumor was totally extirpated, but recurred 18 months later, and the patient died after 4 months. The extirpated tumor was well circumscribed from the surrounding brain tissue and consisted of a sheet-like, dense proliferation of atypical, short spindle or polygonal cells. Extensive geographic necrosis with nuclear pseudopalisading was seen. Although perivascular pseudorosettes were observed in many areas, true ependymal rosettes were absent. Immunohistochemistry for glial fibrillary acidic protein and epithelial membrane antigen and ultrastructural study confirmed the ependymal nature of tumor cells. The histopathological spectrum of anaplastic ependymoma is very wide and reflects the basically dual characteristics of ependymal cells: epithelial and glial phenotypes. The present case indicates that some anaplastic ependymomas strongly express the glial phenotype and also show remarkable anaplastic cytological features, thus closely simulating glioblastoma. The diagnostic criteria for anaplastic ependymoma, and the nosological position of highly anaplastic ependymoma and its possible clinical implications, are briefly discussed.

  17. [Successful long-term control of recurrent primary central nervous system anaplastic large cell lymphoma after autologous hematopoietic stem cell transplantation with concurrent whole brain and spinal cord radiotherapy].

    PubMed

    Hiroshima, Yuki; Kaiume, Hiroko; Kirihara, Takehiko; Takeda, Wataru; Kurihara, Taro; Sato, Keijiro; Shimizu, Ikuo; Ueki, Toshimitsu; Sumi, Masahiko; Ueno, Mayumi; Ichikawa, Naoaki; Asano, Naoko; Watanabe, Masahide; Kobayashi, Hikaru

    2015-12-01

    A 24-year-old woman was hospitalized with seizures in 2002. Magnetic resonance imaging demonstrated an intraspinal mass and inhomogeneous gadolinium enhancement along the cerebrospinal meninges. Cerebrospinal fluid (CSF) cytology showed large atypical cells expressing CD2, cytoplasmic CD3, CD7, CD13 and CD30. The patient was finally diagnosed with primary central nervous system anaplastic large cell lymphoma (ALCL). She completed 5 courses of methotrexate (MTX)/ procarbazine (PCZ)/ vincristine (VCR) (MPV) chemotherapy, followed by 2 courses of high dose cytarabine (AraC) and achieved a complete remission. In 2003, she suffered from headache. CSF analysis showed atypical lymphoid cells expressing CD 30. First CNS relapse was diagnosed. She then underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) after administration of thiotepa, buslfan, and cyclophosphamide. However, second CNS relapse occurred in 2004. She received 5 courses of MPV chemotherapy followed by 36 Gy of craniospinal irradiation. Although there was no recurrence of the CNS disease, a third relapse was detected in the right breast in 2009. Pathological and immunohistochemistry analysis revealed ALK-1 positive ALCL. She was treated with 6 courses of cyclophosphamide/adriamycin/vincristine/predonine (CHOP) chemotherapy and 30.6 Gy of local radiation therapy. She has remained in remission for 6 years, to date, since the last therapy and has an excellent quality of life.

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

    PubMed

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

    2017-01-01

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

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

    PubMed Central

    Shende, Nitin Y; Kumbhalkar, D T

    2017-01-01

    Clear Cell Sarcoma of Kidney (CCSK) is known for its morphologic diversity, aggressive behaviour, tendency to recur and metastasis to bone. Amongst the various morphologic subtypes, anaplastic CCSK is associated with worse prognosis. Here, we report a case of this rare variant of CCSK. A five-year-old boy presented with history of lump and pain in abdomen since one week. The Computed Tomography (CT) scan revealed a large mass occupying the middle and inferior pole of right kidney. The clinical impression was Wilms tumour. Nephrectomy specimen was received and the diagnosis of CCSK anaplastic variant was offered only after excluding the differentials and after performing ancillary tests such as Immunohistochemistry (IHC). Thus, this case emphasizes the diagnostic challenges on morphology and the essential role of IHC in arriving at a definitive diagnosis, because failure to do so may deprive the child from optimal treatment. PMID:28273978

  20. [Surgical seeding of an anaplastic ependymoma].

    PubMed

    Yamada, Masayuki; Sato, Taku; Kuromi, Yosuke; Matsumoto, Yuka; Oda, Keiko; Kishida, Yugo; Tamura, Takamitsu; Ichikawa, Masahiro; Sakuma, Jun; Saito, Kiyoshi

    2013-12-01

    Ependymomas can relapse at the primary site and disseminate to the spinal cord. Furthermore, extraneural metastases are rare. We present a case of anaplastic ependymoma with extraneural metastasis, possibly caused by surgical seeding. An 18-year-old female was referred to us after experiencing frequent convulsive attacks. At age 9 years, she underwent partial resection of a left frontal anaplastic ependymoma, followed by 45 Gy radiation. At age 15 years, a recurrent tumor was totally removed. Three years later, magnetic resonance images revealed a left frontal recurrent tumor and a new parietal lesion. Our preoperative diagnosis of the parietal tumor was a radiation-induced meningioma. However, intraoperative pathological examinations revealed the lesion to be an anaplastic ependymoma. The tumor, which was located in the epidural space and had invaded extensively into the cranial bone, was gross totally removed. Although extremely rare, surgical seeding of anaplastic ependymomas should be considered as a differential diagnosis for recurrent tumors in the surgical field.

  1. Anaplastic glioma: current treatment and management.

    PubMed

    Le Rhun, Emilie; Taillibert, Sophie; Chamberlain, Marc C

    2015-06-01

    Anaplastic glioma (AG) is divided into three morphology-based groups (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma) as well as three molecular groups (glioma-CpG island methylation phenotype [G-CIMP] negative, G-CIMP positive non-1p19q codeleted tumors and G-CIMP positive codeleted tumors). The RTOG 9402 and EORTC 26951 trials established radiotherapy plus (procarbazine, lomustine, vincristine) chemotherapy as the standard of care in 1p/19q codeleted AG. Uni- or non-codeleted AG are currently best treated with radiotherapy only or alkylator-based chemotherapy only as determined by the NOA-04 trial. Maturation of NOA-04 and results of the currently accruing studies, CODEL (for codeleted AG) and CATNON (for uni or non-codeleted AG), will likely refine current up-front treatment recommendations for AG.

  2. Effects of adenovirus-mediated expression of p27Kip1, p21Waf1 and p16INK4A in cell lines derived from t(2;5) anaplastic large cell lymphoma and Hodgkin's disease.

    PubMed

    Turturro, Franceso; Arnold, Marilyn D; Frist, Audrey Y; Seth, Prem

    2002-06-01

    We investigated the response of SUDHL-1 and L428 cells, derived from t(2;5)-anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD), respectively, to recombinant adenoviruses expressing cyclin-dependent kinase inhibitors (CDKIs) p27Kip1 (Adp27), p21Waf1 (Adp21) and p16INK4A (Adp16). Cell cycle analysis of SUDHL-1 cells after 24 h of infection with 200 multiplicity of infection (MOI) of Adp27, Adp21, and Adp16, showed very high levels of cell debris in the subG1 area. The magnitude of cell debris-events was Adp27/Adp21 > Adp16. Cell cycle analysis of L428 cells revealed absence of cell debris and increased G2 phase in all the groups of cells tested as compared to the controls (mock and AdNull). A minimal increase in G1 phase was also evident in cells infected with Adp27 (52%) compared to uninfected cells (43%), AdNull (45%) and to cells infected with Adp21 (37%) and Adp16 (31%). The presence of significant levels of Coxsackie-adenovirus receptor (CAR) on the cell surface of L428 cells excluded the cell membrane-barrier as responsible for the differences in cell observed in response to the recombinant adenovirus-mediated CDKIs expression as compared to SUDHL-1. We also showed that the recombinant adenovirus-mediated cytotoxicity measured as apoptosis was MOI- and vector-dependent in SUDHL-1 cells at lower MOI (100). In conclusion, the therapeutic effect induced by recombinant adenoviruses expressing p27Kip1, p21Waf1 and p16INK4A is cell-dependent in cells derived from selected lymphoid malignancies. Biochemical cellular differences more than cell surface barriers seem to be responsible for differences in response to recombinant adenovirus-mediated expression of cytotoxic genes. Moreover, the cytotoxicity of recombinant adenoviruses expressing p27Kip1, p21Waf1 and p16INK4A may be further explored as a tool for gene therapy of t(2;5)-derived ALCL.

  3. Anaplastic giant cell thyroid carcinoma.

    PubMed

    Wallin, G; Lundell, G; Tennvall, J

    2004-01-01

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

  4. Radiation combined with temozolomide contraindicated for young adults diagnosed with anaplastic glioma

    PubMed Central

    Cai, Jinquan; You, Gan; Wang, Yinyan; Qiu, Xiaoguang; Li, Shouwei; Wu, Chenxing; Yao, Kun; Li, Wenbin; Peng, Xiaoxia; Zhang, Wei; Jiang, Tao

    2016-01-01

    Purpose Age is a major prognostic factor for malignant gliomas. However, few studies have investigated the management of gliomas in young adults. We determined the role of survival and treatment in young adults with advanced gliomas in a large population from the Chinese Glioma Genome Atlas (CGGA). Methods This study included 726 adults (age ≥ 18) with histologically proven anaplastic glioma or glioblastoma multiforme (GBM). The overall and progression-free survival was determined in young (age < 50) and older groups (age ≥ 50). Results The study included an older group (OP) of 264 patients and a younger group (YP) of 462patients. In the OP group with GBM and anaplastic glioma, patients treated with RT combined with temozolomide (TMZ) manifested significantly longer OS and PFS compared with patients assigned to RT alone (P < 0.05). In contrast, the YP group diagnosed with anaplastic glioma failed to show any survival advantage with RT plus TMZ compared with RT alone. Conclusions We observed no survival benefit in young adults (age < 50) with anaplastic glioma when treated with TMZ combined with RT. Our findings warrant further investigation of younger patients diagnosed with anaplastic glioma treated with radiotherapy plus TMZ chemotherapy. PMID:27590514

  5. Combination Chemotherapy and Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Peripheral T-cell Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2016-10-30

    Anaplastic Large Cell Lymphoma, ALK-Negative; Anaplastic Large Cell Lymphoma, ALK-Positive; Hepatosplenic T-Cell Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise Specified; Stage II Angioimmunoblastic T-cell Lymphoma; Stage II Enteropathy-Associated T-Cell Lymphoma; Stage III Angioimmunoblastic T-cell Lymphoma; Stage III Enteropathy-Associated T-Cell Lymphoma; Stage IV Angioimmunoblastic T-cell Lymphoma; Stage IV Enteropathy-Associated T-Cell Lymphoma

  6. Anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis.

    PubMed

    Pomeraniec, I J; Dallapiazza, R F; Sumner, H M; Lopes, M B; Shaffrey, C I; Smith, J S

    2015-12-01

    We present a rare extramedullary ependymoma with diffuse spinal metastatic disease, and review the previous reports of extramedullary spinal ependymomas. Ependymomas are the most common intramedullary spinal cord tumor in adults. These tumors rarely present as extramedullary masses. We treated a 23-year-old man with a history of progressive neck, shoulder and arm pain, with sensory and motor symptoms in the C7 dermatome. MRI of the cervical spine demonstrated a ventral contrast-enhancing lesion with evidence of enhancement along the dura and spinal cord of the upper cervical spine, thoracic spine, and cauda equina. He underwent a tumor debulking procedure without complications. Following surgery, he received craniospinal radiation to treat the remaining tumor and diffuse leptomeningeal disease. The final pathology of the tumor revealed that is was a World Health Organization Grade III anaplastic ependymoma. At the 1 year follow-up, the patient had stable imaging and had returned to his preoperative functional status. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis.

  7. Supratentorial extraventricular anaplastic ependymoma with extracranial metastasis.

    PubMed

    Pachella, Laura A; Kamiya-Matsuoka, Carlos; Lee, Eva Lu T; Olar, Adriana; Yung, W K Alfred

    2015-03-01

    Ependymoma is a relatively rare malignancy accounting for 2.0% of all primary central nervous system tumors in adults. Extracranial metastasis is a very uncommon complication of gliomas, especially of anaplastic ependymomas. The objective of this paper is to show that ependymomas can metastasize to soft tissue and lymph nodes as well as to share our approach to this challenge. We report a male patient with anaplastic ependymoma that recurred, metastasizing to the neck and lymph nodes. Metastatic disease was diagnosed based on clinical presentation of a palpable nodule on the right neck and diffuse cervical lymphadenopathies. A biopsy was obtained and pathology revealed anaplastic ependymoma. Whole-body fluorodeoxyglucose positron emission tomography scan showed metastatic disease in the right mastoid region with diffuse uptake in the cervical lymph nodes. Clinical and radiologic response was achieved after three chemotherapy cycles of etoposide, cisplatin, vincristine, and cyclophosphamide. This case highlights extracranial metastasis to the soft tissue as an atypical presentation of recurrent anaplastic ependymoma. Other reported instances of extracranial metastatic ependymoma with this presentation are discussed. The possible metastatic pathways of intracranial disease are discussed. It also illustrates how extracranial disease remains stable with systemic chemotherapy.

  8. Canine tumour suppressor gene p53 mutation in a case of anaplastic carcinoma of the intestine.

    PubMed

    Mayr, B; Reifinger, M

    2002-01-01

    Tumours localised in the large bowel of dogs were subjected to molecular genetic studies. Highly conserved regions of the tumour suppressor gene p53, including typical tumour hot spots (codons 175, 245, 248, 249, 273 and 282), were analysed. A mutation CGG-->TGG (arginine-->tryptophan) was present in codon 249 in an anaplastic carcinoma in the caecum.

  9. Anaplastic lymphoma kinase: signalling in development and disease

    PubMed Central

    Palmer, Ruth H.; Vernersson, Emma; Grabbe, Caroline; Hallberg, Bengt

    2009-01-01

    RTKs (receptor tyrosine kinases) play important roles in cellular proliferation and differentiation. In addition, RTKs reveal oncogenic potential when their kinase activities are constitutively enhanced by point mutation, amplification or rearrangement of the corresponding genes. The ALK (anaplastic lymphoma kinase) RTK was originally identified as a member of the insulin receptor subfamily of RTKs that acquires transforming capability when truncated and fused to NPM (nucleophosmin) in the t(2;5) chromosomal rearrangement associated with ALCL (anaplastic large cell lymphoma). To date, many chromosomal rearrangements leading to enhanced ALK activity have been described and are implicated in a number of cancer types. Recent reports of the EML4 (echinoderm microtubule-associated protein like 4)–ALK oncoprotein in NSCLC (non-small cell lung cancer), together with the identification of activating point mutations in neuroblastoma, have highlighted ALK as a significant player and target for drug development in cancer. In the present review we address the role of ALK in development and disease and discuss implications for the future. PMID:19459784

  10. Anaplastic ependymoma with ependymoblastic multilayered rosettes.

    PubMed

    Nobusawa, Sumihito; Suzuki, Aya; Nagaishi, Masaya; Isoda, Koji; Ikota, Hayato; Yokoo, Hideaki; Hirato, Junko; Nakazato, Yoichi

    2013-11-01

    Anaplastic ependymoma, World Health Organization grade III, is a malignant glioma with ependymal differentiation characterized by high mitotic activity often accompanied by microvascular proliferation and necrosis, where, generally, much fewer ependymal rosettes are found than in ependymoma, World Health Organization grade II. Ependymal rosettes, forming a single layer of tumor cells, differ from ependymoblastic multilayered rosettes, which are characteristic histologic features of ependymoblastoma, a variant of central nervous system primitive neuroectodermal tumor. Here, we report an autopsy case involving a 24-year-old woman with a frontal lobe tumor, which showed the aggregation of true rosettes with multilayering of tumor cells resembling the ependymoblastoma histology. Molecular and cytogenetic analyses revealed the absence of 19q13.42 amplification, a specific molecular hallmark of ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes, supporting the diagnosis of anaplastic ependymoma.

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

    PubMed

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

    1984-05-01

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

  12. Nivolumab in Treating Patients With Relapsed or Refractory Peripheral T-cell Lymphoma

    ClinicalTrials.gov

    2017-03-06

    Blastic Plasmacytoid Dendritic Cell Neoplasm; Hepatosplenic T-Cell Lymphoma; HTLV-1 Infection; NK-Cell Lymphoma, Unclassifiable; Primary Systemic Anaplastic Large Cell Lymphoma, ALK-Negative; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Angioimmunoblastic T-cell Lymphoma; Recurrent Enteropathy-Associated T-Cell Lymphoma; Recurrent Mycosis Fungoides; Refractory Adult T-Cell Leukemia/Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Angioimmunoblastic T-cell Lymphoma; Refractory Enteropathy-Associated T-Cell Lymphoma; Refractory Mycosis Fungoides; Refractory Nasal Type Extranodal NK/T-Cell Lymphoma; Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified

  13. Occipital Falcine Anaplastic Hemangiopericytoma Mimicking Meningioma

    PubMed Central

    Kanesen, Davendran; Kandasamy, Regunath; Idris, Zamzuri

    2016-01-01

    The rarity of hemangiopericytoma (HPC) and its controversial histological classification result in its frequent misdiagnosis and thus make the treatment quite challenging. It is often difficult to distinguish these tumors from meningiomas based on clinical features and radiological findings. This is a case report of a man, diagnosed clinically and radiologically as meningioma, which turned out to be anaplastic HPC on histological examination. A 30-year-old man presented with 3 months of progressively worsening of headache and blurring of vision. Clinical examination revealed the right homonymous hemianopia with reduced visual acuity and papilledema bilaterally. Magnetic resonance imaging revealed a multilobulated and heterogenous extraaxial lesion attached to the occipital falx. It measured 9.0 cm (AP) × 5.5 cm (W) × 5.8 cm (CC) and expands bilaterally with major bulk on the left. An occipital craniotomy followed by a subtotal tumor excision was only achieved due to profuse bleeding intraoperatively. Histopathology confirmed an anaplastic HPC (WHO Grade 3). The importance of differentiation between HPCs and meningiomas cannot be overemphasized. A preoperative correct diagnosis is difficult, but it is important that it should be made. Multilobulated (mushroom appearance), prominent internal signal voids, relatively narrow dural attachment, and lytic destruction without calcifications are useful findings to distinguish HPCs from meningiomas. PMID:28163517

  14. Occipital Falcine Anaplastic Hemangiopericytoma Mimicking Meningioma.

    PubMed

    Kanesen, Davendran; Kandasamy, Regunath; Idris, Zamzuri

    2016-12-01

    The rarity of hemangiopericytoma (HPC) and its controversial histological classification result in its frequent misdiagnosis and thus make the treatment quite challenging. It is often difficult to distinguish these tumors from meningiomas based on clinical features and radiological findings. This is a case report of a man, diagnosed clinically and radiologically as meningioma, which turned out to be anaplastic HPC on histological examination. A 30-year-old man presented with 3 months of progressively worsening of headache and blurring of vision. Clinical examination revealed the right homonymous hemianopia with reduced visual acuity and papilledema bilaterally. Magnetic resonance imaging revealed a multilobulated and heterogenous extraaxial lesion attached to the occipital falx. It measured 9.0 cm (AP) × 5.5 cm (W) × 5.8 cm (CC) and expands bilaterally with major bulk on the left. An occipital craniotomy followed by a subtotal tumor excision was only achieved due to profuse bleeding intraoperatively. Histopathology confirmed an anaplastic HPC (WHO Grade 3). The importance of differentiation between HPCs and meningiomas cannot be overemphasized. A preoperative correct diagnosis is difficult, but it is important that it should be made. Multilobulated (mushroom appearance), prominent internal signal voids, relatively narrow dural attachment, and lytic destruction without calcifications are useful findings to distinguish HPCs from meningiomas.

  15. Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma.

    PubMed

    Wiestler, Benedikt; Capper, David; Sill, Martin; Jones, David T W; Hovestadt, Volker; Sturm, Dominik; Koelsche, Christian; Bertoni, Anna; Schweizer, Leonille; Korshunov, Andrey; Weiß, Elisa K; Schliesser, Maximilian G; Radbruch, Alexander; Herold-Mende, Christel; Roth, Patrick; Unterberg, Andreas; Hartmann, Christian; Pietsch, Torsten; Reifenberger, Guido; Lichter, Peter; Radlwimmer, Bernhard; Platten, Michael; Pfister, Stefan M; von Deimling, Andreas; Weller, Michael; Wick, Wolfgang

    2014-10-01

    The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMP(pos) (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMP(neg) (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMP(neg) glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMP(pos) tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMP(pos) tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMP(neg) anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.

  16. Novel Approaches in Anaplastic Thyroid Cancer Therapy

    PubMed Central

    Hsu, Kun-Tai; Yu, Xiao-Min; Audhya, Anjon W.; Jaume, Juan C.; Lloyd, Ricardo V.; Miyamoto, Shigeki; Prolla, Tomas A.

    2014-01-01

    Anaplastic thyroid cancer (ATC), accounting for less than 2% of all thyroid cancer, is responsible for the majority of death from all thyroid malignancies and has a median survival of 6 months. The resistance of ATC to conventional thyroid cancer therapies, including radioiodine and thyroid-stimulating hormone suppression, contributes to the very poor prognosis of this malignancy. This review will cover several cellular signaling pathways and mechanisms, including RET/PTC, RAS, BRAF, Notch, p53, and histone deacetylase, which are identified to play roles in the transformation and dedifferentiation process, and therapies that target these pathways. Lastly, novel approaches and agents involving the Notch1 pathway, nuclear factor κB, Trk-fused gene, cancer stem-like cells, mitochondrial mutation, and tumor immune microenvironment are discussed. With a better understanding of the biological process and treatment modality, the hope is to improve ATC outcome in the future. PMID:25260367

  17. The anaplastic lymphoma kinase testing conundrum.

    PubMed

    Conde, Esther; Taniere, Philippe; Lopez-Rios, Fernando

    2015-02-01

    Given the excellent results of the clinical trials with anaplastic lymphoma kinase (ALK) inhibitors, the importance of accurately identifying ALK-positive lung carcinoma patients has never been greater. It brings with it a pressing need for harmonized development of companion diagnostics, for economic, scientific and medical reasons. Therefore, it is crucial that ALK testing assays become more standardized both in performance (analytical phase) and interpretation (post-analytical phase). We find that both methods currently recommended by College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines (FISH and Immunohistochemistry) are reasonable approaches for primary routine ALK testing, if at least 50 tumor cells are scored and protocols are strictly followed. Moreover, due to the high demand to study multiple predictive biomarkers on different assay platforms, quick and reliable approaches to achieve this are essential to guide treatment decisions.

  18. Anaplastic Carcinoma Possibly Arising from a Heterotopic Pancreas.

    PubMed

    Adachi, Yasushi; Mita, Hiroaki; Takahashi, Hideaki; Akino, Kimishige; Kikuchi, Takefumi; Ishii, Yoshifumi; Endo, Takao

    2015-01-01

    Anaplastic carcinoma is a rare pancreatic cancer, and the malignant transformation of a heterotopic pancreas is also rare. We herein report a case of an elderly woman with a mass of unknown origin in the abdominal cavity. Computed tomography identified the extent of the tumor but not the organ of origin. The abdominal tumor eventually metastasized to the liver and lung. An autopsy and immunohistochemical examination revealed an anaplastic carcinoma possibly originating in an ectopic pancreas.

  19. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma.

    PubMed

    Coco, Simona; De Mariano, Marilena; Valdora, Francesca; Servidei, Tiziana; Ridola, Vita; Andolfo, Immacolata; Oberthuer, André; Tonini, Gian Paolo; Longo, Luca

    2012-10-01

    The anaplastic lymphoma kinase (ALK) gene has been found either rearranged or mutated in several neoplasms such as anaplastic large-cell lymphoma, non-small-cell lung cancer, neuroblastoma and anaplastic thyroid cancer. Medulloblastoma (MB) is an embryonic pediatric cancer arising from nervous system, a tissue in which ALK is expressed during embryonic development. We performed an ALK mutation screening in 52 MBs and we found a novel heterozygous germline deletion of a single base in exon 23 (3605delG) in a case with marked anaplasia. This G deletion results in a frameshift mutation producing a premature stop codon in exon 25 of ALK tyrosine kinase domain. We also screened three human MB cell lines without finding any mutation of ALK gene. Quantitative expression analysis of 16 out of 52 samples showed overexpression of ALK mRNA in three MBs. In the present study, we report the first mutation of ALK found in MB. Moreover, a deletion of ALK gene producing a stop codon has not been detected in human tumors up to now. Further investigations are now required to elucidate whether the truncated form of ALK may have a role in signal transduction.

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

    PubMed Central

    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 more anaplastic carcinoma of the thyroid develop in patients without a history of prior radiation than in individuals who have received radiation. We report our recent experience with two patients who demonstrated the sequence of well-differentiated followed by anaplastic thyroid cancer subsequent to radiation and review the question. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 FIG. 5 PMID:7183024

  1. [Anaplastic glioma. Neuropathology, molecular diagnostics and current study concepts].

    PubMed

    Wick, W; Weller, M

    2010-08-01

    According to the current WHO classification anaplastic gliomas comprise pure astrocytomas and oligodendrogliomas and mixed tumors. This review summarizes findings, discusses problems and defines new questions from the phase III trials on anaplastic gliomas. The molecular subgroup analyses of the NOA-04 trial identified three molecular parameters, which predict longer progression-free and overall survival independent from the mode of therapy, radiotherapy or alkylating chemotherapy-. These are 1p/19q codeletion, methylation of the promoter of the O(6)-methylguanyl methyltransferase (MGMT) gene and hot-spot mutations in the isocitrate dehydrogenase 1 (IDH1) gene. The prognostic relevance of these markers is not lower than that of histopathological subclassification but determination is potentially more robust. Therefore, marker profiles should be included into the next WHO brain tumor classification. The current standard of care for first-line treatment in anaplastic gliomas is radiotherapy or chemotherapy. The next steps, e.g. within the international CATNON trial, are to define the role and optimal sequencing of combined modality treatment focusing on radiotherapy and temozolomide. Inclusion in this trial is already based on the WHO grade and the 1p/19q status and not on the histopathological subtype. Furthermore, anaplastic gliomas are an important group of brain tumors for developing future molecular targeted therapies and should therefore be in the main focus of academic and industrial drug development, which aims at improved efficacy and avoiding long-term side-effects.

  2. Breast metastasis of anaplastic oligodendroglioma: a case report.

    PubMed

    Alacacioglu, Ahmet; Unal, Serkan; Canpolat, Selin; Yurt, Alaattin; Oztekin, Ozgur; Coskun, Ali; Karatas, Ayse; Postaci, Hakan; Sop, Gulten

    2012-11-01

    Extracranial metastasis of primary brain tumors is rarely observed. Of all brain malignancies, glioblastomas, medulloblastomas and astrocytomas metastasize most frequently. Metastasis of oligondendroglioma is rare. We present a case of breast metastasis in a 58-year-old man with an anaplastic oligodendroglioma.

  3. Supratentorial extraventricular WHO grade III (anaplastic) ependymoma 17 years after total removal of WHO grade II ependymoma of the fourth ventricle.

    PubMed

    Takeda, Naoya; Nishihara, Masamitsu; Harada, Tomoaki; Kidoguchi, Keiji; Hashimoto, Kimio

    2017-04-01

    We report a WHO grade III ependymoma of the supratentorial interhemispheric fissure and grew to form a large mass with anaplastic transformation without local recurrence 17 years after the total removal of a fourth ventricular WHO grade II ependymoma. We emphasize the necessity of long-term follow-up, even in benign ependymomas.

  4. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy

    PubMed Central

    Webb, Thomas R; Slavish, Jake; George, Rani E; Look, A Thomas; Xue, Liquan; Jiang, Qin; Cui, Xiaoli; Rentrop, Walter B; Morris, Stephan W

    2009-01-01

    Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, was initially identified in constitutively activated oncogenic fusion forms – the most common being nucleophosmin-ALK – in anaplastic large-cell lymphomas, and subsequent studies have identified ALK fusions in diffuse large B-cell lymphomas, systemic histiocytosis, inflammatory myofibroblastic tumors, esophageal squamous cell carcinomas and non-small-cell lung carcinomas. More recently, genomic DNA amplification and protein overexpression, as well as activating point mutations, of ALK have been described in neuroblastomas. In addition to those cancers for which a causative role for aberrant ALK activity is well validated, more circumstantial links implicate the full-length, normal ALK receptor in the genesis of other malignancies – including glioblastoma and breast cancer – via a mechanism of receptor activation involving autocrine and/or paracrine growth loops with the reported ALK ligands, pleiotrophin and midkine. This review summarizes normal ALK biology, the confirmed and putative roles of ALK in the development of human cancers and efforts to target ALK using small-molecule kinase inhibitors. PMID:19275511

  5. A comparative evaluation of supervised and unsupervised representation learning approaches for anaplastic medulloblastoma differentiation

    NASA Astrophysics Data System (ADS)

    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.

  6. Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors.

    PubMed

    af Gennäs, Gustav Boije; Mologni, Luca; Ahmed, Shaheen; Rajaratnam, Mohanathas; Marin, Oriano; Lindholm, Niko; Viltadi, Michela; Gambacorti-Passerini, Carlo; Scapozza, Leonardo; Yli-Kauhaluoma, Jari

    2011-09-05

    In anaplastic large-cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK, such as echinoderm microtubule-associated protein-like 4-ALK, were recently found in patients with non-small-cell lung, breast, and colorectal cancers. Recent research has focused on the development of inhibitors for targeted therapy of these ALK-positive tumors. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we investigated the possibility of using two known inhibitors, doramapimod and sorafenib, which target inactive kinases, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed with doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib does not inhibit ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, which were tested using biochemical assays. Herein we present the design, synthesis, biological activity, and structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.

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

    NASA Astrophysics Data System (ADS)

    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.

  8. Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer

    PubMed Central

    Johnson, Jennifer M; Lai, Stephen Y.; Cotzia, Paolo; Cognetti, David; Luginbuhl, Adam; Pribitkin, Edmund A.; Zhan, Tingting; Mollaee, Mehri; Domingo-Vidal, Marina; Chen, Yunyun; Campling, Barbara; Bar-Ad, Voichita; Birbe, Ruth; Tuluc, Madalina; Outschoorn, Ubaldo Martinez; Curry, Joseph

    2015-01-01

    Aims Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically Monocarboxylate Transporter 1 (MCT1) and Translocase of the Outer Mitochondrial Membrane Member 20 (TOMM20). Methods Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer (PTC), and 8 non-cancerous thyroid) and 9 ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. Results MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (p<0.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (p<0.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (p<0.001). These xenograft tumors have high 13C- pyruvate uptake. Conclusions Anaplastic thyroid cancer has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target. PMID:26615136

  9. Anaplastic mandibular carcinoma in a meerkat (Suricata suricatta).

    PubMed

    Dadone, Liza I; Garner, Michael M; Klaphake, Eric; Johnston, Matthew S; Han, Sushan

    2014-06-01

    An 8-yr-old female slender-tailed meerkat (Suricata suricatta) presented with a necrotic sublingual mass and osteolysis of the mandible. After 1 mo of palliative care, the meerkat was euthanized. The mass was diagnosed histologically as an anaplastic carcinoma with extensive rostral mandibular destruction. Immunohistochemistry for vimentin and cytokeratin was validated in this nontypical species and showed that neoplastic cells expressed both mesenchymal and epithelial characteristics, suggestive of a primitive and poorly differentiated tumor. A review of 150 adult slender-tailed meerkat histopathology reports showed a 2% prevalence of orofacial neoplasia, suggesting that oral neoplasms are uncommon in meerkats.

  10. Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma

    SciTech Connect

    Hansen, H.H.; Dombernowsky, P.; Hirsch, F.R.; Hansen, M.; Rygard, J.

    1980-07-15

    A total of 114 patients with bronchogenic small cell anaplastic carcinoma and staged as having regional disease all underwent combination chemotherapy consisting of CCNU, cyclophosphamide, and methotrexate. They were randomized to receive either radiotherapy to the primary tumor and regional lymph nodes (4000 rad) or extensive radiotherapy, which included the brain, adrenals, and upper retroperitoneal lymph nodes. Fifteen patients were free of disease after 18 months of chemotherapy and the treatment was discontinued. Only 3 patients subsequently relapsed. No difference was observed between the two groups of patients in median survival time, response rate, duration of response, or relapse pattern, including the frequency of brain metastasis.

  11. Bevacizumab and Cediranib Maleate in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma

    ClinicalTrials.gov

    2014-02-14

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2017-03-01

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

  14. Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer.

    PubMed

    Johnson, Jennifer M; Lai, Stephen Y; Cotzia, Paolo; Cognetti, David; Luginbuhl, Adam; Pribitkin, Edmund A; Zhan, Tingting; Mollaee, Mehri; Domingo-Vidal, Marina; Chen, Yunyun; Campling, Barbara; Bar-Ad, Voichita; Birbe, Ruth; Tuluc, Madalina; Martinez Outschoorn, Ubaldo; Curry, Joseph

    2015-12-01

    Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target.

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

    PubMed

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

    2016-05-26

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

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

    PubMed

    Roskoski, Robert

    2017-03-01

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

  17. O-GlcNAcylation enhances anaplastic thyroid carcinoma malignancy.

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2016-03-29

    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.

  19. Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer.

    PubMed

    Mehta, Amit; Zhang, Lisa; Boufraqech, Myriem; Zhang, Yaqin; Patel, Dhaval; Shen, Min; Kebebew, Electron

    2015-06-01

    Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.

  20. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies

    PubMed Central

    Smallridge, Robert C; Marlow, Laura A; Copland, John A

    2010-01-01

    Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of ∼ 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies. PMID:18987168

  1. A New Aurora in Anaplastic Thyroid Cancer Therapy

    PubMed Central

    Baldini, Enke; D'Armiento, Massimino

    2014-01-01

    Anaplastic thyroid cancers (ATC) are among the most aggressive human neoplasms with a dire prognosis and a median survival time of few months from the diagnosis. The complete absence of effective therapies for ATC renders the identification of novel therapeutic approaches sorely needed. Chromosomal instability, a feature of all human cancers, is thought to represent a major driving force in thyroid cancer progression and a number of mitotic kinases showing a deregulated expression in malignant thyroid tissues are now held responsible for thyroid tumor aneuploidy. These include the three members of the Aurora family (Aurora-A, Aurora-B, and Aurora-C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. Over the last few years, several small molecule inhibitors targeting Aurora kinases were developed, which showed promising antitumor effects against a variety of human cancers, including ATC, in preclinical studies. Several of these molecules are now being evaluated in phase I/II clinical trials against advanced solid and hematological malignancies. In the present review we will describe the structure, expression, and mitotic functions of the Aurora kinases, their implications in human cancer progression, with particular regard to ATC, and the effects of their functional inhibition on malignant cell proliferation. PMID:25097550

  2. Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma

    PubMed Central

    Satoh, Shunpei; Takatori, Atsushi; Ogura, Atsushi; Kohashi, Kenichi; Souzaki, Ryota; Kinoshita, Yoshiaki; Taguchi, Tomoaki; Hossain, Md. Shamim; Ohira, Miki; Nakamura, Yohko; Nakagawara, Akira

    2016-01-01

    In neuroblastoma (NB), one of the most common paediatric solid tumours, activation of anaplastic lymphoma kinase (ALK) is often associated with poor outcomes. Although genetic studies have identified copy number alteration and nonsynonymous mutations of ALK, the regulatory mechanism of ALK signalling at protein levels is largely elusive. Neuronal leucine-rich repeat 1 (NLRR1) is a type 1 transmembrane protein that is highly expressed in unfavourable NB and potentially influences receptor tyrosine kinase signalling. Here, we showed that NLRR1 and ALK exhibited a mutually exclusive expression pattern in primary NB tissues by immunohistochemistry. Moreover, dorsal root ganglia of Nlrr1+/+ and Nlrr1−/− mice displayed the opposite expression patterns of Nlrr1 and Alk. Of interest, NLRR1 physically interacted with ALK in vitro through its extracellular region. Notably, the NLRR1 ectodomain impaired ALK phosphorylation and proliferation of ALK-mutated NB cells. A newly identified cleavage of the NLRR1 ectodomain also supported NLRR1-mediated ALK signal regulation in trans. Thus, we conclude that NLRR1 appears to be an extracellular negative regulator of ALK signalling in NB and neuronal development. Our findings may be beneficial to comprehend NB heterogeneity and to develop a novel therapy against unfavourable NB. PMID:27604320

  3. Current standards of care and future directions for "high-risk" pediatric renal tumors: Anaplastic Wilms tumor and Rhabdoid tumor.

    PubMed

    Geller, James I

    2016-01-01

    'High risk' renal tumors of childhood generally includes anaplastic Wilms tumor, rhabdoid tumor, and metastatic renal sarcomas and carcinomas. In this review, the epidemiology, biology, treatment and prognosis of anaplastic Wilms tumor and rhabdoid tumor are presented. Future directions related to management of such cancers are discussed, with insights provided into possible clinical trials in development that consider integration of novel targeted therapies.

  4. Malignant progression to anaplastic meningioma: Neuropathology, molecular pathology, and experimental models.

    PubMed

    Cimino, Patrick J

    2015-10-01

    Meningioma is a common adult intracranial tumor, and while several cases are considered benign, a subset is malignant with biologically aggressive behavior and is refractory to current treatment strategies of combined surgery and radiotherapy. Anaplastic meningiomas are quite aggressive and correspond to a World Health Organization (WHO) Grade III tumor. This highly aggressive phenotype mandates the need for more efficacious therapies. Designing rational therapies for treatment will have its foundation in the biologic understanding of involved genes and molecular pathways in these types of tumors. Anaplastic meningiomas (WHO Grade III) can arise from malignant transformation of lower grade (WHO Grade I/II) tumors, however there is an incomplete understanding of specific genetic drivers of malignant transformation in these tumors. Here, the current understanding of anaplastic meningiomas is reviewed in the context of human neuropathologic specimens and small animal models.

  5. Supratentorial extraventricular anaplastic ependymoma in an adult with repeated intratumoral hemorrhage.

    PubMed

    Iwamoto, Naotaka; Murai, Yasuo; Yamamoto, Yoichiro; Adachi, Koji; Teramoto, Akira

    2014-04-01

    We report the case of a 61-year-old man with supratentorial extraventricular anaplastic ependymoma who presented with repeated intratumoral hemorrhage. The patient was admitted with headache. Computed tomography and magnetic resonance imaging showed an enhancing mass with intratumoral hemorrhage in the right temporal lobe. Gross total resection was performed. The tumor was well demarcated from the brain tissue, and showed no continuity with the ventricular system. Histopathological examination revealed the features of anaplastic ependymoma. Therefore, additional radiation therapy and adjuvant chemotherapy were administered. Ten months later, the tumor recurred with hemorrhage in the spinal canal. This case showed rapid malignant progression and repeated intratumoral hemorrhage within a short period of time, both of which are characteristics of anaplastic ependymomas. Close observation of the central nervous system and adjuvant radiotherapy are mandatory, even if the ependymoma presents with repeated intratumoral hemorrhage.

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

    PubMed Central

    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. PMID:27747121

  7. Magnetic resonance imaging findings of extraventricular anaplastic ependymoma: A report of 11 cases

    PubMed Central

    Leng, Xi; Tan, Xin; Zhang, Chi; Lin, Huan; Qiu, Shijun

    2016-01-01

    Anaplastic ependymomas are rare malignant tumors of the central nervous system. Few studies are available regarding their neuroradiological characteristics. The present study aimed to retrospectively review a series of patients with extraventricular anaplastic ependymoma and to analyze the magnetic resonance imaging (MRI) characteristics to distinguish anaplastic ependymoma from other intracranial tumors. The clinical and pathological images of 11 patients who presented with histologically proven anaplastic ependymoma at Nanfang Hospital (Southern Medical University, Guangzhou, Guangdong, China) between September 2004 and March 2015 were retrospectively reviewed. MRI scans were obtained in all 11 cases. Computed tomography scans were obtained in only 3 cases. In total, 8 tumors were located at the supratentorial parenchyma, and 3 tumors were derived from the cerebellar hemisphere. Images displayed quasi-circular (4/11), irregularly-lobulated (7/11) variable-intensity masses. The masses presented with cysts or necrosis (8/11), hemorrhage (7/11), marked (9/11) or mild (2/11) enhancement, and moderate (4/11), mild (3/11) or absent (4/11) peritumoral edema. The tumors were also frequently closely associated with the lateral ventricle (6/11). Tumors appeared isointense to hypointense on T1-weighted imaging (T1WI) and heterogeneously hyperintense or hypointense on T2WI, demonstrating wreath-like and ring-like characteristics, with intratumoral nodules (3/11) or marked flake-like inhomogeneous (6/11) enhancement on post-contrast MRI. Only 2 solid lesions showed mild enhancement (2/11). Although the MRI features of the extraventricular anaplastic ependymomas varied and were non-specific, these characteristic MRI findings, combined with the locations of the lesions, the age of onset and the short disease course, could be useful in differentiating anaplastic ependymomas from other intracranial neoplasms in the future. PMID:27602137

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

    PubMed

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

    2015-08-01

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

  9. Metastatic anaplastic adenocarcinoma suspected to be of mammary origin in an intact male rabbit (Oryctolagus cuniculus)

    PubMed Central

    Summa, Noémie M.; Eshar, David; Snyman, Heindrich N.; Lillie, Brandon N.

    2014-01-01

    A 7-year-old, intact male, pet dwarf rabbit (Oryctolagus cuniculus) was presented for a ventral abdominal subcutaneous mass. Histolopathology of the resected mass was suggestive of a mammary adenocarcinoma. Six months later, the rabbit died from severe dyspnea. Necropsy showed recurrence of the original mass with hepatic and pulmonary metastasis of the anaplastic adenocarcinoma, suspected to be of mammary origin. PMID:24790235

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

    PubMed Central

    Wu, Jian; Guo, Lei; Qiu, Tian; Ling, Yun; Shan, Ling; Zhou, Haitao; Zhao, Dongbing; Wang, Jian; Liang, Jianwei; Zhao, Jianjun; Jiao, Yuchen; Lu, Ning; Zhao, Hong

    2015-01-01

    Background 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. Patients and Methods 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. Results 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. Conclusions 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. PMID:26678488

  11. Anaplastic Transformation in Mandibular Metastases of Follicular Variant of Papillary Thyroid Carcinoma: A Case Report and Review of the Literature.

    PubMed

    Ambelil, Manju; Sultana, Sadia; Roy, Suvra; Gonzalez, Maria M

    2016-09-01

    Anaplastic transformation of well-differentiated thyroid carcinomas at distant metastatic sites is a rare condition. Most cases described in the literature have occurred in the thyroid or regional lymph nodes. We report a case of anaplastic transformation of the follicular variant of papillary thyroid carcinoma in mandibular metastases. A 76-year-old female presented with a painful and enlarging mandibular mass. She had been treated in the past for the follicular variant of papillary thyroid carcinoma. A palliative hemi-mandibulectomy was performed. Histology revealed a metastatic papillary thyroid carcinoma, follicular variant, with an unusual finding of solid pleomorphic epithelioid and spindle cell areas, consistent with anaplastic transformation.

  12. Coexpression of EpCAM, CD44 Variant Isoforms and Claudin-7 in Anaplastic Thyroid Carcinoma

    PubMed Central

    Okada, Toshihiro; Nakamura, Teruo; Watanabe, Takayuki; Onoda, Naoyoshi; Ashida, Atsuko; Okuyama, Ryuhei; Ito, Ken-ichi

    2014-01-01

    Background Anaplastic thyroid cancer is considered to be one of the most aggressive human malignancies, and the mean survival time after diagnosis is approximately six months, regardless of treatments. This study aimed to examine how EpCAM and its related molecules are involved in the characteristics of anaplastic thyroid carcinoma. Methodology/Principal Findings Two differentiated thyroid cancer cell lines (TPC-1 and FTC-133), and two anaplastic thyroid cancer cell lines (FRO, ACT-1) were analyzed for expression of CD44 standard isoform (CD44s), CD44 variant isoforms, and EpCAM, and human aldehyde dehydrogenase-1 (ALDH1) enzymatic activity using flow cytometry. CD44s expression was higher in TPC-1 and FTC-133 than in the FRO and ACT-1, whereas ALDH1 activities were higher in FRO and ACT-1 than in TPC-1 and FTC-133. An inverse correlation between CD44s expression and ALDH1 activity was observed in all thyroid cancer cell lines. As for the expressions of CD44 variant isoforms, ACT-1 showed higher and FRO showed moderate CD44v6 expressions, whereas either TPC-1 or FTC-133 showed negative CD44v6 expression. EpCAM expressions in FRO and ACT-1 were higher than those in TPC-1 and FTC-133, and EpCAM expressions inversely correlated with those of CD44s. A positive correlation was observed between EpCAM expression and ALDH1 activity in thyroid cancer cell lines. In the RT-PCR analysis, the expression levels of EpCAM, caludin-7 and ALDH1 in FRO and ATC-1 cells were significantly higher than those in TPC-1 and FTC-133 cells. In clinical specimens of thyroid cancers, nuclear expression of EpCAM and high expression of CD44v6 were detected significantly more frequently in anaplastic carcinomas. Conclusions/Significance Our study suggests the possibility that EpCAM, together with CD44v6 and claudin-7 as well as ALDH1, may be involved in the development of the aggressive phenotype of anaplastic thyroid carcinoma. Our findings may suggest a novel therapeutic strategy for treatment

  13. Ectopic cortical anaplastic ependymoma: an unusual case report and literature review.

    PubMed

    Zhang, Ji; Sai, Ke; Wang, Jian; Chen, Yin Shen; Yan, Shu-Mei; Chen, Zhong-Ping

    2014-09-01

    Ependymona occasionally occurs outside the ventricular structures, which is called ectopic ependymona (EE), while pure cortex location is uncommon. However, cortical anaplastic ependymoma (CE) is rare, especially in children. There were only four primary CEs, which is located in the superficial cortex, were reported the age of the patient under 12 years old. The present case is a 20-month-old boy presenting with simple partial seizure was treated in our department. Cranial magnetic resonance imaging (MRI) revealed a fronto-parietal lobe mass of more than 50mm in diameter with mixed signal intensity. Total removal of the mass lesion was performed without any neurological deficit. Pathological examination of the excised tumor were consistent with anaplastic ependymoma (AE). The patient had a good recovery after his surgical resection. Radiotherapy and chemotherapy were not taken into account in view of his age, the favorable site and the complete resection. The management of this unusual tumor is summarized in this paper.

  14. Spermatocytic seminoma: review of the literature and description of a new case of the anaplastic variant.

    PubMed

    Lombardi, Mariano; Valli, Mirca; Brisigotti, Massimo; Rosai, Juan

    2011-02-01

    The aims of this paper were to review the literature of Spermatocytic Seminoma (SS) updating its clinico-pathological features and to present a new case of the exceptionally rare variant of this tumor known as anaplastic which only five cases have been reported. Many studies have confirmed that SS is a distinct neoplasm both clinically and pathologically from classical Seminoma and it differs from the latter especially in regard to behavior, characterized by an almost complete inability to metastasize with only very few convincing examples described with metastatic behavior. There is general agreement that orchidectomy is sufficient therapy for SS and that surveillance following surgery is the preferred management option. Surprisingly, the presence of an anaplastic component does not seem to impact on this excellent prognosis. Very different is the case of sarcomatous transformation, for which further therapy after orchiectomy is advisable.

  15. Autopsy of anaplastic carcinoma of the pancreas producing granulocyte colony-stimulating factor.

    PubMed

    Hayashi, Haruna; Eguchi, Noriaki; Sumimoto, Kyoku; Matsumoto, Kenta; Azakami, Takahiro; Sumida, Tomonori; Tamura, Tadamasa; Sumii, Masaharu; Uraoka, Naohiro; Shimamoto, Fumio

    2016-08-01

    A 50-year-old man presented to a nearby hospital with high fever and anorexia. An abdominal tumor was detected, and he was referred to our hospital. A pancreatic tumor was detected by computed tomography and abdominal ultrasonography. He had high fever, leukocytosis, and high serum granulocyte colony-stimulating factor (G-CSF). We performed a tumor biopsy and histological examination revealed anaplastic carcinoma of the pancreas. Based on the diagnosis, we initiated chemotherapy using gemcitabine plus S-1. However, the tumor rapidly progressed and he deteriorated and died 123 days after admission. As immunohistochemical study showed positive staining for G-CSF in the tumor cell, we diagnosed the tumor producing G-CSF during autopsy. Anaplastic carcinoma of the pancreas producing G-CSF is very rare, with 10 cases, including ours, reported in the literature.

  16. THE MANAGEMENT OF AN ORAL ANAPLASTIC SARCOMA IN A PYGMY HIPPOPOTAMUS (CHOEROPSIS LIBERIENSIS) USING INTRALESIONAL CHEMOTHERAPY.

    PubMed

    Franklinos, Lydia H V; Masters, Nicholas; Feltrer, Yedra; Pocknell, Ann; Bolt, David M; Dakin, Stephanie; Berry, Karla; Molenaar, Fieke M

    2017-03-01

    An adult female captive pygmy hippopotamus (Choeropsis liberiensis) was diagnosed with an oral anaplastic sarcoma. The tumor was surgically debulked and intralesional chemotherapy with mitomycin C (0.4 mg/cm(3) of tumor) and cisplatin (1 mg/cm(3) of tumor) was administered. Chemotherapeutic treatment proved difficult due to the risks of repeated anesthetics and unknown drug efficacies. Marked proliferation of the mass was observed during estrus, and chemotherapy was repeated as an experimental treatment to slow tumor progression in order for the animal to remain in the species breeding program. Tumor proliferation was detected during the first trimester of pregnancy; however, in the lactation period, the mass became quiescent. No adverse reactions to chemotherapeutic drugs were observed and the animal continues to be monitored for tumor progression. This is the first report of an anaplastic sarcoma and of chemotherapy use in a pygmy hippopotamus and it highlights logistical considerations for treating neoplasia in this species.

  17. Doxorubicin has a synergistic cytotoxicity with cucurbitacin B in anaplastic thyroid carcinoma cells.

    PubMed

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

    2017-02-01

    In this study, the combined effect of doxorubicin with cucurbitacin B on survival of anaplastic thyroid carcinoma cells was evaluated. For experiments, 8505C and CAL62 human anaplastic thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, and cytotoxic activity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, multiplexed cytotoxicity assay, and cytotoxicity assay, respectively. Reactive oxygen species production was measured. In experiments, doxorubicin and cucurbitacin B reduced cell viability in a dose- and time-dependent manner. Cotreatment of doxorubicin and cucurbitacin B, compared with treatment of doxorubicin alone, decreased the percentage of viable cells and increased cytotoxic activity. All of the combination index values were lower than 1.0, suggesting the synergism between doxorubicin and cucurbitacin B in induction of cytotoxicity. In cells treated with both doxorubicin and cucurbitacin B, compared with doxorubicin alone, the protein levels of cleaved poly(adenosine diphosphate-ribose) polymerase and cyclooxygenase 2 and reactive oxygen species production were enhanced. In contrast, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma 2 and survivin and B-cell chronic lymphocytic leukemia/lymphoma 2/B-cell chronic lymphocytic leukemia/lymphoma 2-associated x protein ratio were diminished. The protein levels of Janus kinase 2 and signal transducer and activator of transcription 3 were reduced, while phospho-extracellular signal-regulated kinase 1/2 protein levels were elevated without change in total extracellular signal-regulated kinase 1/2 protein levels. These results suggest that doxorubicin synergizes with cucurbitacin B in induction of cytotoxicity in anaplastic thyroid carcinoma cells. Moreover, synergistic cytotoxicity of doxorubicin with cucurbitacin B is mediated by B-cell chronic lymphocytic leukemia/lymphoma 2 family proteins, survivin, and reactive oxygen

  18. Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma

    PubMed Central

    Du, Ziming; Abedalthagafi, Malak; Aizer, Ayal A.; McHenry, Allison R.; Sun, Heather H.; Bray, Mark-Anthony; Viramontes, Omar; Machaidze, Revaz; Brastianos, Priscilla K.; Reardon, David A.; Dunn, Ian F.; Freeman, Gordon J.; Ligon, Keith L.; Carpenter, Anne E.; Alexander, Brian M.; Agar, Nathalie Y.; Rodig, Scott J.; Bradshaw, Elizabeth M.; Santagata, Sandro

    2015-01-01

    There are no effective medical treatments for WHO grade III (anaplastic) meningioma. Patients with this high-grade malignancy have a median survival of less than two years. Therapeutics that modulate the mechanisms that inhibit local immune responses in the tumor microenvironment are showing significant and durable clinical responses in patients with treatment refractory high-grade tumors. We examined the immune infiltrate of 291 meningiomas including WHO grade I-III meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In anaplastic meningioma, there is a sharp decrease in the number of T cells, including the numbers of CD4+ and CD8+ T cells and cells expressing PD-1 and there is also an increase in the number of FOXP3 expressing immunoregulatory (Treg) cells. PD-L1 expression is increased in anaplastic meningioma – both mRNA and protein. Using patient derived meningioma cell, we confirm that PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. This work indicates that high-grade meningioma harbor an immunosuppressive tumor microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the aggressive phenotype of these tumors. PMID:25609200

  19. Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection

    PubMed Central

    Saburi, Masuho; Ogata, Masao; Satou, Takako; Yoshida, Natsumi; Nagamatsu, Kentaro; Nashimoto, Yuko; Moroga, Yui; Takano, Kuniko; Kohno, Kazuhiro; Shirao, Kuniaki

    2016-01-01

    A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations. PMID:27904117

  20. Differential pattern of integrin receptor expression in differentiated and anaplastic thyroid cancer cell lines.

    PubMed

    Hoffmann, S; Maschuw, K; Hassan, I; Reckzeh, B; Wunderlich, A; Lingelbach, S; Zielke, A

    2005-09-01

    Adhesion of tumor cells to the extracellular matrix (ECM) is a crucial step for the development of metastatic disease and is mediated by specific integrin receptor molecules (IRM). The pattern of metastatic spread differs substantially among the various histotypes of thyroid cancer (TC). However, IRM have only occasionally been characterized in TC until now. IRM expression was investigated in 10 differentiated (FTC133, 236, 238, HTC, HTC TSHr, XTC, PTC4.0/4.2, TPC1, Kat5) and two anaplastic TC cell lines (ATC, C643, Hth74), primary cultures of normal thyroid tissue (Thy1,3), and thyroid cancer specimens (TCS). Expression of 16 IRM (beta1-4, beta7, alpha1-6, alphaV, alphaIIb, alphaL, alphaM, alphaX) and of four IRM heterodimers (alpha2beta1, alpha5beta1, alphaVbeta3, alphaVbeta5), was analyzed by fluorescent-activated cell sorter (FACS) and immunohistochemical staining. Thyroid tumor cell adhesion to ECM proteins and their IRM expression in response to thyrotropin (TSH) was assessed. Follicular TC cell lines presented high levels of integrins alpha2, alpha3, alpha5, beta1, beta3 and low levels of alpha1, whereas papillary lines expressed a heterogenous pattern of IRM, dominated by alpha5 and beta1. ATC mainly displayed integrins alpha2, alpha3, alpha5, alpha6, beta1 and low levels of alpha1, alpha4 and alphaV. Integrin heterodimers correlated with monomer expression. Evaluation of TCS largely confirmed these results with few exceptions, namely alpha4, alpha6, and beta3. The ability of TC cell lines to adhere to purified ECM proteins correlated with IRM expression. TSH induced TC cell adhesion in a dose-dependent fashion, despite an unchanged array of IRM expression or level of a particular IRM. Thyroid carcinoma cell lines of different histogenetic background display profoundly different patterns of IRM expression that appear to correlate with tumor aggressiveness. In vitro adhesion to ECM proteins and IRM expression concur. Finally, TSH-stimulated adhesion of

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

    PubMed

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

    2016-07-01

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

    J Drugs Dermatol. 2016;15(7):894-895.

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

    PubMed

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

    2016-03-01

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

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

    PubMed Central

    Katayama, Ryohei; Sakashita, Takuya; Yanagitani, Noriko; Ninomiya, Hironori; Horiike, Atsushi; Friboulet, Luc; Gainor, Justin F.; Motoi, Noriko; Dobashi, Akito; Sakata, Seiji; Tambo, Yuichi; Kitazono, Satoru; Sato, Shigeo; Koike, Sumie; John Iafrate, A.; Mino-Kenudson, Mari; Ishikawa, Yuichi; Shaw, Alice T.; Engelman, Jeffrey A.; Takeuchi, Kengo; Nishio, Makoto; Fujita, Naoya

    2015-01-01

    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. PMID:26870817

  4. Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: long term results of RTOG BR0131.

    PubMed

    Vogelbaum, Michael A; Hu, Chen; Peereboom, David M; Macdonald, David R; Giannini, Caterina; Suh, John H; Jenkins, Robert B; Laack, Nadia N; Brachman, David G; Shrieve, Dennis C; Souhami, Luis; Mehta, Minesh P

    2015-09-01

    We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma. Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range 1.1-10.1), median progression-free survival (PFS) is 5.8 years (95 % CI 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78 % (95 % CI 61-95 %) and 83 % (95 % CI 67-98 %), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67 %, 95 % CI 55-79 %). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs.

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

    PubMed Central

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

    2016-01-01

    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 (<50%) rhabdoid or papillary component (group B2). Homogeneous enhancement on MRI was associated with improved PFS compared to heterogeneous enhancement (p=0.025). Depending on pathology, the mean PFS was 134.9±31.6 months for group A, 46.6±13.4 months for group B1, and 118.7±19.2 months for group B2. The mean OS was 138.5±24.6 months for group A and 59.7±16.8 months for group B1. All recurrent tumors were of the previously diagnosed pathology, except for one tumor from group B1, which recurred as an atypical meningioma without a papillary component. Group B1 tumors showed a more 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

  6. In vitro evaluation of the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma.

    PubMed

    Dong, J J; Zhou, Y; Liu, Y T; Zhang, Z W; Zhou, X J; Wang, H J; Liao, L

    2013-05-06

    Anaplastic thyroid carcinoma (ATC) is a severe thyroid malignancy with poor prognosis, due to its early metastasis and unresponsiveness to both radiation and chemotherapy. Nevirapine, a non-nucleoside reverse transcriptase inhibitor, has been used as a re-differentiation agent to treat cancers in several human cancer models. So far, the effects of nevirapine on human thyroid anaplastic carcinoma cells have not been documented. The aim of this study was to evaluate the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma. Cell proliferation was determined by methly thiazolyl tetrazolium (MTT) assay. Cell apoptosis was analyzed by Hoechst 33258 staining. The mRNA expression of NIS and TSHR was determined by real-time quantitative reverse transcription-polymerase chain reaction (real time RT-PCR). Iodine uptake was determined by (125)I radioactivity assay. At all doses (100, 200, 350, 500 μmol/L) tested, nevirapine significantly inhibited cell proliferation after 48 h treatment. At high dose (500 μmol/L), nevirapine significantly increased the percentage of apoptotic cells compared with control (P<0.01). At lower doses (200 μmol/L and 350 μmol/L), nevirapine did not induce cell apoptosis, but up-regulated NIS and THSR mRNA expression in a dose-dependent manner. In FRO cells pre-treated with nevirapine, the increase in NIS expression had no obvious effect on iodine uptake. These findings indicate that nevirapine has an anti-proliferative effect on FRO cells, which correlates with an induction of cell differentiation.

  7. Expression of cell adhesion molecules and doublecortin in canine anaplastic meningiomas.

    PubMed

    Ide, T; Uchida, K; Suzuki, K; Kagawa, Y; Nakayama, H

    2011-01-01

    Tumor cell invasion into the surrounding nervous tissue is one of the histologic hallmarks of anaplastic meningiomas. To identify other possible markers for aggression in canine meningiomas, the relationship between histologic features and the expression of molecules involved in cell adhesion, cell proliferation, and invasion was examined. Immunohistochemistry for epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), β-catenin, doublecortin (DCX), and Ki-67 was performed for 55 cases of canine meningioma. DCX was preferentially expressed in tumor cells invading the brain parenchyma (12 of 14 cases), suggesting its involvement in the invasion process. Regardless of the histologic type, E-cadherin and N-cadherin expression was observed in 31 of 55 and 44 of 55 cases, respectively. There was a significant positive correlation between DCX and N-cadherin expression and a significant negative correlation between E-cadherin and N-cadherin expression, suggesting that decreased E-cadherin and increased N-cadherin expression induce DCX expression. Typical membranous β-catenin expression was observed in 10 of 55 cases, whereas nuclear translocation was observed in 33 cases. Nuclear β-catenin expression was frequently found in anaplastic meningiomas (12 of 14 cases). The Ki-67 labeling indices were significantly higher in anaplastic meningiomas than in other types. These findings indicate that the expression of N-cadherin and DCX and the nuclear translocation of β-catenin are closely associated with the presence of invasion and anaplasia in canine meningiomas. Notably, granular cell meningiomas were negative for almost all the molecules examined, suggesting that they have a different tumor biology than other meningiomas.

  8. Atypical Carcinoid Tumor with Anaplastic Lymphoma Kinase (ALK) Rearrangement Successfully Treated by an ALK Inhibitor.

    PubMed

    Nakajima, Masayuki; Uchiyama, Naoki; Shigemasa, Rie; Matsumura, Takeshi; Matsuoka, Ryota; Nomura, Akihiro

    This is the first report in which crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, reduced an atypical carcinoid tumor with ALK rearrangement. A 70-year-old man developed a tumor in the left lung and multiple metastases to the lung and brain. The pathology of transbronchial biopsied specimens demonstrated an atypical carcinoid pattern. Combined with immunohistochemical findings, we diagnosed the tumor as atypical carcinoid. ALK gene rearrangement was observed by both immunohistochemical (IHC) and fluorescence in situ hybridization. He was treated with chemotherapy as first-line therapy, however, the tumor did not respond to chemotherapy. Thereafter, he was treated with crizotinib, which successfully reduced the tumors.

  9. Ollier disease with anaplastic astrocytoma: A review of the literature and a unique case

    PubMed Central

    Gajavelli, Srikanth; Nakhla, Jonathan; Nasser, Rani; Yassari, Reza; Weidenheim, Karen M.; Graber, Jerome

    2016-01-01

    Background: Ollier disease is a rare, nonfamilial disorder that primary affects the long bones and cartilage of joints with multiple enchondromas. It is associated with a higher risk of central nervous system (CNS) malignancies; although the incidence is unknown. Case Description: Here, we present the case of a 55-year-old woman who developed an anaplastic astrocytoma with a known diagnosis of Ollier disease with a survival time of over 3 years. Conclusion: This report draws attention to the rarity of this disease and the paucity of information regarding CNS involvement in Ollier disease, as well as reviews the current literature. PMID:27656320

  10. Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report.

    PubMed

    Kessler, Brice A; Bookhout, Christine; Jaikumar, Sivakumar; Hipps, John; Lee, Yueh Z

    2015-01-01

    We report the neuroimaging and histopathologic findings of a 12-year-old female patient with a disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural metastatic disease. These tumors may represent distinct pathology primarily seen in pediatric patients. Neuroimaging demonstrates diffuse, progressive enhancement of the leptomeninges often with interval development of intraparenchymal lesions on follow-up. Disease is typically confined to the central nervous system, though diffuse peritoneal disease was seen in our case, possibly through metastatic seeding of the abdomen via ventriculoperitoneal shunt.

  11. [Incidence of anaplastic tumor in structure of other histologic forms of the thyroid gland cancer].

    PubMed

    Vinnik, Iu A; Gorbenko, V N; Vas'ko, A R; Kikhtenko, E V; Gargin, V V

    2014-01-01

    The degrees of invasiveness, proliferative activity, morphofunctional activity of nuclei in the thyroidal gland tumors were studied, while analyzing material, obtained in 1343 patients, suffering thyroidal gland cancer (THGC) and operated on in 2000-2013 yrs. Morphological point quantity of malignancy (as a criterion of the tumor progression grade) and mitotic activity in cellular population were determined in various kinds of THGC. Undifferentiated (anaplastic carcinoma) type of THGC is the most malignant one. There were determined a spindle-like, giant-cell and squamous-cell forms of undifferentiated THGC. The presence of sites of differentiated cancer in 33% of histological preparations witnesses the interrelationship with the earlier existed pathological process.

  12. Granulocyte colony-stimulating factor-producing pancreatic anaplastic carcinoma in ascitic fluid at initial diagnosis: A case report.

    PubMed

    Kubota, Nao; Naito, Yoshiki; Kawahara, Akihiko; Taira, Tomoki; Yamaguchi, Tomohiko; Yoshida, Tomoko; Abe, Hideyuki; Takase, Yorihiko; Fukumitsu, Chihiro; Murata, Kazuya; Ishida, Yusuke; Okabe, Yoshinobu; Kimura, Yoshizo; Tanigawa, Masahiko; Mihara, Yutaro; Nakayama, Masamichi; Yamaguchi, Rin; Akiba, Jun; Yano, Hirohisa

    2017-02-10

    Granulocyte colony-stimulating factor (G-CSF)-producing pancreatic tumors are extremely rare. These tumors have an aggressive clinical course and no established treatment. Here, we report an autopsy case of G-CSF-production in pancreatic anaplastic carcinoma (PAC). A 72-year-old woman presented with a large pancreatic head mass and multiple liver metastases. Laboratory data showed leukocytosis (leukocyte count 113.3 × 10(3) /µL) and high serum G-CSF levels (441 pg/mL; normal range: <39.0 pg/mL). The ascitic fluid was submitted to our pathology laboratory at initial diagnosis. Cytopathology showed that smears from the ascitic fluid were highly cellular and contained numerous malignant cells, mainly in loose groupings. Occasional pseudoglandular formations and giant cells were also present. The malignant cells were round, and no spindle-shaped cells were visible. The nuclei were round to ovoid with coarsely granular chromatin and large prominent nucleoli. Upon immunocytochemistry, tumor cells were positive for G-CSF and vimentin; there was no E-cadherin expression. Histopathological examination of the tumor showed a mixed composition of adenocarcinomatous and sarcomatous regions. Upon immunohistochemistry, both components were positive for G-CSF. Few CD34-positive myeloblasts were observed in the bone marrow. Thus, we diagnosed this as a case of G-CSF production in PAC with leukocytosis. To the best of our knowledge, this is the first report on G-CSF expression immunocytochemically confirmed in PAC. Diagn. Cytopathol. © 2017 Wiley Periodicals, Inc.

  13. Anaplastic ganglioglioma: a report of three cases and review of the literature

    PubMed Central

    Lucas, John Thomas; Huang, Andrew Jonathan; Mott, Ryan T.; Lesser, Glenn J.; Tatter, Stephen Bradley; Chan, Michael David

    2015-01-01

    Gangliogliomas are rare tumors of the central nervous system that are thought to arise from a glioneuronal precursor and consist of both neuronal and glial elements. Grade III, or anaplastic ganglioglioma (AGG), most commonly affects children and young adults, generally arises in a supratentorial location, is highly epileptogenic, and often results in diffuse local and distant failure within the craniospinal axis. Pathologically, these tumors are graded by the degree of malignancy in their glial portion and radiologic diagnosis is difficult due to the wide variation in its degree of solid and cystic components, contrast uptake, and calcification patterns. This report presents three cases of AGG, with initial treatment including subtotal resection followed by conformal radio-therapy. In the case where the AGG developed in the setting of an existent low-grade astrocytoma, the patient received no chemotherapy. Both of the other de novo cases were managed with adjuvant chemoradiotherapy with temozolomide. Recurrence occurred at 6, 16, and 20 months following therapy. Two of the three patients experienced symptomatic decline at recurrence, but experienced Karnofsky performance status (KPS) improvement after salvage therapy, including the reduction of cranial neuropathy and balance. All patients had a significant reduction in presenting symptoms following salvage therapy. Patients died at 23, 20, and 22 months following initial surgical management, respectively. A review of anaplastic and malignant gangliogliomas is presented in the context of these three cases. PMID:25862009

  14. Anaplastic thyroid cancer: outcome and the mutation/expression profiles of potential targets.

    PubMed

    Wu, Hao; Sun, Yue; Ye, Huihui; Yang, Shi; Lee, Stephanie L; de las Morenas, Antonio

    2015-07-01

    Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy of the thyroid. No effective treatment modalities are currently available. Targeted therapy against protein kinases showed promising results in preclinical studies. Our goal was to assess the mutational status of potential therapeutic targets, as well as the biomarker for immunotherapy in the clinical context. Using allele specific PCR, Sanger sequencing, fragment analysis and immunohistochemistry, we assessed BRAF, KRAS, EGFR mutations and protein overexpression of C-KIT and PDL1 in anaplastic thyroid cancer specimens. Results were compared to clinical information and patient outcome to assess the utility of these biomarkers. There were 13 patients in our study with a median overall survival of 19 weeks. Of the 13 ATC patients, 3 (23 %) had BRAF V600E mutation. C-KIT overexpression was found in 1 (8 %) patient who responded well to a tyrosine kinase inhibitor. PDL1 expression was seen in 3 (23 %) patients, none of them were surgical candidates due to unresectability and poor performance status. KRAS codon 12/13 and EGFR exon 18, 19, 20 and 21 were all wild type in our patients. Protein kinase inhibitors and immunotherapy may be useful adjuvant therapies for ATC.

  15. Successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy, radiation and surgery.

    PubMed

    Noguchi, Hitoshi; Yamashita, Hiroto; Murakami, Tsukasa; Hirai, Keisuke; Noguchi, Yasushi; Maruta, Junko; Yokoi, Tadao; Noguchi, Shiro

    2009-01-01

    Anaplastic thyroid carcinoma (ATC) is the most aggressive of thyroid cancers whose treatment is not yet established and mortality is extremely high. Recent in vitro studies have shown that valproic acid (VA), a newly identified histone deacetilase (HDAC) inhibitor, induces apoptosis, modulates differentiation gene expression of thyroid tumors and enhances the sensitivity of anaplastic cancer cell lines to doxorubicin. We report a case of successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy consisting of cisplatin and doxorubicin, external and intra-operative radiation and surgery. Tumor volume decreased by 50.7% under CT measurement and 44.6% under sonogram measurement over the course of the treatment. No significant rebound of tumor size was observed between each cycle of chemotherapy. Serial cytology performed via fine needle aspiration (FNA) presented a rapidly changing profile of cell types, starting with anaplastic and proceeding through increasingly well differentiated presentations. Only microscopic remnants of ATC cells were found in the histological examination of the resected thyroid. Ga scintigraphy and whole body PET scan six months after surgery revealed no evidence of recurrence or metastasis. As of Nov. 22, 2008, the patient is alive and disease free two years after diagnosis.

  16. Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

    PubMed Central

    Liu, Yanlan; Gunda, Viswanath; Zhu, Xi; Xu, Xiaoding; Wu, Jun; Askhatova, Diana; Farokhzad, Omid C.; Parangi, Sareh; Shi, Jinjun

    2016-01-01

    Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of ∼100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP) -mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (∼50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies. PMID:27342857

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

    SciTech Connect

    Speirs, Christina K.; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd A.; Tran, David D.; Linette, Gerry; Chicoine, Michael R.; Dacey, Ralph G.; Rich, Keith M.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H.; Huang, Jiayi

    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.

  18. Genomically Driven Precision Medicine to Improve Outcomes in Anaplastic Thyroid Cancer

    PubMed Central

    Patel, Krupal; Mymryk, Joe S.; Barrett, John W.; Nichols, Anthony C.

    2014-01-01

    Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate. As cancer is a genetic disease, genetic alterations such as mutations, fusions, activation of oncogenes, and silencing of tumor suppressors contribute to its aggressiveness. With the use of next-generation sequencing and the Cancer Genome Atlas, mutation-directed therapy is recognized as the upcoming standard of care. In this review, we highlight the known genetic landscape of ATC and the need for a comprehensive genetic characterization of this disease in order to identify additional therapeutic targets to improve patient outcomes. PMID:25276134

  19. Anaplastic carcinoma of the pancreas: Case report and literature review of reported cases in Japan

    PubMed Central

    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 < 10.0 g/dL) and elevated leucocyte counts (> 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. PMID:27784976

  20. Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy, and hyperfractionated accelerated external radiotherapy

    SciTech Connect

    De Crevoisier, Renaud . E-mail: rdecrevo@mdanderson.org; Baudin, Eric; Bachelot, Anne; Leboulleux, Sophie; Travagli, Jean-Paul; Caillou, Bernard; Schlumberger, Martin

    2004-11-15

    Purpose: To analyze a prospective protocol combining surgery, chemotherapy (CT), and hyperfractionated accelerated radiotherapy (RT) in anaplastic thyroid carcinoma. Methods and materials: Thirty anaplastic thyroid carcinoma patients (mean age, 59 years) were treated during 1990-2000. Tumor extended beyond the capsule gland in 26 patients, with tracheal extension in 8. Lymph node metastases were present in 18 patients and lung metastases in 6. Surgery was performed before RT-CT in 20 patients and afterwards in 4. Two cycles of doxorubicin (60 mg/m{sup 2}) and cisplatin (120 mg/m{sup 2}) were delivered before RT and four cycles after RT. RT consisted of two daily fractions of 1.25 Gy, 5 days per week to a total dose of 40 Gy to the cervical lymph node areas and the superior mediastinum. Results: Acute toxicity (World Health Organization criteria) was Grade 3 or 4 pharyngoesophagitis in 10 patients; Grade 4 neutropenia in 21, with infection in 13; and Grade 3 or 4 anemia and thrombopenia in 8 and 4, respectively. At the end of the treatment, a complete local response was observed in 19 patients. With a median follow-up of 45 months (range, 12-78 months), 7 patients were alive in complete remission, of whom 6 had initially received a complete tumor resection. Overall survival rate at 3 years was 27% (95% confidence interval 10-44%) and median survival 10 months. In multivariate analysis, tracheal extension and macroscopic complete tumor resection were significant factors in overall survival. Death was related to local progression in 5% of patients, to distant metastases in 68%, and to both in 27%. Conclusions: Main toxicity was hematologic. High long-term survival was obtained when RT-CT was given after complete surgery. This protocol avoided local tumor progression, and death was mainly caused by distant metastases.

  1. Utilization and impact of adjuvant therapy in anaplastic oligodendroglioma: an analysis on 1692 patients.

    PubMed

    Shin, Jacob Y; Diaz, Aidnag Z

    2016-09-01

    The aim of this study was to determine the utilization rates and impact of adjuvant therapy on overall survival (OS) for anaplastic oligodendroglioma (AO). Data were extracted from the National Cancer Data Base (NCDB). Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 1692 patients with AO who underwent surgery were identified. 945 (55.9 %) received adjuvant radiotherapy with concomitant chemotherapy (chemoRT), 102 (6.0 %) adjuvant radiotherapy (RT) sequentially followed by chemotherapy, 244 (14.4 %) adjuvant RT alone, and 401 (23.7 %) received no adjuvant therapy. Patients were more likely to receive adjuvant chemoRT if they were diagnosed in 2009-2013 vs. 2004-2008 (p < 0.001), had Karnofsky Performance Status >70 vs. <70 (p = 0.018), had private insurance vs. Medicaid vs. no insurance (p < 0.001), or had median income ≥$63,000 vs. <$63,000 (p = 0.014). Those who received adjuvant chemoRT (concomitant or sequential) had significantly better 5-year OS than those who received adjuvant RT alone or no adjuvant therapy (59.8 % vs. 65.0 % vs. 44.9 % vs. 45.6 %, p < 0.001). This significant 5-year OS benefit was also observed regardless of age. There was no difference in OS when comparing concomitant chemoRT to sequential RT and chemotherapy (p = 0.481). On multivariate analysis, receipt of adjuvant chemoRT (concomitant or sequential) remained an independent prognostic factor for improved OS. Adjuvant chemoRT (concomitant or sequential) is an independent prognostic factor for improved OS in anaplastic oligodendroglioma and should be considered for all clinically suitable patients who have undergone surgery for the disease.

  2. Prognostic relevance of miRNA-155 methylation in anaplastic glioma.

    PubMed

    Schliesser, Maximilian Georg; Claus, Rainer; Hielscher, Thomas; Grimm, Christiane; Weichenhan, Dieter; Blaes, Jonas; Wiestler, Benedikt; Hau, Peter; Schramm, Johannes; Sahm, Felix; Weiß, Elisa K; Weiler, Markus; Baer, Constance; Schmidt-Graf, Friederike; Schackert, Gabriele; Westphal, Manfred; Hertenstein, Anne; Roth, Patrick; Galldiks, Norbert; Hartmann, Christian; Pietsch, Torsten; Felsberg, Joerg; Reifenberger, Guido; Sabel, Michael Christoph; Winkler, Frank; von Deimling, Andreas; Meisner, Christoph; Vajkoczy, Peter; Platten, Michael; Weller, Michael; Plass, Christoph; Wick, Wolfgang

    2016-12-13

    The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles. Remarkably, 98% of the RNA within a cell is not translated into proteins. Of those, especially microRNAs (miRNAs) have been shown not only to have a major influence on physiologic processes but also to be deregulated and prognostic in malignancies.To find novel survival markers and treatment options we performed unbiased DNA methylation screens that revealed 12 putative miRNA promoter regions with differential DNA methylation in anaplastic gliomas. Methylation of these candidate regions was validated in different independent patient cohorts revealing a set of miRNA promoter regions with prognostic relevance across data sets. Of those, miR-155 promoter methylation and miR-155 expression were negatively correlated and especially the methylation showed superior correlation with patient survival compared to established biomarkers.Functional examinations in malignant glioma cells further cemented the relevance of miR-155 for tumor cell viability with transient and stable modifications indicating an onco-miRNA activity. MiR-155 also conferred resistance towards alkylating temozolomide and radiotherapy as consequence of nuclear factor (NF)κB activation.Preconditioning glioma cells with an NFκB inhibitor reduced therapy resistance of miR-155 overexpressing cells. These cells resembled tumors with a low methylation of the miR-155 promoter and thus mir-155 or NFκB inhibition may provide treatment options with a special focus on patients with IDH wild type tumors.

  3. Prognostic relevance of miRNA-155 methylation in anaplastic glioma

    PubMed Central

    Schliesser, Maximilian Georg; Claus, Rainer; Hielscher, Thomas; Grimm, Christiane; Weichenhan, Dieter; Blaes, Jonas; Wiestler, Benedikt; Hau, Peter; Schramm, Johannes; Sahm, Felix; Weiß, Elisa K.; Weiler, Markus; Baer, Constance; Schmidt-Graf, Friederike; Schackert, Gabriele; Westphal, Manfred; Hertenstein, Anne; Roth, Patrick; Galldiks, Norbert; Hartmann, Christian; Pietsch, Torsten; Felsberg, Joerg; Reifenberger, Guido; Sabel, Michael Christoph; Winkler, Frank; von Deimling, Andreas; Meisner, Christoph; Vajkoczy, Peter; Platten, Michael; Weller, Michael; Plass, Christoph; Wick, Wolfgang

    2016-01-01

    The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles. Remarkably, 98% of the RNA within a cell is not translated into proteins. Of those, especially microRNAs (miRNAs) have been shown not only to have a major influence on physiologic processes but also to be deregulated and prognostic in malignancies. To find novel survival markers and treatment options we performed unbiased DNA methylation screens that revealed 12 putative miRNA promoter regions with differential DNA methylation in anaplastic gliomas. Methylation of these candidate regions was validated in different independent patient cohorts revealing a set of miRNA promoter regions with prognostic relevance across data sets. Of those, miR-155 promoter methylation and miR-155 expression were negatively correlated and especially the methylation showed superior correlation with patient survival compared to established biomarkers. Functional examinations in malignant glioma cells further cemented the relevance of miR-155 for tumor cell viability with transient and stable modifications indicating an onco-miRNA activity. MiR-155 also conferred resistance towards alkylating temozolomide and radiotherapy as consequence of nuclear factor (NF)κB activation. Preconditioning glioma cells with an NFκB inhibitor reduced therapy resistance of miR-155 overexpressing cells. These cells resembled tumors with a low methylation of the miR-155 promoter and thus mir-155 or NFκB inhibition may provide treatment options with a special focus on patients with IDH wild type tumors. PMID:27880937

  4. LncRNA profile study reveals four-lncRNA signature associated with the prognosis of patients with anaplastic gliomas

    PubMed Central

    Wang, Wen; Yang, Fan; Zhang, Lu; Chen, Jing; Zhao, Zheng; Wang, Haoyuan; Wu, Fan; Liang, Tingyu; Yan, Xiaoyan; Li, Jiye; Lan, Qing; Wang, Jiangfei; Zhao, Jizong

    2016-01-01

    Anaplastic glioma is Grade III and the median overall survival is about 37.6 months. However, there are still other factors that affect the prognosis for anaplastic glioma patients due to variable overall survival. So we screened four-lncRNA signature (AGAP2-AS1, TPT1-AS1, LINC01198 and MIR155HG) from the lncRNA expression profile from the GSE16011, CGGA and REMBRANDT datasets. The patients in low risk group had longer overall survival than high risk group (median OS 2208.25 vs. 591.30 days; P < 0.0001). Moreover, patients in the low risk group showed similar overall survival to Grade II patients (P = 0.1669), while the high risk group showed significant different to Grade IV (P = 0.0005) with similar trend. So based on the four-lncRNA, the anaplastic gliomas could be divided into grade II-like and grade IV-like groups. On the multivariate analysis, it showed the signature was an independent prognostic factor (P = 0.000). The expression of four lncRNAs in different grades showed that AGAP2-AS1, LINC01198 and MIR155HG were increased with tumor grade, while TPT1-AS1 was decreased. Knockdown of AGAP2-AS1 can inhibit the cell proliferation, migration and invasion, while increase the apoptosis cell rates in vitro. In conclusion, our results showed that the four-lncRNA signature has prognostic value for anaplastic glioma. Moreover, clinicians should conduct corresponding therapies to achieve best treatment with less side effects for two groups patients. PMID:27764782

  5. Sequentially Programmed Magnetic Field Therapy in the Management of Recurrent Anaplastic Astrocytoma: A Case Report and Literature Review

    PubMed Central

    Vasishta, V.G.

    2010-01-01

    Background Anaplastic astrocytomas are progressive brain tumors with a tendency to infiltrate the surrounding tissue. Recurrence is very common, with recurrent tumors being extremely refractory to existing therapies. Case Presentation: A 33-year-old woman presented with a history of an unprovoked fall, followed by seizures. An MRI scan revealed a mass in the fronto-temporo-parietal region of the brain, suggesting a primary tumor. She underwent craniotomy and surgical debulking of the tumor. The histology of the tumor tissue revealed an anaplastic astrocytoma. Follow-up MRI scans indicated the presence of a residual, rapidly progressing tumor. A 6-week course of fractionated radiation and concurrent chemotherapy with Temodar® (temozolomide capsules) did not stop tumor progression. Intervention: Due to the failure of conventional therapies in preventing rapid disease progression, the patient volunteered to undergo a 28-day course of Sequentially Programmed Magnetic Field (SPMF) therapy. Results Immediate post-therapy MRI scan showed a cessation of tumor growth, and follow-up imaging at 6, 12, 24 and 36 months revealed a gradual but steady decrease in the size of the tumor. The patient reported an alleviation of clinical symptoms and a subjective improvement in the quality of life at 6, 12, 24 and 36 months following SPMF therapy. Conclusion The remarkable improvement of this patient suggests that SPMF therapy may be a valuable option for anaplastic astrocytoma, especially in recurrent and rapidly progressing tumors. PMID:20740195

  6. A case report of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct.

    PubMed

    Okazaki, Mitsuyoshi; Makino, Isamu; Kitagawa, Hirohisa; Nakanuma, Shinichi; Hayashi, Hironori; Nakagawara, Hisatoshi; Miyashita, Tomoharu; Tajima, Hidehiro; Takamura, Hiroyuki; Ohta, Tetsuo

    2014-01-21

    We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct. A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor. Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas, accompanied with severe dilatation of the main pancreatic duct, which was diagnosed as an intraductal papillary-mucinous neoplasm. We performed distal pancreatectomy and splenectomy. The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma (giant cell type) and adenocarcinoma in the pancreas. There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct. The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery. In this case, we could observe a remarkable intraductal tumor growth into the main pancreatic duct. We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth.

  7. Rapid increase in cystic volume of an anaplastic astrocytoma misdiagnosed as neurocysticercosis: A case report

    PubMed Central

    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

  8. Therapeutic strategies and mechanisms of drug resistance in Anaplastic Lymphoma Kinase (ALK)-rearranged lung cancer.

    PubMed

    Katayama, Ryohei

    2017-02-06

    Anaplastic lymphoma kinase (ALK) gene encoding the receptor tyrosine kinase ALK is expressed as a fusion gene in a variety of carcinomas. The expression of ALK is nearly undetectable in adults, and its activation is normally regulated by its ligands, FAM150A/B. However, ALK gene rearrangements result in different ALK fusion proteins that are constitutively expressed via the active promoter of fusion partner genes. ALK fusion proteins dimerize in a ligand-independent manner and lead to the dysregulation of cell proliferation via abnormal constitutive activation of ALK tyrosine kinase. Many ALK tyrosine kinase inhibitors (TKIs) have been developed to date, are three of which are currently in clinical use for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). ALK TKIs often achieve marked tumor regression in NSCLC patients with ALK rearrangements; however, ALK TKI-resistant tumors inevitably emerge within a few years in most cases. In this review, we summarize diverse ALK TKI resistance mechanisms identified in NSCLC with ALK rearrangements, and review potential therapeutic strategies to overcome ALK TKI resistance in these patients.

  9. Moesin-dependent cytoskeleton remodelling is associated with an anaplastic phenotype of pancreatic cancer.

    PubMed

    Abiatari, Ivane; Esposito, Irene; Oliveira, Tiago De; Felix, Klaus; Xin, Hong; Penzel, Roland; Giese, Thomas; Friess, Helmut; Kleeff, Jörg

    2010-05-01

    Cell motility is controlled by the dynamic cytoskeleton and its related proteins, such as members of the ezrin/radixin/moesin (ERM) family, which act as signalling molecules inducing cytoskeleton remodelling. Although ERM proteins have been identified as important factors in various malignancies, functional redundancy between these proteins has hindered the dissection of their individual contribution. The aim of the present study was to analyse the functional role of moesin in pancreatic malignancies. Cancer cells of different malignant lesions of human and transgenic mice pancreata were evaluated by immunohistochemistry. For functional analysis, cell growth, adhesion and invasion assays were carried out after transient and stable knock-down of moesin expression in pancreatic cancer cells. In vivo tumourigenicity was determined using orthotopic and metastatic mouse tumour models. We now show that moesin knock-down increases migration, invasion and metastasis and influences extracellular matrix organization of pancreatic cancer. Moesin-regulated migratory activities of pancreatic cancer cells were in part promoted through cellular translocation of beta-catenin, and re-distribution and organization of the cytoskeleton. Analysis of human and different transgenic mouse pancreatic cancers demonstrated that moesin is a phenotypic marker for anaplastic carcinoma, suggesting that this ERM protein plays a specific role in pancreatic carcinogenesis.

  10. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

    PubMed Central

    Song, Zilan; Wang, Meining; Zhang, Ao

    2015-01-01

    The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y. PMID:26579422

  11. Nestin expression as an independent indicator of poor prognosis for patients with anaplastic thyroid cancer

    PubMed Central

    KURATA, KENTO; ONODA, NAOYOSHI; NODA, SATORU; KASHIWAGI, SHINICHIRO; ASANO, YUKA; KAWAJIRI, HIDEMI; TAKASHIMA, TSUTOMU; TANAKA, SAYAKA; OHSAWA, MASAHIKO; HIRAKAWA, KOSEI

    2015-01-01

    The protein nestin, a neuronal stem cell marker, has been reported to indicate a poor prognosis in various tumours. Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies in humans, and its molecular background has not been identified. The present study evaluated the expression of nestin and its significance in ATC. Tissue samples from 23 patients with ATC were subjected to immunohistochemical staining and the staining intensity of nestin in the cytoplasm was evaluated. The expression of nestin in the tumour cytoplasm was confirmed in 6 of the 23 tissue samples (26.1%). Between the nestin-positive group (n=6) and the nestin-negative group (n=17), there were no significant differences in the clinicopathological factors of the patients. However, the nestin-positive group exhibited significantly worse prognoses than the nestin-negative group (median survival time, 86.5 vs. 306 days; P<0.01, log-rank test). The multivariate analysis indicated that nestin expression was a prognostic indicator for the ATC patients (hazard ratio, 5.59; 95% confidence interval, 1.63–19.50; P<0.01), which is independent of the known clinical indicators. Nestin expression has the potential to be an independent indicator of a poor prognosis for patients with ATC. PMID:26622582

  12. Effects of BP-14, a novel cyclin-dependent kinase inhibitor, on anaplastic thyroid cancer cells.

    PubMed

    Allegri, Lorenzo; Baldan, Federica; Mio, Catia; Puppin, Cinzia; Russo, Diego; Kryštof, Vladimir; Damante, Giuseppe

    2016-04-01

    Anaplastic thyroid carcinoma (ATC) is an extremely aggressive human malignancy characterized by a marked degree of invasiveness, absense of features of thyroid differentiation and resistance to current medical treatment. It is well known that ATCs are characterized by deregulation of genes related to cell cycle regulation, i.e., cyclin-dependent kinases (CDKs) and endogenous cyclin-dependent kinase inhibitors (CDKIs). Therefore, in the present study, the effect of a novel exogenous cyclin-dependent kinase inhibitor, BP-14, was investigated in three human ATC cell lines. The ATC-derived cell lines FRO, SW1736 and 8505C were treated with BP-14 alone or in combination with the mTOR inhibitor everolimus. In all ATC cell lines, treatment with BP-14 decreased cell viability and, in two of them, BP-14 modified expression of genes involved in epithelial-mesenchymal transition. Thus, our data indicate that BP-14 is a potential new compound effective against ATC. Combined treatment with BP-14 and the mTOR inhibitor everolimus had a strong synergistic effect on cell viability in all three cell lines, suggesting that the combined used of CDK and mTOR inhibitors may be a useful strategy for ATC treatment.

  13. The role of chemotherapy for pure and mixed anaplastic oligodendroglial tumors.

    PubMed

    Dunbar, Erin M

    2009-08-01

    Pure and mixed anaplastic oligodendrogliomas (AO/mixed-AOs) remain terminal primary brain tumors, without a defined optimal initial therapy, and without sufficiently active and tolerable therapies at recurrence/progression (R/P). Very heterogeneous international therapy recommendations remain. Historical advances have resulted in only modest improvements in outcome. AO/mixed-AOs with 1p/19q co-deletion are prognostically favorable, regardless of therapy, and must be identified as early as possible. Following resection, outcome data on initial therapy with radiation (RT) remain the most mature, although controversies regarding its true toxicities and optimal timing continue. Recently, the landmark RTOG 9402 and EORTC 26951 trials showed that the addition of Procarbazine, CCNU, Vincristine chemotherapy to RT, at anytime during initial therapy, prolongs progression-free survival, but not survival, and not without moderate toxicity. Despite a lack of definitive evidence, this strategy has commonly been extrapolated to Temozolomide. Chemo-sensitivity of AO/mixed-AOs provides the rationale for the chemotherapy-only strategies being explored. In the setting of recurrence/progression (R/P), chemotherapy, small molecule (targeted), biologic, and other strategies have been relatively disappointing, toxic, and cumbersome. Partly secondary to biases regarding the relative toxicities of tumor burden vs. treatment effect, therapy remains highly individualized. Future international research must prospectively evaluate health-related quality of life, toxicity, and molecular genetic markers.

  14. Hyperfractionated Accelerated Radiotherapy (HART) for Anaplastic Thyroid Carcinoma: Toxicity and Survival Analysis

    SciTech Connect

    Dandekar, Prasad; Rhys-Evans, Peter; Harrington, Kevin; Nutting, Christopher; Newbold, Kate

    2009-06-01

    Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancers, and the current protocol of hyperfractionated accelerated radiotherapy was initiated to improve survival while limiting toxicities. Methods and Materials: All patients with ATC from 1991 to 2002 were accrued and received megavoltage radiotherapy from the mastoid processes to the carina up to 60 Gy in twice-daily fractions of 1.8 and 2 Gy, 6 hours apart. Results: Thirty-one patients were accrued with a median age of 69 years, and 55% were women. Debulking was performed in 26%, and total thyroidectomy, in 6%, whereas 68% received radical radiotherapy alone. Local control data were available for 27 patients: 22% had a complete response, 26% had a partial response, 15% showed progressive disease, and 37% showed static disease. Median overall survival for all 31 patients was 70 days (95% confidence interval, 40-99). There was no significant difference in median survival between patients younger (70 days) and older than 70 years (42 days), between men (70 days) and women (49days), and between patients receiving postoperative radiotherapy (77 days) and radical radiotherapy alone (35 days). Grade III or higher skin erythema was seen in 56% patients; desquamation in 21%; dysphagia in 74%; and esophagitis in 79%. Conclusion: The current protocol failed to offer a significant survival benefit, was associated with severe toxicities, and thus was discontinued. There is a suggestion that younger patients with operable disease have longer survival, but this would require a larger study to confirm it.

  15. Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma

    PubMed Central

    Villa, Raffaella; Collini, Paola; Alaggio, Rita; Zin, Angelica; Bonvini, Paolo; Antonescu, Cristina R; Boldrini, Renata; Caserini, Roberto; Moro, Massimo; Centonze, Giovanni; Meazza, Cristina; Massimino, Maura; Bergamaschi, Luca; Luksch, Roberto; Chiaravalli, Stefano; Bisogno, Gianni; Zaffaroni, Nadia; Daidone, MariaGrazia

    2016-01-01

    Rhabdomyosarcoma (RMS) is the most frequent soft tissue tumor in childhood and arises from immature mesenchymal cells committed to skeletal muscle differentiation. Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in several cancers. Moreover, ALK full-length receptor protein has been observed in RMS, although its clinical and functional significance is yet controversial. The role of ALK and its clinical relevance were investigated in a selected cohort of 74 FFPE pediatric RMS and a panel of RMS cell lines, evaluating its gene and protein status, utilizing Fluorescent In Situ Hybridization (FISH), immunohistochemistry (IHC) and Western blot approaches. Moreover, to get insight into its possible therapeutic relevance, effects of ALK silencing on cell proliferation, invasion and apoptosis were studied in RMS cells. ALK IHC positivity was significantly correlated with gene copy number gain, the alveolar subtype, PAX3/7-FOXO1 rearrangements, the presence of metastasis at diagnosis and a worse overall outcome. Furthermore, EML4-ALK fusion gene associated with higher protein expression was identified in an embryonal RMS. ALK silencing in RH30 ALK positive cells strongly inhibited invasion capability. Overall, our data suggest a potential role of ALK in pediatric RMS. PMID:27385213

  16. Giant cells in anaplastic mammary carcinoma of the dog and cat.

    PubMed

    Della Salda, L; Sarli, G; Benazzi, C; Marcato, P S

    1993-11-01

    Four uncommon anaplastic mammary carcinomas containing numerous giant cells are described in three dogs and one cat. The giant cells of all cases were studied by means of monoclonal and polyclonal antibodies to detect epithelial (carcinoembryonic antigen and keratin) and mesenchymal (vimentin, lysozyme and S-100 protein) differentiation. Most of them proved to have an epithelial immunophenotype. Ultrastructurally, scattered bundles of tonofilaments but no lysosome-like bodies could be detected. One tumour had an additional, different type of giant cell, which had a benign multinucleated osteoclast-like appearance, gave positive staining for acid phosphatase, had a histiocytic-stromal immunohistochemical pattern, and was, ultrastructurally, multinucleate with irregular folds and no evidence of tonofilaments. In one case some giant cells had an epithelial immunophenotype and others a stromal immunophenotype, even though their histological and ultrastructural features were the same. In the least histologically differentiated tumour the giant cells presented a coexpression of intermediate filaments. This supported the theory that there might be a stem cell origin for most canine mammary tumours.

  17. Ethanol activates midkine and anaplastic lymphoma kinase signaling in neuroblastoma cells and in the brain.

    PubMed

    He, Donghong; Chen, Hu; Muramatsu, Hisako; Lasek, Amy W

    2015-11-01

    Alcohol engages signaling pathways in the brain. Midkine (MDK) is a neurotrophic factor that is over-expressed in the prefrontal cortex of alcoholics. MDK and one of its receptors, anaplastic lymphoma kinase (ALK), also regulate behavioral responses to ethanol in mice. The goal of this study was to determine whether MDK and ALK expression and signaling are activated by ethanol. We found that ethanol treatment of neuroblastoma cells increased MDK and ALK expression. We also assessed activation of ALK by ethanol in cells and found that ALK and ALK-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation increased rapidly with ethanol exposure. Similarly, treatment of cells with recombinant MDK protein increased ALK, ERK and STAT3 phosphorylation, suggesting that ethanol may utilize MDK to activate ALK signaling. In support of this, transfection of cells with MDK siRNAs attenuated ALK signaling in response to ethanol. Ethanol also activates ERK signaling in the brain. We found that inhibition of ALK or knockout of MDK attenuated ethanol-induced ERK phosphorylation in mouse amygdala. These results demonstrate that ethanol engages MDK and ALK signaling, which has important consequences for alcohol-induced neurotoxicity and the regulation of behaviors related to alcohol abuse.

  18. Radiation-induced anaplastic ependymoma mimicking a skull base meningioma: A case report

    PubMed Central

    SPALLONE, ALDO; MARCHIONE, PASQUALE; DI CAPUA, MARIO; BELVISI, DANIELE

    2016-01-01

    The present study describes the case of a 63-year-old woman presenting with headache, dizziness and vomiting due to a an ovoid mass in the left pre-bulbar cistern, apparently arising from the lower clivus and the foramen magnum. The clinical history revealed the subtotal removal of a right cerebellar low-grade glioma 15 years previously and subsequent conventional 60-Gy radiotherapy. Notably, following gross total resection, histopathological examination showed microscopic features that resulted in a diagnosis of anaplastic ependymoma. The patient underwent surgery to remove the mass and post-operative chemotherapy with temozolomide. A progressive improvement of neurological signs and symptoms was observed during the postoperative course. At the 6-month follow-up, the patient was free from clinical and radiological recurrence. The unusual features of this rare secondary brain tumor were the extrassial location in the posterior fossa, the unusual age-associated location of the histological subtype and the fact that it closely mimicked a skull-base meningioma. PMID:26893630

  19. Langerhans cells in anaplastic Kaposi sarcoma with a paucivascular phenotype: a potential diagnostic pitfall.

    PubMed

    Ramdial, Pratistadevi K; Sing, Yetish; Naicker, Shaun; Calonje, Eduardo; Sewram, Vikash; Singh, Bhugwan

    2011-04-01

    Anaplastic Kaposi sarcoma (AKS), a rare variant of Kaposi sarcoma, has a poorly recognized histomorphologic spectrum, including a paucivascular phenotype, that mimics a range of undifferentiated malignancies. This study, that highlights the hitherto undocumented phenomenon of S100-protein-positive Langerhans cells (SLCs) as a potential diagnostic pitfall in paucivascular AKS, involved review of nine such AKS that required diagnostic immunohistochemical (IHC) work-up. All biopsies had a predominant or exclusive spindle or epithelioid cell infiltrate. The first three tumors were diagnosed as malignant peripheral nerve sheath tumor (2) and metastatic melanoma (1), based on S100-protein immunopositivity. Biopsy of a co-existent pigmented sole lesion (patient 3) demonstrated nodular KS. Subsequent IHC investigation of these three tumors demonstrated an endothelial phenotype and HHV8 immunopositivity, confirming AKS. CD1a and langerin staining of the S100-protein-positive cells confirmed Langerhans cells as the cause of the diagnostic pitfall. Subsequently, six further paucivascular AKS with intratumoral SLCs were recognized on histomorphological and IHC appraisal. In conclusion, heightened awareness of the histomorphologic spectrum, appropriate IHC investigation, and informed appraisal thereof, are critical to the diagnosis of AKS with an undifferentiated phenotype, and the avoidance of IHC pitfalls, such as those caused by under-recognition and misinterpretation of bystander SLCs in AKS.

  20. Interleukin-11 promotes epithelial-mesenchymal transition in anaplastic thyroid carcinoma cells through PI3K/Akt/GSK3β signaling pathway activation

    PubMed Central

    Jiang, Yue; Sun, Ruimei; Chen, Xue; Chu, Hongying; Zeng, Musheng; Sun, Chuanzheng

    2016-01-01

    Metastasis is the major cause of treatment failure in anaplastic thyroid carcinoma (ATC) patients. In the preliminary study, we demonstrated that interleukin (IL)-11 expression is positively correlated with distant metastasis in ATC. However, the mechanisms underlying remain largely unknown. Here, we found that cobalt chloride (a hypoxia mimetic) promoted IL-11 expression via HIF-1α activation. Furthermore, the resultant increase in IL-11 expression significantly induced epithelial-mesenchymal transition (EMT) in ATC cells, accompanied by Akt/GSK3β pathway activation and increased invasive and migratory abilities. Conversely, HIF-1α or IL-11 knockdown, or treating cells with a neutralizing antibody against IL-11, a PI3K inhibitor, or Akt inhibitor V, significantly suppressed the induction of EMT and counteracted the enhancements in invasive and migratory abilities. These results indicate that hypoxia increases IL-11 secretion in ATC cells via HIF-1α induction and that IL-11 then induces EMT in these cells via the PI3K/Akt/GSK3β pathway, ultimately improving their invasive and migratory potential. This study elucidates the prometastatic role played by IL-11 in ATC metastasis and indicates it as a potential target for the treatment of cancer metastasis. However, many questions remain to be explored. PMID:27487122

  1. Targeting TGF-β1 suppresses survival of and invasion by anaplastic thyroid carcinoma cells

    PubMed Central

    Sun, Wenhai; Xu, Yanyan; Zhao, Cheng; Hao, Fengyun; Chen, Dong; Guan, Jinping; Zhang, Kejun

    2017-01-01

    Background and aims: Overexpression of transforming growth factor (TGF)-β1 has been implicated in promoting cell survival, migration and invasion in many cancers, including anaplastic thyroid cancer (ATC). In the present study, we studied the effect of suppressing TGF-β1 by RNA silencing on the survival, invasion and metastasis of ATC cells. Methods: Small interfering RNA (siRNA) constructs targeting TGF-β1 were validated and used to develop clonal derivatives of the ATC cell line, 8505C. The cells were used in several in vitro assays, including migration, invasion, survival rate, colony formation and apoptosis. A wound healing assay was used to determine the migration of cells in culture and a Boyden chamber transwell assay was used for invasion. Further, clones were used in an in vivo mouse model to study the kinetics of tumor growth and metastatic growth in lungs. Results: Targeting TGF-β1 expression in 8505C cells caused a 70% decrease in migration and a 78% decrease in invasion, as well as a 68% decrease in proliferation and a 19% increase in apoptosis in vitro. The growth of primary tumors in vivo was also inhibited when compared with parental 8505C cells; however, the number of mice bearing lung metastases was not significantly decreased. Conclusions: Targeting TGF-β1 may be effective in inhibiting primary tumor formation, but not metastasis, by ATC cells. TGF-β1 inhibition in combination with other tumor-targeted therapies may be more effective in inhibiting ATC. PMID:28386367

  2. A spindle cell anaplastic pancreatic carcinoma with rhabdoid features following curative resection

    PubMed Central

    Abe, Tomoyuki; Amano, Hironobu; Hanada, Keiji; Okazaki, Akihisa; Yonehara, Shuji; Kuranishi, Fumito; Nakahara, Masahiro; Kuroda, Yoshinori; Noriyuki, Toshio

    2016-01-01

    Anaplastic pancreatic carcinoma (ANPC) accounts for ~5% of all pancreatic ductal adenocarcinoma cases. Due to its rarity, its clinical features and surgical outcomes remain to be clearly understood. A 74-year-old woman was admitted to Onomichi General Hospital (Onomichi, Japan) in April 2015 without any significant past medical history. Contrast-enhanced computed tomography (CT) revealed a 9.5×8.0 cm tumor in the body and tail of the pancreas. The patient developed acute abdominal pain 3 weeks later and the CT revealed massive abdominal bleeding caused by tumor rupture. The tumor increased in size and reached 12.0×10.0 cm in maximal diameter. The tumor doubling time was estimated to be 13 days. 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT confirmed the absence of distant metastasis since FDG accumulation was detected only in the tumor lesion. Emergency distal pancreatectomy and splenectomy were performed. Histologically, the tumor was classified as a spindle cell ANPC with rhabdoid features. The patient succumbed to mortality 8 months following the surgery while undergoing systemic adjuvant chemotherapy for multiple liver metastases. ANPC is difficult to detect in the early stages due to its progressive nature and atypical radiological findings. Long-term survival can be achieved only by curative resection; therefore, surgical resection must be performed whenever possible, even if the chance of long-term survival following surgery is considered dismal. As the present case suggested, spindle cell ANPC with rhabdoid features is highly aggressive and curative-intent resection must not be delayed. PMID:27446572

  3. Genetic inhibition of Anaplastic Lymphoma Kinase rescues cognitive impairments in Neurofibromatosis 1 mutant mice.

    PubMed

    Weiss, Joseph B; Weber, Sydney J; Torres, Eileen Ruth S; Marzulla, Tessa; Raber, Jacob

    2017-03-15

    Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations occur in approximately 90% of patients with neurofibromatosis. A major, disabling phenotypic consequence of reduced NF1 function is cognitive impairment; a possibly related behavioral phenotype is impaired sleep. Recent results in Drosophila have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 for both associative learning and sleep. Inhibition of Alk improves associative learning and sleep in heterozygous NF1 mutant flies. The results in Drosophila provide a strong motivation to investigate NF1/Alk genetic interactions in mice. In Drosophila, activation of Alk by its ligand, Jelly belly (Jeb), is the physiologically relevant target of negative regulation by NF1. Therefore, we tested whether genetic inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments in mice. Our results are consistent with the hypothesis that NF1 functions in mice biochemically to inhibit signaling from Alk through Ras. The cognitive phenotypes observed in heterozygous NF1 mutant mice are rescued or ameliorated by genetic inhibition of Alk activity. In two tests of hippocampus-dependent learning, the Morris water maze and extinction of contextual fear, mutation of one or both alleles of Alk was sufficient to improve performance to wild type or near wild type levels in NF1-/+ mice. In addition, in NF1 mice genetic inhibition of Alk improves circadian activity levels. These data are intriguing in light of the circadian alterations seen in NF1 patients and indicate that inhibition of Alk activity may cognitively benefit patients with Neurofibromatosis 1.

  4. 2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells.

    PubMed

    Roswall, Pernilla; Bu, Shizhong; Rubin, Kristofer; Landström, Maréne; Heldin, Nils-Erik

    2006-02-01

    Anaplastic thyroid carcinoma (ATC) is one of the most malignant tumors in humans, and currently there is no effective treatment. In the present study we investigated the effect of an endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), on the growth of human ATC cells. 2-ME treatment had a strong growth inhibitory effect on five human ATC cell lines (HTh7, HTh 74, HTh83, C643, and SW1736), but showed no effect on one cell line (KAT-4). Cell cycle analysis of the growth-inhibited cells showed that 2-ME induced a G2/M-arrest, followed by an increased fraction of cells in sub-G1. Analysis of internucleosomal DNA laddering as well as DNA fragmentation in a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay demonstrated a high number of cells undergoing apoptosis after 2-ME treatment. An increased activation of caspase-3 and caspase-8 by 2-ME was observed, and inhibition of caspase-3 decreased the apoptotic effect. Addition of 2-ME increased activity of p38 mitogen-activated protein kinase (MAPK) in the sensitive HTh7 as well as the refractory KAT-4 cells, however, activation of stress-activated protein kinase/c-jun aminoterminal kinase (SAPK/JNK) was seen only in the HTh7 cells. Inhibitors of p38 MAPK and SAPK/JNK significantly attenuated the 2-ME effect. Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs.

  5. Spanish consensus for the management of patients with anaplastic cell thyroid carcinoma.

    PubMed

    Gómez Sáez, José Manuel; Jiménez-Fonseca, Paula; Santamaría Sandi, Javier; Capdevila Castillón, Jaume; Navarro González, Elena; Zafón Llopis, Carles; Ramón Y Cajal Asensio, Teresa; Riesco Eizaguirre, Garcilaso; Grande Pulido, Enrique; Galofré Ferrater, Juan Carlos

    2015-03-01

    Anaplastic thyroid cancer (ATC) is the most aggressive solid tumour known and is a rare but highly lethal form of thyroid cancer that requires a multidisciplinary team approach. No Spanish consensus exists for management of patients with ATC. The Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the GETHI (Grupo Español de Enfermedades Huérfanas e Infrecuentes) of the Spanish Society of Oncology, in agreement with the Boards of these Societies, commissioned an independent task force to develop a wide consensus on ATC. The relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The consensus includes the characteristics, diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, systemic therapy, supportive care during active treatment), approaches to advanced/metastatic disease, palliative care options, monitoring, and long-term follow-up of ATC. For operable disease, a combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin, cisplatin and paclitaxel, is the best treatment strategy. Cytotoxic drugs are poorly effective for advanced/metastatic ATC. On the other hand, targeted agents may represent a viable therapeutic option. Patients with stage IVA/IVB resectable disease have the best prognosis, particularly if a multimodal approach is used, and some stage IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be considered for clinical trials or for hospice/palliative care depending on their preference. This is the first Spanish consensus for ATC, and provides recommendations for management of this extremely aggressive malignancy. Novel systemic therapies are being tested, and more effective combinations are needed to improve patient outcomes. Although more aggressive radiotherapy has reduced locoregional recurrence, mean

  6. Single Agent Nanoparticle for Radiotherapy and Radio-Photothermal Therapy in Anaplastic Thyroid Cancer

    PubMed Central

    Zhou, Min; Chen, Yunyun; Adachi, Makoto; Wen, Xiaoxia; Erwin, Bill; Mawlawi, Osama; Lai, Stephen Y.; Li, Chun

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies. The aggressive behavior of ATC and its resistance to traditional treatment limit the efficacy of radiotherapy, chemotherapy, and surgery. The purpose of this study is aimed at enhancing the therapeutic efficacy of radiotherapy (RT) combined with photothermal therapy (PTT) in murine orthotopic model of ATC, based on our developed single radioactive copper sulfide (CuS) nanoparticle platform. We prepare a new dual-modality therapy for ATC consisting of a single-compartment nanoplatform, polyethylene glycol-coated [64Cu]CuS NPs, in which the radiotherapeutic property of 64Cu is combined with the plasmonic properties of CuS NPs. Mice with Hth83 ATC were treated with PEG[64Cu]CuS NPs and/or near infrared laser. Antitumor effects were assessed by tumor growth and animal survival. We found that in mice bearing orthotopic human Hth83 ATC tumors, micro-PET/CT imaging and biodistribution studies showed that about 50% of the injected dose of PEG-[64Cu]CuS NPs was retained in tumor 48 h after intratumoral injection. Human absorbed doses were calculated from biodistribution data. In antitumor experiments, tumor growth was delayed by PEG-[64Cu]CuS NP-mediated RT, PTT, and combined RT/PTT, with combined RT/PTT being most effective. In addition, combined RT/PTT significantly prolonged the survival of Hth83 tumor-bearing mice compared to no treatment, laser treatment alone, or NP treatment alone without producing acute toxic effects. These findings indicate that this single-compartment multifunctional NPs platform merits further development as a novel therapeutic agent for ATC. PMID:25913249

  7. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors.

    PubMed

    Lassman, Andrew B; Iwamoto, Fabio M; Cloughesy, Timothy F; Aldape, Kenneth D; Rivera, Andreana L; Eichler, April F; Louis, David N; Paleologos, Nina A; Fisher, Barbara J; Ashby, Lynn S; Cairncross, J Gregory; Roldán, Gloria B; Wen, Patrick Y; Ligon, Keith L; Schiff, David; Robins, H Ian; Rocque, Brandon G; Chamberlain, Marc C; Mason, Warren P; Weaver, Susan A; Green, Richard M; Kamar, Francois G; Abrey, Lauren E; DeAngelis, Lisa M; Jhanwar, Suresh C; Rosenblum, Marc K; Panageas, Katherine S

    2011-06-01

    Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.

  8. Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines.

    PubMed

    Baldini, Enke; Tuccilli, Chiara; Prinzi, Natalie; Sorrenti, Salvatore; Antonelli, Alessandro; Gnessi, Lucio; Morrone, Stefania; Moretti, Costanzo; Bononi, Marco; Arlot-Bonnemains, Yannick; D'Armiento, Massimino; Ulisse, Salvatore

    2014-10-01

    Aurora kinases are serine/threonine kinases that play an essential role in cell division. Their aberrant expression and/or function induce severe mitotic abnormalities, resulting in either cell death or aneuploidy. Overexpression of Aurora kinases is often found in several malignancies, among which is anaplastic thyroid carcinoma (ATC). We have previously demonstrated the in vitro efficacy of Aurora kinase inhibitors in restraining cell growth and survival of different ATC cell lines. In this study, we sought to establish which Aurora might represent the preferential drug target for ATC. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) on four human ATC cell lines (CAL-62, BHT-101, 8305C, and 8505C) were analysed. Both inhibitors reduced cell proliferation in a time- and dose-dependent manner, with IC50 ranges of 44.3-134.2 nM for MLN8237 and of 9.2-461.3 nM for AZD1152. Immunofluorescence experiments and time-lapse videomicroscopy yielded evidence that each inhibitor induced distinct mitotic phenotypes, but both of them prevented the completion of cytokinesis. As a result, poliploidy increased in all AZD1152-treated cells, and in two out of four cell lines treated with MLN8237. Apoptosis was induced in all the cells by MLN8237, and in BHT-101, 8305C, and 8505C by AZD1152, while CAL-62 exposed to AZD1152 died through necrosis after multiple rounds of endoreplication. Both inhibitors were capable of blocking anchorage-independent cell growth. In conclusion, we demonstrated that either Aurora-A or Aurora-B might represent therapeutic targets for the ATC treatment, but inhibition of Aurora-A appears more effective for suppressing ATC cell proliferation and for inducing the apoptotic pathway.

  9. Single agent nanoparticle for radiotherapy and radio-photothermal therapy in anaplastic thyroid cancer.

    PubMed

    Zhou, Min; Chen, Yunyun; Adachi, Makoto; Wen, Xiaoxia; Erwin, Bill; Mawlawi, Osama; Lai, Stephen Y; Li, Chun

    2015-07-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies. The aggressive behavior of ATC and its resistance to traditional treatment limit the efficacy of radiotherapy, chemotherapy, and surgery. The purpose of this study is aimed at enhancing the therapeutic efficacy of radiotherapy (RT) combined with photothermal therapy (PTT) in murine orthotopic model of ATC, based on our developed single radioactive copper sulfide (CuS) nanoparticle platform. We prepare a new dual-modality therapy for ATC consisting of a single-compartment nanoplatform, polyethylene glycol-coated [(64)Cu]CuS NPs, in which the radiotherapeutic property of (64)Cu is combined with the plasmonic properties of CuS NPs. Mice with Hth83 ATC were treated with PEG-[(64)Cu]CuS NPs and/or near infrared laser. Antitumor effects were assessed by tumor growth and animal survival. We found that in mice bearing orthotopic human Hth83 ATC tumors, micro-PET/CT imaging and biodistribution studies showed that about 50% of the injected dose of PEG-[(64)Cu]CuS NPs was retained in tumor 48 h after intratumoral injection. Human absorbed doses were calculated from biodistribution data. In antitumor experiments, tumor growth was delayed by PEG-[(64)Cu]CuS NP-mediated RT, PTT, and combined RT/PTT, with combined RT/PTT being most effective. In addition, combined RT/PTT significantly prolonged the survival of Hth83 tumor-bearing mice compared to no treatment, laser treatment alone, or NP treatment alone without producing acute toxic effects. These findings indicate that this single-compartment multifunctional NPs platform merits further development as a novel therapeutic agent for ATC.

  10. Anaplastic astrocytoma mimicking herpes simplex encephalitis in 13-year old girl.

    PubMed

    Talathi, Saurabh; Gupta, Neha; Reddivalla, Naresh; Prokhorov, Sergey; Gold, Menachem

    2015-11-01

    Astrocytoma is the most common childhood brain tumor. Anaplastic astrocytoma (AA) are high grade gliomas (HGG), found very rarely in pediatric patients. AA mainly results from a dedifferentiation of a low grade astrocytoma. Clinical features of supra-tentorial tumors vary according to their anatomic location, biologic aggressiveness and age of the patient. They can be either completely asymptomatic or present with signs of raised intracranial pressure, seizures (about 40% of cases), behavior changes, speech disorders, declining school performance, or hemiparesis. There have been published adult cases of brain tumor misdiagnosed as viral encephalitis. Due to variety of clinical presentations, diagnosis of AA can be challenging. Here we report a case of a 13 year old girl who presented with clinical features suggestive of viral encephalitis, such as fever, headache, dizziness, and first seizure with postictal sleep and prolonged drowsiness. However, her brain MRI findings were consistent with long standing mass effect from the underlying intracranial contents and that coupled with her history of unusual taste led to further investigations and the diagnosis of the AA. In retrospect, this presentation could have been a temporal epileptic aura. High grade astrocytomas are particularly difficult to treat with a two-year survival rates range from 10% to 30%. The treatment is multimodal with gross total surgical resection of the tumor, followed by radiotherapy with or without nitrosourea-containing chemotherapy regimen. Recent promising results seen with the use of temozolamide in adults has not been yet demonstrated in the pediatric patients. The extent of tumor resection remains the most significant indicator of survival and early recognition of this tumor is essential. This case report emphasizes the fact that mass lesions in the temporal lobe, including high-grade astrocytoma, should be considered in the differential diagnosis of suspected herpes simplex encephalitis

  11. 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography for Other Thyroid Cancers: Medullary, Anaplastic, Lymphoma and So Forth

    PubMed Central

    Araz, Mine; Çayır, Derya

    2017-01-01

    Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) is used in staging, restaging, and evaluation of therapy response in many cancers as well as differentiated thyroid carcinomas especially in non-iodine avid variants. Its potential in less frequent thyroid tumors like medullary, anaplastic thyroid cancers, thyroid lymphoma and metastatic tumors of the thyroid however, is not well established yet. The aim of this review is to provide an overview on the recent applications and indications of 18F-FDG PET/CT in these tumors and to focus on the controversies in the clinical setting. PMID:28291004

  12. [Early magnetic resonance imaging detection of a cavernous angioma after cranial radiotherapy for an anaplastic ependymoma in a boy].

    PubMed

    Martínez León, M I

    2013-01-01

    Radiotherapy forms part of most therapeutic, preventive, and conditioning regimens in pediatric oncology. Numerous late secondary effects of cranial radiation are well known. However, radiation-induced cavernous angiomas (RICA) have been reported only sporadically and even fewer cases of earlier presentation of RICA have been reported. In this brief report, we describe a RICA that appeared in a boy treated for a CNS tumor (an infratentorial anaplastic ependymoma) after a short latency period between the end of radiotherapy and the development of the RICA. We comment on the different variables proposed to explain the formation of these lesions, as well as on their imaging features, treatment, prognosis, and follow-up.

  13. 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.

    PubMed

    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.

  14. Down-regulation of transcription elogation factor A (SII) like 4 (TCEAL4) in anaplastic thyroid cancer

    PubMed Central

    Akaishi, Junko; Onda, Masamitsu; Okamoto, Junichi; Miyamoto, Shizuyo; Nagahama, Mitsuji; Ito, Kouichi; Yoshida, Akira; Shimizu, Kazuo

    2006-01-01

    Background Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and appears to arise mainly from transformation of pre-existing differentiated thyroid cancer (DTC). However, the carcinogenic mechanism of anaplastic transformation remains unclear. Previously, we investigated specific genes related to ATC based on gene expression profiling using cDNA microarray analysis. One of these genes, transcription elongation factor A (SII)-like 4 (TCEAL4), encodes a member of the transcription elongation factor A (SII)-like gene family. The detailed function of TCEAL4 has not been described nor has any association between this gene and human cancers been reported previously. Methods To investigate the role of TCEAL4 in ATC carcinogenesis, we examined expression levels of TCEAL4 in ACLs as well as in other types of thyroid cancers and normal human tissue. Results Expression of TCEAL4 was down-regulated in all 11 ACLs as compared to either normal thyroid tissues or papillary and follicular thyroid cancerous tissues. TCEAL4 was expressed ubiquitously in all normal human tissues tested. Conclusion To our knowledge, this is the first report of altered TCEAL4 expression in human cancers. We suggest that loss of TCEAL4 expression might be associated with development of ATC from DTC. Further functional studies are required. PMID:17076909

  15. Granulocyte Colony-stimulating Factor Producing Anaplastic Carcinoma of the Pancreas: Case Report and Review of the Literature.

    PubMed

    Vinzens, Sarah; Zindel, Joel; Zweifel, Martin; Rau, Tilman; Gloor, Beat; Wochner, Annette

    2017-01-01

    We report on the case of a 67-year-old man with granulocyte colony-stimulating factor (G-CSF) producing anaplastic carcinoma of the pancreas. Preoperative routine tests revealed an elevated white blood cell (WBC) count of 25.2 G/l, consisting almost exclusively of neutrophilic granulocytes (23.31 G/l) with a predominance of segmented neutrophils (78% of all neutrophilic granulocytes), and elevated levels of C-reactive protein at 87 mg/l. Upon surgery, local tumour infiltration was more extensive than expected from preoperative imaging. However, no peritoneal dissemination was found and curative resection was attempted. Only seven days after the operation, signs of relapse were seen upon computed tomograpy. Histology revealed an undifferentiated anaplastic carcinoma, on the basis of a poorly differentiated ductal adenocarcinoma. Immunohistochemistry demonstrated G-CSF and G-CSF-Receptor expression in some CD68-positive syncytial macrophages. Granulocyte colony-stimulating factor (G-CSF) in serum was elevated at 5.6 pg/ml, which further raised to 43 pg/ml one week after FOLFIRINOX chemotherapy (oxaliplatin, irinotecan, 5-fluorouracil), while WBC decreased from 103.3 G/l to 59.3 G/l. Granulocyte macrophage-colony stimulating factor (GM-CSF) in serum was normal (<0.5 pg/ml). The patient died on postoperative day 34.

  16. Precision Medicine Approach to Anaplastic Thyroid Cancer: Advances in Targeted Drug Therapy Based on Specific Signaling Pathways.

    PubMed

    Samimi, Hilda; Fallah, Parviz; Naderi Sohi, Alireza; Tavakoli, Rezvan; Naderi, Mahmood; Soleimani, Masoud; Larijani, Bagher; Haghpanah, Vahid

    2017-03-01

    Personalized medicine is a set of diagnostic, prognostic and therapeutic approaches in which medical interventions are carried out based on individual patient characteristics. As life expectancy increases in developed and developing countries, the incidence of diseases such as cancer goes up among people in the community. Cancer is a disease that the response to treatment varies from one person to another and also it is costly for individuals, families, and society. Among thyroid cancers, anaplastic thyroid carcinoma (ATC) is the most aggressive, lethal and unresponsive form of the disease. Unfortunately, current drugs are not targetable, and therefore they have restricted role in ATC treatment. Consequently, mortality of this cancer, despite advances in the field of diagnosis and treatment, is one of the most important challenges in medicine. Cellular, molecular and genetic evidences play an important role in finding more effective diagnostic and therapeutic approaches. Review of these evidences confirms the application of personalized medicine in cancer treatment including ATC. A growing body of evidence has elucidated that cellular and molecular mechanisms of cancer would pave the way for defining new biomarkers for targeted therapy, taking into account individual differences. It should be noted that this approach requires further progress in the fields of basic sciences, pharmacogenetics and drug design. An overview of the most important aspects in individualized anaplastic thyroid cancer treatment will be discussed in this review.

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

    PubMed Central

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

    2015-01-01

    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

  18. Influence of insurance status and income in anaplastic astrocytoma: an analysis of 4325 patients.

    PubMed

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

    2016-11-18

    To determine the impact of insurance status and income for anaplastic astrocytoma (AA). Data were extracted from the National Cancer Data Base. Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 4325 patients with AA diagnosed from 2004 to 2013 were identified. 2781 (64.3%) had private insurance, 925 (21.4%) Medicare, 396 (9.2%) Medicaid, and 223 (5.2%) were uninsured. Those uninsured were more likely to be Black or Hispanic versus White or Asian (p < 0.001), have lower median income (p < 0.001), less educated (p < 0.001), and not receive adjuvant chemoradiation (p < 0.001). 1651 (38.2%) had income ≥$63,000, 1204 (27.8%) $48,000-$62,999, 889 (20.5%) $38,000-$47,999, and 581 (13.4%) had income <$38,000. Those with lower income were more likely to be Black or Hispanic versus White or Asian (p < 0.001), uninsured (p < 0.001), reside in a rural area (p < 0.001), less educated (p < 0.001), and not receive adjuvant chemoradiation (p < 0.001). Those with private insurance had significantly higher overall survival (OS) than those uninsured, on Medicaid, or on Medicare (p < 0.001). Those with income ≥$63,000 had significantly higher OS than those with lower income (p < 0.001). On multivariate analysis, age, insurance status, income, and adjuvant therapy were independent prognostic factors for OS. Being uninsured and having income <$38,000 were independent prognostic factors for worse OS in AA. Further investigations are warranted to help determine ways to ensure adequate medical care for those who may be socially disadvantaged so that outcome can be maximized for all patients regardless of socioeconomic status.

  19. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

    PubMed Central

    Ibrahimpasic, Tihana; Boucai, Laura; Shah, Ronak H.; Dogan, Snjezana; Ricarte-Filho, Julio C.; Krishnamoorthy, Gnana P.; Schultz, Nikolaus; Berger, Michael F.; Sander, Chris; Taylor, Barry S.; Ghossein, Ronald; Ganly, Ian; Fagin, James A.

    2016-01-01

    BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. METHODS. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). RESULTS. Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation. CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality. FUNDING. This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family

  20. Anaplastic thyroid carcinoma and foscarnet use in a multitarget treatment documented by 18F-FDG PET/CT

    PubMed Central

    Giannetta, Elisa; Isidori, Andrea M.; Durante, Cosimo; Di Gioia, Cira; Longo, Flavia; Tombolini, Vincenzo; Bulzonetti, Nadia; Graziadio, Chiara; Pofi, Riccardo; Gianfrilli, Daniele; Verrienti, Antonella; Carletti, Raffaella; Filetti, Sebastiano; Lenzi, Andrea; Baroli, Alberto

    2017-01-01

    Abstract Rationale: The case reported the rapid remission of disease recurrence achieved adding foscarnet, a DNA polymerase inhibitor that interacts with fibroblast growth factor 2, to low molecular weight heparin and sunitinib for the first time in a patient with an anaplastic thyroid cancer (ATC). Patient concerns: A 65-year-old woman with a multinodular goiter referred for a rapid enlargement of a nodule. Histological examination revealed an ATC with a little area of papillary thyroid cancer (PTC). The patient was resistant to selective single-target treatment. DIagnoses: Immunophenotyping and gene analyses found a significant increase in FGF2 and FGFR1 expression in the primary ATC area (FGF2 = 38.2 ± 6.2% in ATC vs 34.6 ± 6.0% in the differentiated area of PTC, P < 0.05; FGFR1: 41.7 ± 6.0% in ATC vs 34.4 ± 4.2% in PTC, P < 0.001) and in metastatic neck lymph nodes (P < 0.001 vs normal control tissues). Unlike conventional imaging, 18F-FDG PET/CT with PERCIST 1.0 criteria promptly and quantitatively detected disease recurrence and remission before and after multitarget therapy, combining anatomic, metabolic, and functional data. Interventions: Foscarnet was administered given the positivity for FGF2, FGFR1 and FGFR4 in ATC. Low molecular wight heparin and Sunitinib were coadministere to limiti metastatic progression and on neck tumor masse, respectively. Outcomes: The rationale for the clinical response to this innovative multitarget association with foscarnet is based on the histological and genetic finding that fibroblast growth factors and their receptor super-family are up-regulated in the primary anaplastic thyroid tumor and in the metastatic lymph node of our patient. Lessons: We propose that fibroblast growth factors and their receptor super-family play a key role as potential therapeutic targets in anaplastic thyroid cancer and the positive relevance of this suggestion for patient care, especially for an

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

    PubMed

    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 <19 years of age, with a focus on treatment and outcome features. One hundred forty-three patients, between 0.3 and 18.7 years old, diagnosed between 2000 and 2015 were included in the study. PTCL not otherwise specified was the largest subgroup, followed by extranodal NK/T cell lymphoma, hepatosplenic T cell lymphoma (HS TCL), and subcutaneous panniculitis-like T cell lymphoma (SP TCL). Probability of overall survival (pOS) at 5 years for the whole group was 0.56 ± 0.05, and probability of 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.

  2. Microcomputer-based technique for 3-D reconstruction and volume measurement of computed tomographic images. Part 2: Anaplastic primary brain tumors.

    PubMed

    Albright, R E; Fram, E K

    1988-12-01

    Serial computed tomography (CT) plays an integral part in monitoring effects of therapy for primary anaplastic brain tumors. Despite advances in CT technology, clinicians often cannot obtain accurate quantitative volume information to complement the qualitative assessment of tumor change. This paper presents a microcomputer-based method that provides both quantitative volume measurements and 3-D reconstructions of primary anaplastic brain tumors based on their hard copy CT or magnetic resonance imaging studies. The findings of this study demonstrate that planimetry is feasible for routine clinical use and is superior in accuracy to the spherical geometric model, which is shown to significantly overestimate tumor volume. The findings of 62 quantitative tumor studies (17 patients) showed a direct relationship between the total tumor volume and the volume of the hypodense intratumor core. There was no evidence of a relationship between the total tumor volume and the amount of peritumor low density (edema).

  3. Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation.

    PubMed

    Vaubel, Rachael A; Caron, Alissa A; Yamada, Seiji; Decker, Paul A; Eckel Passow, Jeanette E; Rodriguez, Fausto J; Nageswara Rao, Amulya A; Lachance, Daniel; Parney, Ian; Jenkins, Robert; Giannini, Caterina

    2017-02-09

    Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n=15), +2 (n=11), +5 (n=10), +21 (n=10), +20 (n=9), +12 (n=8), +15 (n=8) and losses -22 (n=11), -14 (n=7), -13 (n=5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (p=0.009) and 14 (p=0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (p=0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n=2), matched primary/tumor recurrence (n=7), or both (n=1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not

  4. Effect of single-chain antibody targeting of the ligand-binding domain in the anaplastic lymphoma kinase receptor

    PubMed Central

    Stylianou, DC; Auf der Maur, A; Kodack, DP; Henke, RT; Hohn, S; Toretsky, JA; Riegel, AT; Wellstein, A

    2013-01-01

    The tyrosine kinase receptor anaplastic lymphoma kinase (ALK) and its ligand, the growth factor pleiotrophin (PTN), are highly expressed during the development of the nervous system and have been implicated in the malignant progression of different tumor types. Here, we describe human single-chain variable fragment (scFv) antibodies that target the ligand-binding domain (LBD) in ALK and show the effect in vitro and in vivo. The ALK LBD was used as a bait in a yeast two-hybdrid system to select human scFv from a library with randomized complementarity-determining region 3 domains. Surface plasmon resonance showed high-affinity binding of the selected scFv. The anti-ALK scFv competed for binding of PTN to ALK in intact cells and inhibited PTN-dependent signal transduction through endogenous ALK. Invasion of an intact endothelial cell monolayer by U87MG human glioblastoma cells was inhibited by the anti-ALK scFv. In addition, the growth of established tumor xenografts in mice was reversed after the induction of the conditional expression of the anti-ALK scFv. In archival malignant brain tumors expression levels of ALK and PTN were found elevated and appear correlated with poor patient survival. This suggests a rate-limiting function of the PTN/ALK interaction that may be exploited therapeutically. PMID:19633684

  5. Allelic loss of 9p21.3 is a prognostic factor in 1p/19q codeleted anaplastic gliomas

    PubMed Central

    Alentorn, Agustí; Dehais, Caroline; Ducray, François; Carpentier, Catherine; Mokhtari, Karima; Figarella-Branger, Dominique; Chinot, Olivier; Cohen-Moyal, Elisabeth; Ramirez, Carole; Loiseau, Hugues; Elouahdani-Hamdi, Selma; Beauchesne, Patrick; Langlois, Olivier; Desenclos, Christine; Guillamo, Jean-Sébastien; Dam-Hieu, Phong; Ghiringhelli, François; Colin, Philippe; Godard, Joel; Parker, Fabrice; Dhermain, Frédéric; Carpentier, Antoine F.; Frenel, Jean-Sebastien; Menei, Philippe; Bauchet, Luc; Faillot, Thierry; Fesneau, Mélanie; Fontaine, Denys; Motuo-Fotso, Marie-Jeannette; Vauleon, Elodie; Gaultier, Claude; Le Guerinel, Caroline; Gueye, Edouard-Marcel; Noel, Georges; Desse, Nicolas; Durando, Xavier; Barrascout, Eduardo; Wager, Michel; Ricard, Damien; Carpiuc, Ioana; Delattre, Jean-Yves

    2015-01-01

    Objectives: We aimed to study the potential clinical relevance of 9p allelic loss, with or without copy number variation, in 1p/19q codeleted anaplastic oligodendroglial tumors (AOTs). Methods: This study enrolled 216 patients with 1p/19q codeleted AOT. The prognostic value of 9p allelic loss was investigated using a French nation-wide prospective registry, POLA (prise en charge des tumeurs oligodendrogliales anaplasiques) and high-density single nucleotide polymorphism arrays. We validated our results using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) dataset. Results: The minimal common region of allelic loss in chromosome arm 9p was 9p21.3. Allelic loss of 9p21.3, detected in 41.7% of tumors, was associated with shorter progression-free and overall survival rates in univariate (p = 0.008 and p < 0.001, respectively) and multivariate analyses (p = 0.009 and p = 0.009, respectively). This finding was validated in the REMBRANDT dataset in univariate and multivariate analysis (p = 0.01 and p = 0.01, respectively). Conclusion: Our study highlights a novel potential prognostic biomarker in 1p/19q codeleted AOT. Further prospective studies are warranted to investigate our finding. PMID:26385879

  6. Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

    PubMed

    Bielle, Franck; Ducray, François; Mokhtari, Karima; Dehais, Caroline; Adle-Biassette, Homa; Carpentier, Catherine; Chanut, Anaïs; Polivka, Marc; Poggioli, Sylvie; Rosenberg, Shai; Giry, Marine; Marie, Yannick; Duyckaerts, Charles; Sanson, Marc; Figarella-Branger, Dominique; Idbaih, Ahmed

    2016-08-20

    The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3(id) ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3(id) . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3(id) overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3(id) is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3(id) recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3(id) and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3(id) . A better understanding of spatial and temporal intratumor cell heterogeneity in O3(id) will open new therapeutic avenues overcoming resistance to current antitumor treatments.

  7. Poorly differentiated and anaplastic thyroid carcinomas: chromosomal and oligo-array profile of five new cell lines.

    PubMed

    Rodrigues, R F; Roque, L; Krug, T; Leite, V

    2007-04-23

    Information on gene alterations associated to poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) is scarce. Using human cancer cell lines as a tool for gene discovery, we performed a cytogenetic and oligo-array analysis in five new cell lines derived from two PDTC and three ATC. In PDTC we evidenced, as important, the involvement of the MAPK/ERK kinase pathway, and downregulation of a group of suppressor genes that include E-cadherin. In ATC, downregulation of a specific group of oncosuppressor genes was also observed. Our ATC cell lines presented chromosomal markers of gene amplification, and we were able to identify for the first time the nature of the involved amplicon target genes. We found that the main molecular differences between the two cell line types were related to signal transduction pathways, cell adhesion and motility process. TaqMan experiments performed for five amplicon target genes and for two genes, which allowed a clear distinction between ATC and PDTC: CDH13 and PLAU corroborated array results, not only in the cell lines, but also in an additional set of primary 14 PDTC and three ATC. We suggest that our findings may represent new tools for the development of more effective therapies to the hitherto untreatable ATC.

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

    SciTech Connect

    Shao, Mingchen; Geng, Yiwei; Lu, Peng; Xi, Ying; Wei, Sidong; Wang, Liuxing; Fan, Qingxia; Ma, Wang

    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.

  9. Dysphasia and Phantosmia as First Presentation of Multifocal Cerebral Anaplastic Astrocytomas: Case Report and Review of the Literatures

    PubMed Central

    Kong, Xiangyi; Wang, Yu; Liu, Shuai; Lu, Zhaohui; Wu, Huanwen; Mao, Xinxin; Cheng, Xin; Gao, Jun; Guan, Jian; Yang, Yi; Li, Yongning; Xing, Bing; Ma, Wenbin; Wang, Renzhi

    2015-01-01

    Abstract Multifocal cerebral gliomas (MCGs) represent approximately 10% of gliomas and are frequently mistaken as metastases of an unknown primary cancer site. Most MCGs are glioblastomas with <4 lesions supratentorially, and are lack of typical symptoms and special detections. Through a rare MCG case, we aim to present this rarity and emphasize the need to correctly diagnose multiple intracranial lesions using a variety of diagnostic modalities to ensure that the patient receives proper treatment. We present a case of multifocal cerebral anaplastic astrocytomas with a total of 8 lesions located in the left frontal lobe and invading the lateral ventricle, presenting with dysphasia and phantosmia. The disease course, including diagnosis and treatment, is presented and analyzed in detail. The pertinent literature is reviewed regarding this uncommon entity. After an initial impression of brain metastasis from lung cancer because of the magnetic resonance imaging (MRI) resemblance and history of chronic bronchitis, we were able to use positron emission tomography (PET) and excisional biopsy to get the final diagnosis. After 10 months, the patient's overall condition deteriorated and succumbed to his disease. MCGs are easy to be misdiagnosed as metastatic diseases. In addition to MRI, PET adds more biochemical and molecular information and is helpful in the differentiation. Although uncommon, if multiple lesions are present in various locations in the hemispheres, MCG should be kept in mind. PMID:25997068

  10. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3

    PubMed Central

    Kasprzycka, Monika; Marzec, Michal; Liu, Xiaobin; Zhang, Qian; Wasik, Mariusz A.

    2006-01-01

    The mechanisms of malignant cell transformation mediated by the oncogenic, chimeric nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) tyrosine kinase remain only partially understood. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells secrete IL-10 and TGF-β and express FoxP3, indicating their T regulatory (Treg) cell phenotype. The secreted IL-10 suppresses proliferation of normal immune, CD3/CD28-stimulated peripheral blood mononuclear cells and enhances viability of the ALK+TCL cells. The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells. NPM/ALK, in turn, induces the phenotype through activation of its key signal transmitter, signal transducer and activator of transcription 3 (STAT3). These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4+ T cells. These results also provide an additional rationale to therapeutically target the chimeric kinase and/or STAT3 in ALK+TCL. PMID:16766651

  11. miR-182 promotes tumor growth and increases chemoresistance of human anaplastic thyroid cancer by targeting tripartite motif 8

    PubMed Central

    Liu, Yao; Zhang, Bing; Shi, Tiefeng; Qin, Huadong

    2017-01-01

    Chemotherapy is one of the most effective forms of cancer treatment and has been used in the treatment of various malignant tumors. We have gained significant insight into the mechanisms of chemoresistance but the details of the molecular mechanisms remain unclear. In the present study, we found that tripartite motif 8 (TRIM8) expression was downregulated in anaplastic thyroid cancer (ATC) tissues and cell lines. This downregulation of TRIM8 was significantly correlated with the upregulation of miR-182 in human ATC tissues. Bioinformatic analysis and luciferase reporter assays identified TRIM8 as a direct target of miR-182 in ATC. A functional assay using an MTT assay and colony formation showed that miR-182 induced cellular growth by repressing TRIM8 expression. Additionally, overexpressed miR-182 contributed to the chemoresistance of ATC cells by the repression of TRIM8 expression. In conclusion, these results demonstrate that miR-182/TRIM8 may be a therapeutic target for the treatment of chemoresistant human thyroid papillary cancer. PMID:28280352

  12. Development of secondary anaplastic oligoastrocytoma after matched unrelated bone marrow transplantation in a child with acute myeloid leukemia.

    PubMed

    Panigrahi, Soumya; Das, Mayukh; Stagler, Dalia; Konstantini, Shlomi; Gmori, Moshe; Slavin, Shimon; Nagler, Arnon

    2003-01-01

    The growing incidences of secondary malignancies in long-term survivors of childhood leukemia following allogeneic bone marrow transplantation (alloBMT) are increasingly being reported. Among the late complications of conventional myeloablative alloBMT, the occurrence of secondary malignant solid tumors is of major concern. Secondary malignant and benign brain tumors such as astrocytoma, meningioma and glioblastoma have been described in long-term survivors of conventional myeloablative alloBMT. Here we report a case of secondary anaplastic oligoastrocytoma that developed 7 years after matched unrelated alloBMT for relapsing childhood acute myeloid leukemia (AML) with CNS involvement. Although isolated CNS relapse of primary leukemia following alloBMT is not uncommon, it is important to identify and define potential risk factors that may lead to the development of secondary brain tumors in children who received high-dose chemotherapy and irradiation prior to alloBMT presenting with progressive neurological symptoms and to differentiate them from leukemia relapse with CNS involvement.

  13. Occurrence of anaplastic oligodendroglioma in a patient with Williams syndrome: a case report with analysis of mutational profile of tumor.

    PubMed

    Omalu, B I; Nnebe-Agumadu, U H

    2009-06-01

    Williams syndrome is a rare congenital developmental disorder characterized by a constellation of distinctive facial dysmorphisms, mental retardation, cardiovascular anomalies, infantile hypercalcemia, delayed developmental milestones, dental and musculoskeletal anomalies and distinctive personality traits. A majority of patients with Williams syndrome exhibit a hemizygous micro-deletion of chromosome 7q11.23, which is the locus of some 20-30 genes including the ELN gene that encodes the structural protein elastin. Chromosome 7q contains putative tumor suppressor genes and is one of the chromosomes that are frequently involved in chromosomal aberrations in human malignancies. A paucity of tumors (three) has been reported in the literature to occur in patients with Williams syndrome. We report a case of anaplastic oligodendroglioma that occurred in a 31-year-old man with Williams syndrome. Mutational profiling by loss of heterozygosity analysis using a panel of polymorphic micro-satellite markers indicated combined deletion of chromosome 1p and 19q. We draw attention to this apparently rare or possibly under-reported occurrence of tumors in patients with Williams syndrome and suggest that Central Nervous System [CNS] tumors be considered as differential diagnoses in such patients when they present with unanticipated neurologic symptoms that are not attributable to those commonly associated with Williams syndrome.

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

    PubMed

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

    2001-03-01

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

  15. Analysis of clinical characteristics and prognosis of patients with anaplastic lymphoma kinase‐positive and surgically resected lung adenocarcinoma

    PubMed Central

    Tao, Hong; Cai, Yiran; Shi, Liang; Tang, Junfang; Liu, Zhidong; Wang, Zitong; Bai, Lianqi

    2016-01-01

    Background Recent research into lung cancer‐related driver genes has identified a distinctive molecular subtype of non‐small cell lung cancer (NSCLC) – anaplastic lymphoma kinase (ALK)‐positive NSCLC. We evaluated the clinical features and survival rates of ALK‐positive lung adenocarcinoma patients who had undergone surgery but had not received ALK inhibitor therapy, along with the characteristics of patients with distant metastases. Methods Clinical data of 40 patients with ALK‐positive, postsurgical lung adenocarcinoma were retrospectively analyzed. Relationships between the patients’ clinical characteristics, distant metastases, and their disease‐free survival (DFS) and overall survival (OS) rates were assessed. Results Most patients were relatively young, never‐smokers, had peripheral tumors, and the tumors were either moderately or poorly differentiated. The most common organ of distant metastases was the brain. The median time from surgery to brain metastasis was 17.2 months. The median OS following brain metastasis was 9.4 months. DFS in patients with early stage disease, peripheral tumors, no lymph node metastases, and treated with adjuvant therapy was significantly longer than for those with late stage disease (P = 0.015), central tumors (P = 0.000), lymph node metastases (P = 0.026), and not treated with adjuvant therapy (P = 0.000). Patients with early stage disease, peripheral tumors, and treated with adjuvant therapy obtained markedly longer OS than those with late stage disease (P = 0.021), central tumors (P = 0.003), and not treated with adjuvant therapy (P = 0.006). Conclusion Patients with ALK‐positive surgically resected lung adenocarcinoma have distinctive clinical characteristics. The brain is the most common site of extrapulmonary metastasis. Survival is associated with stage, tumor location, and the administration of adjuvant therapy. PMID:27779369

  16. Network analysis of microRNAs, transcription factors, target genes and host genes in human anaplastic astrocytoma

    PubMed Central

    XUE, LUCHEN; XU, ZHIWEN; WANG, KUNHAO; WANG, NING; ZHANG, XIAOXU; WANG, SHANG

    2016-01-01

    Numerous studies have investigated the roles played by various genes and microRNAs (miRNAs) in neoplasms, including anaplastic astrocytoma (AA). However, the specific regulatory mechanisms involving these genes and miRNAs remain unclear. In the present study, associated biological factors (miRNAs, transcription factors, target genes and host genes) from existing studies of human AA were combined methodically through the interactions between genes and miRNAs, as opposed to studying one or several. Three regulatory networks, including abnormally expressed, related and global networks were constructed with the aim of identifying significant gene and miRNA pathways. Each network is composed of three associations between miRNAs targeted at genes, transcription factors (TFs) regulating miRNAs and miRNAs located on their host genes. Among these, the abnormally expressed network, which involves the pathways of previously identified abnormally expressed genes and miRNAs, partially indicated the regulatory mechanism underlying AA. The network contains numerous abnormal regulation associations when AA emerges. By modifying the abnormally expressed network factors to a normal expression pattern, the faulty regulation may be corrected and tumorigenesis of AA may be prevented. Certain specific pathways are highlighted in AA, for example PTEN which is targeted by miR-21 and miR-106b, regulates miR-25 which in turn targets TP53. PTEN and miR-21 have been observed to form feedback loops. Furthermore, by comparing and analyzing the pathway predecessors and successors of abnormally expressed genes and miRNAs in three networks, similarities and differences of regulatory pathways may be identified and proposed. In summary, the present study aids in elucidating the occurrence, mechanism, prevention and treatment of AA. These results may aid further investigation into therapeutic approaches for this disease. PMID:27347075

  17. Antisense-miR-21 enhances differentiation/apoptosis and reduces cancer stemness state on anaplastic thyroid cancer.

    PubMed

    Haghpanah, Vahid; Fallah, Parviz; Tavakoli, Rezvan; Naderi, Mahmood; Samimi, Hilda; Soleimani, Masoud; Larijani, Bagher

    2016-01-01

    Anaplastic thyroid carcinoma (ATC) is the most aggressive malignancy in thyroid cancers. Resistance to current therapies is still a challenge. MicroRNAs are a class of small non-coding RNAs, regulating gene expression. MiR-21 is an oncomiR that is overexpressed in nearly all cancers including ATC. Accumulating evidence suggested that miR-21 has a role in cancer stemness state, apoptosis, cell cycle progression, and differentiation. Therefore, we evaluated the application of Off-miR-21 to sequester the microRNA for therapeutic purposes on ATC cell lines. In this study, C643 and SW1736 were transducted by hsa-miR-21 antagomir (Off-miR-21). PTEN gene expression was performed as a known target of miR-21. Stemness state in cancer stem cells (CSCs) was evaluated by the changes of CSC biomarkers including Oct-4 and ABCG2. Apoptosis was assessed by PDCD4 and Mcl-1 gene expression and flow cytometry. Sodium/iodide symporter (NIS) and thyroglobulin (TG) were measured as ATC differentiation markers. In addition, cell cycle progression was investigated via the alterations of p21 gene expression and flow cytometry. Specific downregulation of miR-21 induced the differentiation and apoptosis in C643 and SW1736. Inversely, the treatment inhibited stemness state and cell cycle progression. Knockdown of miR-21 significantly increased the expression of PDCD4, p21, NIS, and TG while leading to decreased expression of Oct-4, ABCG2, and Mcl-1.Taken together, the results suggest that miR-21, as an oncomiR, has a role not only in stemness state but also in tumor growth, differentiation, and apoptosis. Hence, suppression of miR-21 could pave the way for ATC therapy.

  18. The impact of concurrent temozolomide with adjuvant radiation and IDH mutation status among patients with anaplastic astrocytoma.

    PubMed

    Kizilbash, Sani H; Giannini, Caterina; Voss, Jesse S; Decker, Paul A; Jenkins, Robert B; Hardie, John; Laack, Nadia N; Parney, Ian F; Uhm, Joon H; Buckner, Jan C

    2014-10-01

    This study assesses the controversial role of temozolomide (TMZ) concurrent with adjuvant radiation (RT) in patients with anaplastic astrocytoma (AA). The impact of isocitrate dehydrogenase (IDH) status on therapy and outcomes is also examined. All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant RT were identified retrospectively for clinical data extraction. IDH status was determined by IDH1-R132H immunostain and sequencing for other mutations in IDH1/IDH2. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were fit for univariable/multivariable analyses. 136 patients had received concurrent TMZ while 29 had not. Of these, IDH status was determined on 114 and 27 patients, respectively. On univariable analysis, improved five-year survival was independently associated with concurrent TMZ (46.2 vs. 29.3%, p = 0.02) and IDH mutation (78.9 vs. 22.0%, p < 0.001). IDH mutation was additionally associated with a greater likelihood of extensive resection possibly secondary to a more favorable tumor location. Gross total/subtotal resections also led to improved survival when compared to biopsy alone on univariable analysis. On multivariable analysis, the association with five-year survival persisted for both concurrent TMZ and IDH mutation, but not with extent of surgery. Both IDH mutation and concurrent TMZ are associated with improved five-year survival in patients with AA who are receiving adjuvant RT. Secondarily, the association between five-year survival and extent of resection is lost on multivariable analysis. This suggests a possible association between IDH mutation, tumor location and consequent resectability.

  19. p21 participates in the regulation of anaplastic thyroid cancer cell proliferation by miR-146b

    PubMed Central

    Wang, Shiyang; Chen, Yangjing; Bai, Yanxia

    2016-01-01

    Anaplastic thyroid carcinoma (ATC) originates from completely undifferentiated cells, and is the most lethal type of thyroid-derived tumor. Numerous microRNAs have significant roles in tumorigenesis by targeting relevant genes. The role of microRNA 146b (miR-146b) in ATC remains to be elucidated. In order to characterize the role of miR-146b in ATC, overexpression or interference of miR-146b was induced in ATC cell lines, and cell proliferation and migration were evaluated. The potential targets of miR-146b were searched in the Gene Expression Omnibus database for ATC and matched non-tumor control samples. The expression level of potential targets was detected following overexpression or interference of miR-146b in ATC cell lines. In the present study, cell proliferation was promoted when overexpression of miR-146b was induced in ATC, and inhibited when interference of miR-146b was induced, which indicated that miR-146b affects the proliferation of ATC cells in vitro. In addition, cell migration of ATC was also affected by miR-146b. During the search for potential targets of miR-146b in ATC, p21 (also known as p21Waf1/Cip1 or CDKN1A) was noted for its role in cell cycle progression and tumor pathogenesis. The expression level of p21 was influenced by the level of miR-146b, and the results of the present study demonstrated that the level of p21 was increased when FRO cells were transformed with miR-146b mimic, and p21 was downregulated when FRO cells transformed with anti-miR-146b. In conclusion, p21 may participate in the regulation of ATC cell proliferation by miR-146b. PMID:27602131

  20. Identification of high versus lower risk clinical subgroups in a group of adult patients with supratentorial anaplastic astrocytomas.

    PubMed

    Decaestecker, C; Salmon, I; Camby, I; Dewitte, O; Pasteels, J L; Brotchi, J; Van Ham, P; Kiss, R

    1995-05-01

    The present work investigates whether computer-assisted techniques can contribute any significant information to the characterization of astrocytic tumor aggressiveness. Two complementary computer-assisted methods were used. The first method made use of the digital image analysis of Feulgen-stained nuclei, making it possible to compute 15 morphonuclear and 8 nuclear DNA content-related (ploidy level) parameters. The second method enabled the most discriminatory parameters to be determined. This second method is the Decision Tree technique, which forms part of the Supervised Learning Algorithms. These two techniques were applied to a series of 250 supratentorial astrocytic tumors of the adult. This series included 39 low-grade (astrocytomas, AST) and 211 high-grade (47 anaplastic astrocytomas, ANA, and 164 glioblastomas, GBM) astrocytic tumors. The results show that some AST, ANA and GBM did not fit within simple logical rules. These "complex" cases were labeled NC-AST, NC-ANA and NC-GBM because they were "non-classical" (NC) with respect to their cytological features. An analysis of survival data revealed that the patients with NC-GBM had the same survival period as patients with GBM. In sharp contrast, patients with ANA survived significantly longer than patients with NC-ANA. In fact, the patients with ANA had the same survival period as patients who died from AST, while the patients with NC-ANA had a survival period similar to those with GBM. All these data show that the computer-assisted techniques used in this study can actually provide the pathologist with significant information on the characterization of astrocytic tumor aggressiveness.

  1. 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

    SciTech Connect

    Gan, Gregory N.; Weickhardt, Andrew J.; Scheier, Benjamin; Doebele, Robert C.; Gaspar, Laurie E.; Kavanagh, Brian D.; Camidge, D. Ross

    2014-03-15

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

  2. Detection of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review.

    PubMed

    Yi, Eunhee S; Chung, Jin-Haeng; Kulig, Kimary; Kerr, Keith M

    2012-06-01

    Anaplastic lymphoma kinase (ALK) encodes a receptor tyrosine kinase, and ALK gene rearrangement (ALK+) is implicated in the oncogenesis of non-small cell lung carcinomas (NSCLCs), especially adenocarcinomas. The ALK inhibitor crizotinib was approved in August 2011 by the US Food and Drug Administration (FDA) for treating late-stage NSCLCs that are ALK+, with a companion fluorescent in situ hybridization (FISH) test using the Vysis ALK Break Apart FISH Probe Kit. This review covers pertinent issues in ALK testing, including approaches to select target patients for the test, pros and cons of different detection methods, and mechanisms as well as monitoring of acquired crizotinib resistance in ALK+ NSCLCs.

  3. AT-57LONG-TERM CLINICAL RESULTS OF EXTENSIVE TUMOR REMOVAL FOLLOWED BY ACNU-BASED CHEMORADIOTHERAPY FOR 147 ANAPLASTIC GLIOMAS

    PubMed Central

    Takayuki, Yasuda; Masayuki, Nitta; Takashi, Maruyama; Taichi, Saito; Satoko, Ikuta; Yoshikazu, Okada; Hiroshi, Iseki; Yoshihiro, Muragaki

    2014-01-01

    INTRODUCTION: Recent randomized trials showed that highly extent of resection (EOR) and PCV chemoradiotherapy had therapeutic long-term efficacy to anaplastic glioma (AG). From 2000, we have consistently enforced extensive removal and ACNU-based chemoradiotherapy for AG. We report retrospective clinical results of a single institution. METHODS: We reviewed 147 cases of primary AG between 2000 and 2011 (Male : Female = 94:53, average age; 43.9 year-old). 69 were anaplastic astrocytoma (41%), 43 were anaplastic oligoastrocytoma (29%), and 44 were anaplastic oligodendroglioma (30%). The intraoperative MRI was performed in 133 cases (90%), and awake surgery was performed in 58 cases (39%). Gross-total removal was 46 (31%), partial removal was 89 (61%), and biopsy was 12 (8%) (average; 83%, median; 95%). After resection, 60 Gy radiotherapy and ACNU or PAV chemotherapy were performed. The average Mib-1 index was 15%. The mean observation periods were 57 months and 95% follow-up rate. RESULTS: Overall survival (OS) wasn't reached median. The 3y-OS was 82%, 5y-OSs was 72%, and 10y-OS was 66%. There was no statistical significance among AA, AOA, AO (5y-OS; 64%, 79%, 77%). The each 5 years survival rate of gross-total resection, partial resection, and biopsy were 83%, 70%, 39%, and there was statistical significance (P = 0.0024). Extent of resection (EOR) correlated OS in AA (P = 0.02) but not in oligodendroglial subtypes (P = 0.6). Statistical significant factors were EOR (P = 0.0024) and Mib-1 index (P = 0.013). The significant factors in multi variable analysis were EOR (more than 95% or not, HR 2.5) and Mib-1 index (more than 13% or not, HR 2.3). The median PFS was 8.3, and 5y-PFS was 59%,and 10y-PFS was 45%. CONCLUSION: Our long-term clinical results of AG treated with extensive resection and ACNU-based chemoradiotherapy were better than previous reports. The EOR contributed better prognosis especially for AA.

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

    PubMed

    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.

  5. “Drop” Metastases from an Operated Case of Intracranial Anaplastic Ependymoma Identified on Fluoro-2-deoxyglucose Positron Emission Tomography/Computed Tomography

    PubMed Central

    Chandra, Piyush; Purandare, Nilendu; Shah, Sneha; Agrawal, Archi; Rangarajan, Venkatesh

    2017-01-01

    The seeding of tumor through cerebrospinal fluid (CSF) from primary intracranial tumors is very rare, often goes undetected, and is usually identified only on autopsy. CSF cytology along with magnetic resonance imaging constitutes the standard approach of diagnosing this grave condition. Use of fluoro-2-deoxyglucose positron emission tomography/computed tomography (PET/CT) in indentifying spinal metastases from primary intracranial malignancies is very limited and has been reported in patients with metastatic glioblastoma multiforme and medulloblastomas. We present a rare case of metastatic anaplastic ependymoma to show the potentially clinically utility of PET/CT in diagnosing leptomeningeal or the so-called “drop” metastases. PMID:28242994

  6. Intracoelomic anaplastic sarcoma in an intersex Madagascar tree boa (Sanzinia madagascariensis).

    PubMed

    Sharpe, Sam; Lamm, Catherine G; Killick, Rowena

    2013-01-01

    An adult Madagascar tree boa (Sanzinia madagascariensis) underwent coeliotomy for investigation of a coelomic mass. At surgery, a large mass originating from the peri-pancreatic adipose tissue and involving the gall bladder was removed. The snake did not recover from general anesthesia. A complete postmortem was performed, and samples were submitted to the University of Glasgow for histopathology. On histological examination, the mass was composed of adipose tissue infiltrated with a poorly demarcated spindle cell neoplasm. The neoplastic cells were highly pleomorphic with abundant cytoplasm and frequent clear cytoplasmic vacuoles, suggestive of adipocyte origin. Immunohistochemical characterization of the mass was inconclusive. Metastatic neoplastic cells were present within vessels in the liver, lungs, and brain. As an incidental finding, the gonads contained both maturing ovarian follicles and seminiferous tubules with intact germinal epithelium and evidence of spermatogenesis, along with other features of male and female gonad anatomy. The current report describes a rare neoplasm in snakes within an intersex Madagascar tree boa.

  7. Anaplastic astrocytoma: prognostic factors and survival in 4807 patients with emphasis on receipt and impact of adjuvant therapy.

    PubMed

    Shin, Jacob Y; Diaz, Aidnag Z

    2016-09-01

    To determine the receipt and impact of adjuvant therapy on overall survival (OS) for anaplastic astrocytoma (AA). Data were extracted from the National Cancer Data Base (NCDB). Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 4807 patients with AA diagnosed from 2004 to 2013 who underwent surgery were identified. 3243 (67.5 %) received adjuvant chemoRT, 525 (10.9 %) adjuvant radiotherapy (RT) alone, 176 (3.7 %) adjuvant chemotherapy alone and 863 (18.0 %) received no adjuvant therapy. Patients were more likely to receive adjuvant chemoRT if they were diagnosed in 2009-2013 (p = 0.022), were ≤ 50 years (p < 0.001), were male (p = 0.043), were Asian or White race (p < 0.001), had private insurance (p < 0.001), had income ≥$38,000 (p < 0.001), or underwent total resection (p < 0.003). Those who received adjuvant chemoRT had significantly better 5-year OS than the other adjuvant treatment types (41.8 % vs. 31.2 % vs. 29.8 % vs. 27.4 %, p < 0.001). This significant 5-year OS benefit was also observed regardless of age at diagnosis. Of those undergoing adjuvant chemoRT, those receiving ≥59.4 Gy had significantly better 5-year OS than those receiving <59.4 Gy (44.4 % vs. 25.9 %, p < 0.001). There was no significant difference in OS when comparing 59.4 Gy to higher RT doses. On multivariate analysis, receipt of adjuvant chemoRT, age at diagnosis, extent of disease, and insurance status were independent prognostic factors for OS. Adjuvant chemoRT is an independent prognostic factor for improved OS in AA and concomitant chemoRT should be considered for all clinically suitable patients who have undergone surgery for the disease.

  8. Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

    PubMed Central

    Mukai, Mayumi; Takahashi, Keiko; Hayashi, Yuzo; Nakachi, Kei; Kusunoki, Yoichiro

    2012-01-01

    Background We previously noted that among atomic bomb survivors (ABS), the relative frequency of cases of adult papillary thyroid cancer (PTC) with chromosomal rearrangements (mainly RET/PTC) was significantly greater in those with relatively higher radiation exposure than those with lower radiation exposure. In contrast, the frequency of PTC cases with point mutations (mainly BRAFV600E) was significantly lower in patients with relatively higher radiation exposure than those with lower radiation exposure. We also found that among ABS, the frequency of PTC cases with no detectable gene alterations in RET, neurotrophic tyrosine kinase receptor 1 (NTRK1), BRAF, or RAS was significantly higher in patients with relatively higher radiation exposure than those with lower radiation exposure. However, in ABS with PTC, the relationship between the presence of the anaplastic lymphoma kinase (ALK) gene fused with other gene partners and radiation exposure has received little study. In this study, we tested the hypothesis that the relative frequency of rearranged ALK in ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, would be greater in those having relatively higher radiation exposures. Methods The 105 subjects in the study were drawn from the Life Span Study cohort of ABS of Hiroshima and Nagasaki who were diagnosed with PTC between 1956 and 1993. Seventy-nine were exposed (>0 mGy), and 26 were not exposed to A-bomb radiation. In the 25 ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, we examined archival, formalin-fixed, paraffin-embedded PTC specimens for rearrangement of ALK using reverse transcription–polymerase chain reaction and 5′ rapid amplification of cDNA ends (5′ RACE). Results We found rearranged ALK in 10 of 19 radiation-exposed PTC cases, but none among 6 patients with PTC with no radiation exposure. In addition, solid/trabecular-like architecture in PTC was closely associated with ALK

  9. Immunocytochemical analysis of glucose transporter protein-1 (GLUT-1) in typical, brain invasive, atypical and anaplastic meningioma.

    PubMed

    van de Nes, Johannes A P; Griewank, Klaus G; Schmid, Kurt-Werner; Grabellus, Florian

    2015-02-01

    Glucose transporter-1 (GLUT-1) is one of the major isoforms of the family of glucose transporter proteins that facilitates the import of glucose in human cells to fuel anaerobic metabolism. The present study was meant to determine the extent of the anaerobic/hypoxic state of the intratumoral microenvironment by staining for GLUT-1 in intracranial non-embolized typical (WHO grade I; n = 40), brain invasive and atypical (each WHO grade II; n = 38) and anaplastic meningiomas (WHO grade III, n = 6). In addition, GLUT-1 staining levels were compared with the various histological criteria used for diagnosing WHO grade II and III meningiomas, namely, brain invasion, increased mitotic activity and atypical cytoarchitectural change, defined by the presence of at least three out of hypercellularity, sheet-like growth, prominent nucleoli, small cell change and "spontaneous" necrosis. The level of tumor hypoxia was assessed by converting the extent and intensity of the stainings by multiplication in an immunoreactive score (IRS) and statistically evaluated. The results were as follows. (1) While GLUT-1 expression was found to be mainly weak in WHO grade I meningiomas (IRS = 1-4) and to be consistently strong in WHO grade III meningiomas (IRS = 6-12), in WHO grade II meningiomas GLUT-1 expression was variable (IRS = 1-9). (2) Histologically typical, but brain invasive meningiomas (WHO grade II) showed no or similarly low levels of GLUT-1 expression as observed in WHO grade I meningiomas (IRS = 0-4). (3) GLUT-1 expression was observed in the form of a patchy, multifocal staining reaction in 76% of stained WHO grade I-III meningiomas, while diffuse staining (in 11%) and combined multifocal and areas of diffuse staining (in 13%) were only detected in WHO grades II and III meningiomas, except for uniform staining in angiomatous WHO grade I meningioma. (4) "Spontaneous" necrosis and small cell change typically occurred away from the intratumoral capillary

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

    PubMed

    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.

  11. Extranodal NK/T-cell lymphoma, nasal type, arising in association with saline breast implant: expanding the spectrum of breast implant-associated lymphomas.

    PubMed

    Aladily, Tariq N; Nathwani, Bharat N; Miranda, Roberto N; Kansal, Rina; Yin, C Cameron; Protzel, Richard; Takowsky, Gary S; Medeiros, L Jeffrey

    2012-11-01

    Extranodal NK/T-cell lymphoma, nasal type, is a rare type of non-Hodgkin lymphoma that is most common in Asia and is driven by Epstein-Barr virus infection. These tumors usually arise in the nasal region; in rare cases they can involve extranasal sites, most often skin, with involvement of the breast being rare. Lymphomas arising adjacent to breast implants are rare, and most cases reported to date have been anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Here we report a 41-year-old white woman with bilateral saline breast implants placed for cosmetic reasons who almost 9 years later developed painful swelling at the right-breast implant site. Excisional biopsy revealed lymphoma composed of monomorphic large cells associated with necrosis and angioinvasion. Immunohistochemical analysis showed an aberrant, NK/T-cell immunophenotype with the lymphoma cells being CD2+, CD3+, CD56+, partial CD30+, granzyme B, TIA-1+, CD4+, CD5+, CD7+, and CD8+. In situ hybridization analysis showed Epstein-Barr virus-encoded RNA within the neoplastic cells. Polymerase chain reaction analysis showed monoclonal T-cell receptor-γ chain gene rearrangement. These findings support the diagnosis of extranodal NK/T-cell lymphoma, nasal type. On the basis of our review of the literature, this case is unique. In addition, we believe this case is important to report, because it expands the spectrum of T-cell lymphomas that can be associated with breast implants and may be a forerunner of additional cases to follow.

  12. Neoadjuvant cisplatin plus temozolomide versus standard treatment in patients with unresectable glioblastoma or anaplastic astrocytoma: a differential effect of MGMT methylation.

    PubMed

    Capdevila, Laia; Cros, Sara; Ramirez, Jose-Luis; Sanz, Carolina; Carrato, Cristina; Romeo, Margarita; Etxaniz, Olatz; Hostalot, Cristina; Massuet, Ana; Cuadra, Jose Luis; Villà, Salvador; Balañà, Carmen

    2014-03-01

    Patients with unresectable glioblastoma or anaplastic astrocytoma have a dismal prognosis. The role of neoadjuvant chemotherapy prior to irradiation in these patients has been studied primarily in non-randomized studies. We have compared the effect of neoadjuvant chemotherapy plus radiotherapy versus concomitant radiotherapy plus temozolomide in a retrospective analysis of two consecutive series of patients in whom surgery consisted of biopsy only. From 2003 to 2005, 23 patients received two cycles of temozolomide plus cisplatin followed by radiotherapy (Cohort 1), and from 2006 to 2010, 23 additional patients received concomitant radiotherapy and temozolomide followed by adjuvant temozolomide (Cohort 2). In Cohort 1, 91.3 % of patients received all planned chemotherapy cycles. Progression-free and overall survival were 3.3 and 8.5 months, respectively. In Cohort 2, progression-free and overall survival were 5.1 and 11.2 months, respectively. No differences between the two groups were observed in rate of completion of radiotherapy, progression-free or overall survival. MGMT methylation was assessed in 91.3 % of patients. In Cohort 1, patients without MGMT methylation showed a trend towards shorter progression-free survival (P = 0.09), while in Cohort 2, patients without MGMT methylation had longer progression-free survival (P = 0.04). In the overall patient population, neoadjuvant temozolomide plus cisplatin had neither a positive nor negative influence on outcome. However, our findings indicate that patients with methylated MGMT may derive greater benefit from neoadjuvant temozolomide than those with unmethylated MGMT.

  13. In contrast to agonist monoclonal antibodies, both C-terminal truncated form and full length form of Pleiotrophin failed to activate vertebrate ALK (anaplastic lymphoma kinase)?

    PubMed

    Mathivet, Thomas; Mazot, Pierre; Vigny, Marc

    2007-12-01

    Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase essentially and transiently expressed during development in specific regions of the central and peripheral nervous system. ALK expression persists at a lower level in the adult brain. Thus, it might play an important role in both the normal development and function of the nervous system. The nature of the cognate ligand of this receptor in vertebrates is still a matter of debate. Pleiotrophin and midkine have been proposed as ligands of ALK but several independent studies do not confirm this hypothesis. Interestingly, a recent study proposed that a C-terminal truncated form of Pleiotrophin (Pleiotrophin.15) and not the full length form (Pleiotrophin.18) promotes glioblastoma proliferation in an ALK-dependent fashion. These data were obviously a strong basis to conciliate the conflicting results so far reported in the literature. In the present study, we first purified to homogeneity the two forms of Pleiotrophin secreted by HEK 293 cells. In contrast to agonist monoclonal antibodies, both Pleiotrophin.15 and Pleiotrophin.18 failed to activate ALK in neuroblastoma and glioblastoma cells expressing this receptor. Thus, for our point of view, ALK is still an orphan receptor in vertebrates.

  14. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

    PubMed Central

    Pugliese, Mariateresa; Gallo, Marco; Brignardello, Enrico; Milla, Paola; Orlandi, Fabio; Limone, Paolo Piero; Arvat, Emanuela; Boccuzzi, Giuseppe; Piovesan, Alessandro

    2016-01-01

    Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. PMID:27766105

  15. An interaction map of small-molecule kinase inhibitors with anaplastic lymphoma kinase (ALK) mutants in ALK-positive non-small cell lung cancer.

    PubMed

    Ai, Xinghao; Shen, Shengping; Shen, Lan; Lu, Shun

    2015-05-01

    Human anaplastic lymphoma kinase (ALK) has become a well-established target for the treatment of ALK-positive non-small cell lung cancer (NSCLC). Here, we have profiled seven small-molecule inhibitors, including 2 that are approved drugs, against a panel of clinically relevant mutations in ALK tyrosine kinase (TK) domain, aiming at a comprehensive understanding of molecular mechanism and biological implication underlying inhibitor response to ALK TK mutation. We find that (i) the gatekeeper mutation L1196M causes crizotinib resistance by simultaneously increasing and decreasing the binding affinities of, respectively, ATP and inhibitor to ALK, whereas the secondary mutation C1156Y, which is located far away from the ATP-binding site of ALK TK domain, causes the resistance by inducing marked allosteric effect on the site, (ii) the 2nd and 3rd generation kinase inhibitors exhibit relatively high sensitivity towards ALK mutants as compared to 1st generation inhibitors, (iii) the pan-kinase inhibitor staurosporine is insensitive for most mutations due to its high structural compatibility, and (iv) ATP affinity to ALK is generally reduced upon most clinically relevant mutations. Furthermore, we also identify six novel mutation-inhibitor pairs that are potentially associated with drug resistance. In addition, the G1202R and C1156Y mutations are expected to generally cause resistance for many existing inhibitors, since they can address significant effect on the geometric shape and physicochemical property of ALK active pocket.

  16. U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive.

    PubMed

    Malik, Shakun M; Maher, Virginia Ellen; Bijwaard, Karen E; Becker, Robert L; Zhang, Lijun; Tang, Shenghui W; Song, Pengfei; Liu, Qi; Marathe, Anshu; Gehrke, Brenda; Helms, Whitney; Hanner, Diane; Justice, Robert; Pazdur, Richard

    2014-04-15

    On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%-70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%-59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen.

  17. Involvement of cysteine-rich protein 61 in the epidermal growth factor-induced migration of human anaplastic thyroid cancer cells.

    PubMed

    Chin, Li-Han; Hsu, Sung-Po; Zhong, Wen-Bin; Liang, Yu-Chih

    2016-05-01

    Anaplastic thyroid cancer (ATC) is among the most aggressive types of malignant cancer. Epidermal growth factor (EGF) plays a crucial role in the pathogenesis of ATC, and patients with thyroid carcinoma typically exhibit increased cysteine-rich protein 61 (Cyr61). In this study, we found that EGF treatment induced cell migration, stress fiber formation, Cyr61 mRNA and protein expressions, and Cyr61 protein secretion in ATC cells. The recombinant Cyr61 protein significantly induced cell migration; however, inhibition of Cyr61 activity by a Cyr61-specific antibody abrogated EGF-induced cell migration. EGF treatment also affected epithelial-to-mesenchymal transition (EMT)-related marker protein expression, as evidenced by an increase in vimentin and a decrease in E-cadherin expression. Inhibition of Cyr61 expression by Cyr61 siRNA decreased cell migration and reversed the EMT-related marker protein expression. EGF treatment increased the phosphorylation of the extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), and finally activated Cyr61 promoter plasmid activity. Our results suggest that Cyr61 is induced by EGF through the ERK/CREB signal pathway and that it plays a crucial role in the migration and invasion of ATC cells; moreover, Cyr61 might be a therapeutic target for metastatic ATC.

  18. Diagnosis of anaplastic lymphoma kinase rearrangement in cytological samples through a fluorescence in situ hybridization-based assay: Cytological smears versus cell blocks.

    PubMed

    Zito Marino, Federica; Rossi, Giulio; Brunelli, Matteo; Malzone, Maria Gabriella; Liguori, Giuseppina; Bogina, Giuseppe; Morabito, Alessandro; Rocco, Gaetano; Franco, Renato; Botti, Gerardo

    2017-02-14

    Anaplastic lymphoma kinase (ALK) status analysis of lung cytological specimens should be successfully encouraged in routine practice because biopsy specimens are not always available. To date, the US Food and Drug Administration has approved both fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) as diagnostic tests for identifying ALK-positive patients eligible for treatment with crizotinib. Although ALK IHC is an optimal diagnostic tool, FISH becomes mandatory in equivocal cases. ALK FISH of paraffin-embedded tissue material is still the gold standard, whereas the cytological specimen assay has not yet been completely standardized. Many controversial data have been reported on the adequacy of cytology cell blocks (CBs) versus conventional smears for FISH testing. This review discusses some critical issues related to ALK FISH of cytological samples, including the triaging of collected specimens to optimize the material, the use of CBs versus conventional smears, and alternative methods for an ALK rearrangement diagnosis. Conventional smears have the advantages of an immediate evaluation, no probe tissue-related artifactual loss, no fixation-related alterations, and usually sufficient material for an analytic preparation. On the other hand, CBs have several advantages, including the appropriate conservation of the tissue architecture, an absence of problems related to cell overlapping, and the ability to evaluate neoplastic cells in a dark field. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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

    PubMed Central

    Carina, Valeria; Tomasello, Laura; Pitrone, Maria; Baiamonte, Concetta; Amato, Marco Calogero

    2015-01-01

    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. PMID:25705224

  20. Alectinib-Induced Erythema Multiforme and Successful Rechallenge with Alectinib in a Patient with Anaplastic Lymphoma Kinase-Rearranged Lung Cancer

    PubMed Central

    Kimura, Tatsuo; Sowa-Osako, Junko; Nakai, Toshiyuki; Ohyama, Ayako; Kawaguchi, Tomoya; Tsuruta, Daisuke; Ohsawa, Masahiko; Hirata, Kazuto

    2016-01-01

    Background Alectinib is an oral drug developed for the treatment of patients with fusion gene encoding echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged non-small cell lung cancer (NSCLC). Here, we present the case of a patient treated with alectinib who developed a hypersensitivity reaction with successful rechallenge treatment. Case Presentation A 39-year-old woman who was a passive smoker was referred to Osaka City University Hospital for the evaluation of a skin event caused by treatment for NSCLC with the fusion gene EML4-ALK. The skin reaction was observed on the anterior chest, upper arms, and ear auricles on day 11 of treatment with oral alectinib. The skin event presented as widely distributed erythematous macules that were confluent, indicating a severe and life-threatening form. The skin lesions started to resolve after the initiation of treatment with 40 mg prednisolone. After regrowth of the tumor, she received a rechallenge program for alectinib for 2 weeks; thereafter, alectinib treatment was successfully reinitiated. Conclusion To the best of our knowledge, we present the first case in which alectinib, which binds to the adenosine triphosphate site of EML4-ALK, induced erythema multiforme. Moreover, successful readministration of alectinib through our rechallenge program has not been reported so far. PMID:28101031

  1. Inhibition of p21 and Akt potentiates SU6656-induced caspase-independent cell death in FRO anaplastic thyroid carcinoma cells.

    PubMed

    Kim, S H; Kang, J G; Kim, C S; Ihm, S-H; Choi, M G; Yoo, H J; Lee, S J

    2013-06-01

    SU6656 is a small-molecule indolinone that selectively inhibits Src family kinase and induces death of cancer cells. The aim of the present study was to investigate the influence of SU6656 on cell survival and to assess the role of p21 and PI3K/Akt signaling in cell survival resulting from SU6656 treatment in anaplastic thyroid carcinoma (ATC) cells. When 8505C, CAL62, and FRO ATC cells were treated with SU6656, the viability of 8505C and CAL62 ATC cells decreased only after treatment with SU6656 at a dosage of 100 μM for 72 h, while the viability of FRO ATC cells decreased after treatment with SU6656 in a concentration- and time-dependent manner. Cell viability was not changed by pretreatment with the broad-spectrum caspase inhibitor z-VAD-fmk. Phospho-Src protein levels were reduced, and p21 protein levels were elevated. Phospho-ERK1/2 protein levels were multiplied without alteration of total ERK1/2, total Akt, and phospho-Akt protein levels. Regarding FRO ATC cells, the decrement of cell viability, the increment of cleaved PARP-1 protein levels, and the decrement of phospho-Src protein levels were shown in p21 siRNA- or LY294002-pretreated cells compared to SU6656-treated control cells. ERK1/2 siRNA transfection did not affect cell viability and protein levels of cleaved PARP-1, p21, and Akt. In conclusion, these results suggest that SU6656 induces caspase-independent death of FRO ATC cells by overcoming the resistance mechanism involving p21 and Akt. Suppression of p21 and Akt enhances the cytotoxic effect of SU6656 in FRO ATC cells.

  2. Anaplastic lymphoma kinase (ALK 1) staining and molecular analysis in inflammatory myofibroblastic tumours of the bladder: a preliminary clinicopathological study of nine cases and review of the literature.

    PubMed

    Freeman, Alex; Geddes, Nicola; Munson, Philippa; Joseph, Jean; Ramani, Pramila; Sandison, Ann; Fisher, Cyril; Parkinson, M Connie

    2004-07-01

    Inflammatory myofibroblastic tumours (IMFT) may arise at any anatomical site, including lung, soft tissues, retroperitoneum and bladder. Although morphologically similar, these lesions encompass a spectrum of entities with differing aetiology, ranging from reactive/regenerative proliferations to low-grade neoplasms with a risk of local recurrence, but no significant metastatic potential. Vesical IMFT usually presents as a polypoid mass with a pale firm cut surface and can be of considerable size, mimicking a malignant tumour clinically and radiologically. Its good outcome, however, warrants conservative surgical excision, emphasising the importance of identification and distinction from malignant tumours of the bladder that may require more radical surgery and/or adjuvant therapy. We conducted a preliminary retrospective, comparative immunocytochemical study of 20 bladder tumours, including nine IMFTs, five spindle cell (sarcomatoid) carcinomas, two rhabdomyosarcomas, two leiomyosarcomas and two neurofibromas. The results confirmed IMFT positivity for smooth muscle actin, desmin and cytokeratin in 78-89% cases, resulting in potential confusion with sarcomatoid carcinoma or leiomyosarcoma. In contrast, cytoplasmic anaplastic lymphoma kinase (ALK 1) staining was present in eight IMFT (89%), but was not seen in any other lesion examined. The ALK 1 staining was confirmed by fluorescence in situ hybridisation, with translocation of the ALK gene present in 15-60% tumour cells in four of six IMFT examined, but not in four cases of sarcomatoid carcinoma or three of leiomyosarcoma. In conclusion, ALK 1 staining may be of value in the distinction of vesical IMFT from morphologically similar entities, and often reflects ALK gene translocations in these lesions.

  3. Cognition and Quality of Life After Chemotherapy Plus Radiotherapy (RT) vs. RT for Pure and Mixed Anaplastic Oligodendrogliomas: Radiation Therapy Oncology Group Trial 9402

    SciTech Connect

    Wang Meihua; Cairncross, Gregory; Shaw, Edward

    2010-07-01

    Purpose: Radiation Therapy Oncology Group 9402 compared procarbazine, lomustine, and vincristine (PCV) chemotherapy plus radiation therapy (PCV + RT) vs. RT alone for anaplastic oligodendroglioma. Here we report longitudinal changes in cognition and quality of life, effects of patient factors and treatments on cognition, quality of life and survival, and prognostic implications of cognition and quality of life. Methods and Materials: Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL). Scores were analyzed for survivors and within 5 years of death. Shared parameter models evaluated MMSE/B-QOL with survival. Results: For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those who died, MMSE scores remained stable initially, whereas B-QOL slowly declined; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (p = 0.0413 for MMSE; p = 0.0016 for B-QOL) and were superior with age <50 years (p < 0.001 for MMSE; p = 0.0554 for B-QOL) and Karnofsky Performance Score (KPS) 80-100 (p < 0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV + RT (HR = 0.66, 95% CI = 0.49-0.9, p = 0.0084; HR = 0.74, 95% CI = 0.54-1.01, p = 0.0592) in models with MMSE and B-QOL. In addition, there were no differences in MMSE and B-QOL scores between arms (p = 0.4752 and p = 0.2767, respectively); higher scores predicted longer survival. Conclusion: MMSE and B-QOL scores held steady in the upper range in both arms for survivors. Younger, fitter patients had better MMSE and B-QOL and longer survival.

  4. Mitotic index, microvascular proliferation, and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations

    PubMed Central

    Figarella-Branger, Dominique; Mokhtari, Karima; Dehais, Caroline; Jouvet, Anne; Uro-Coste, Emmanuelle; Colin, Carole; Carpentier, Catherine; Forest, Fabien; Maurage, Claude-Alain; Vignaud, Jean-Michel; Polivka, Marc; Lechapt-Zalcman, Emmanuelle; Eimer, Sandrine; Viennet, Gabriel; Quintin-Roué, Isabelle; Aubriot-Lorton, Marie-Hélène; Diebold, Marie-Danièle; Loussouarn, Delphine; Lacroix, Catherine; Rigau, Valérie; Laquerrière, Annie; Vandenbos, Fanny; Michalak, Sophie; Sevestre, Henri; Peoch, Michel; Labrousse, François; Christov, Christo; Kemeny, Jean-Louis; Chenard, Marie-Pierre; Chiforeanu, Danchristian; Ducray, François; Idbaih, Ahmed; Desenclos, Christine; Menei, Philippe; Al Nader, Edmond; Godard, Joel; Servagi-Vernat, Stéphanie; Carpentier, Antoine; Loiseau, Hugues; Dam-Hieu, Phong; Guillamo, Jean Sebastien; Emery, Evelyne; Verelle, Pierre; Durando, Xavier; Faillot, Thierry; Le Guerinel, Caroline; Ghiringhelli, François; Parker, Fabrice; Adam, Clovis; Dubois, François; Ramirez, Carole; Gueye, Edouard Marcel; Honnorat, Jerome; Chinot, Olivier; Bauchet, Luc; Beauchesne, Patrick; Campone, Mario; Frenel, Jean Sébastien; Fontaine, Denys; Campello, Chantal; Roger, Pascal; Heitzmann, Anne; Fesneau, Mélanie; Delattre, Jean Yves; Elouadhani-Hamdi, Selma; Ricard, Damien; Colin, Philippe; Vauléon, Elodie; Langlois, Olivier; Fotso, Marie Janette Motsuo; Andraud, Marie; Mouton, Servane; Noel, Georges; Desse, Nicolas; Soulard, Raoulin; Cohen-Moyal, Elisabeth; Lubrano, Vincent; Dhermain, Frederic

    2014-01-01

    Background The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AOs). Methods The histological characteristics of 203 AO patients, enrolled in the French national network POLA, were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. Results 1p/19q codeletion was present in 79% of cases and was associated with alpha-internexin expression (P < 10−4), IDH1/2 mutation (P < 10−4), chromosome 4 loss (P < 10−3), and better overall survival (P < 10−4). Based on mitotic index, microvascular proliferation (MVP), and necrosis, 3 groups of 1p/19q codeleted AOs were identified: (group 1) AO with more than 5 mitoses per 10-HPF, no MVP, and no necrosis; (group 2) AO with MVP and no necrosis; and (group 3) AO with MVP and necrosis. Compared with group 1, groups 2 and 3 AOs had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared with group 2, group 3 AOs had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q codeleted AOs, chromosomal instability was associated with shorter progression-free survival (P = .024) and shorter overall survival (P = .023). Conclusions The present study shows that oligodendrogliomas with classic histological features remain a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q codeleted AOs are also heterogeneous. Interestingly, mitotic index, MVP, and necrosis help to classify them into 3 groups associated with distinct genomic alterations. PMID:24723566

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

    SciTech Connect

    Combs, Stephanie E.; Schulz-Ertner, Daniela; Debus, Juergen; Deimling, Andreas von; Hartmann, Christian

    2011-12-01

    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

  6. Effect of Slug-Mediated Down-Regulation of E-Cadherin on Invasiveness and Metastasis of Anaplastic Thyroid Cancer Cells

    PubMed Central

    Sheng, Li; Zhang, Shanjuan; Xu, Hui

    2017-01-01

    Background Slug has been found to promote migration and invasion of many cancer cells, including anaplastic thyroid cancer (ATC). Thus, targeting Slug expression could provide new approaches for the treatment of patients with ATC. Material/Methods Small interfering RNA (siRNA) targeting Slug (Slug siRNA) was used to construct clonal derivatives in the metastatic ATC SW1736 cells. Slug cDNA transfection was used to restore the Slug expression in the Slug siRNA-transfected SW1736 cells (Slug siRNA/SW1736). E-cadherin siRNA was used to inhibit E-cadherin expression in the Slug siRNA/SW1736 cells. The SW1736 cell migration, invasion, and signaling pathway was analyzed in vitro. Furthermore, the stable Slug siRNA-transfected SW1736 clones were used for the lung metastasis assay in an in vivo mouse model. Results Targeting Slug expression in SW1736 cells showed a 45% decrease in migration and an 85% decrease in invasiveness in vitro. Knockdown of E-cadherin by E-cadherin siRNA transfection or Slug overexpression by Slug cDNA transfection restored the invasive and migrative ability in SW1736 cells. In addition, we found an 80% decrease in the number of macroscopic lung metastases nodes of mice by in vivo analysis. Western blot assay showed that Slug expression was inhibited and E-cadherin expression was increased in the Slug siRNA-transfected tumors. Conclusions Targeting Slug signaling pathway is effective in preventing lung metastasis in ATC. PMID:28070118

  7. Significant cytostatic effect of everolimus on a gefitinib-resistant anaplastic thyroid cancer cell line harboring PI3KCA gene mutation

    PubMed Central

    ONODA, NAOYOSHI; NAKAMURA, MASANORI; AOMATSU, NAOKI; NODA, SATORU; KASHIWAGI, SHINICHIRO; KURATA, KENTO; UCHINO, SHINYA; HIRAKAWA, KOSEI

    2015-01-01

    We previously demonstrated the efficacy of gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), on an anaplastic thyroid cancer (ATC) cell line. We also observed that gefitinib was not effective in regulating cell growth in a different ATC cell line that exhibited an altered EGFR-initiated signal transduction pathway. In the present study, we attempted to regulate the downstream effector of EGFR-Akt-mammalian target of rapamycin (mTOR) pathway by an mTOR inhibitor, everolimus. A total of 8 ATC cell lines were employed, 7 of which were established in our institute. OCUT-2 was known to carry a mutation in the phosphoinositide-3-kinase, catalytic, α polypeptide gene (PI3KCA) and to be gefitinib-resistant, whereas ACT-1 exhibited a remarkable growth arrest by gefitinib. All the cell lines were tested for the cytotoxic effect of everolimus. The mechanisms of cellular toxicity were investigated by EGFR stimulation, cell cycle and concurrent exposure to paclitaxel. In OCUT-2, but not in any of the other cell lines, everolimus achieved a significant growth inhibition (inhibition of 30 and 50% was achieved by concentrations of 0.8 and 5 nM, respectively). The growth in OCUT-2 was inhibited by everolimus, even with concordant EGFR stimulation. This effect was demonstrated by a G2M cell cycle arrest. An additive effect of everolimus onto the cytotoxic effect of paclitaxel was demonstrated at a dose of 1–2 nM. A significant growth inhibitory effect of everolimus on the gefitinib-resistant ATC cell line was demonstrated, suggesting a possible correlation between the efficacy of everolimus and PI3KCA gene mutation and the significance of molecular-targeted therapy in the management of ATC. PMID:26137260

  8. Sphingosine 1-phosphate and human ether-a'-go-go-related gene potassium channels modulate migration in human anaplastic thyroid cancer cells.

    PubMed

    Asghar, Muhammad Yasir; Viitanen, Tero; Kemppainen, Kati; Törnquist, Kid

    2012-10-01

    Anaplastic thyroid cancer (ATC) is the most aggressive form of human thyroid cancer, lacking any effective treatment. Sphingosine 1-phosphate (S1P) receptors and human ether-a'-go-go-related gene (HERG (KCNH2)) potassium channels are important modulators of cell migration. In this study, we have shown that the S1P(1-3) receptors are expressed in C643 and THJ-16T human ATC cell lines, both at mRNA and protein level. S1P inhibited migration of these cells and of follicular FTC-133 thyroid cancer cells. Using the S1P(1,3) inhibitor VPC-23019, the S1P(2) inhibitor JTE-013, and the S1P(2) receptor siRNA, we showed that the effect was mediated through S1P(2). Treatment of the cells with the Rho inhibitor C3 transferase abolished the effect of S1P on migration. S1P attenuated Rac activity, and inhibiting Rac decreased migration. Sphingosine kinase inhibitor enhanced basal migration of cells, and addition of exogenous S1P inhibited migration. C643 cells expressed a nonconducting HERG protein, and S1P decreased HERG protein expression. The HERG blocker E-4031 decreased migration. Interestingly, downregulating HERG protein with siRNA decreased the basal migration. In experiments using HEK cells overexpressing HERG, we showed that S1P decreased channel protein expression and current and that S1P attenuated migration of the cells. We conclude that S1P attenuates migration of C643 ATC cells by activating S1P(2) and the Rho pathway. The attenuated migration is also, in part, dependent on a S1P-induced decrease of HERG protein.

  9. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO.

    PubMed

    Reuss, David E; Mamatjan, Yasin; Schrimpf, Daniel; Capper, David; Hovestadt, Volker; Kratz, Annekathrin; Sahm, Felix; Koelsche, Christian; Korshunov, Andrey; Olar, Adriana; Hartmann, Christian; Reijneveld, Jaap C; Wesseling, Pieter; Unterberg, Andreas; Platten, Michael; Wick, Wolfgang; Herold-Mende, Christel; Aldape, Kenneth; von Deimling, Andreas

    2015-06-01

    The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A II(WHO2007)) and anaplastic astrocytoma WHO grade III (AA III(WHO2007)). Patients with A II(WHO2007) are significantly younger and survive significantly longer than those with AA III(WHO2007). So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations. Three independent series including a total of 1360 adult diffuse astrocytic gliomas with IDH mutation containing 683 A II(IDHmut), 562 AA III(IDHmut) and 115 GBM(IDHmut) have been examined for age distribution and survival. In all three series patients with A II(IDHmut )and AA III(IDHmut) were of identical age at presentation of disease (36-37 years) and the difference in survival between grades was much less (10.9 years for A II(IDHmut), 9.3 years for AA III(IDHmut)) than that reported for A II(WHO2007) versus AA III(WHO2007). Our analyses imply that the differences in age and survival between A II(WHO2007) and AA III(WHO2007) predominantly depend on the fraction of IDH-non-mutant astrocytomas in the cohort. This data poses a substantial challenge for the current practice of astrocytoma grading and risk stratification and is likely to have far-reaching consequences on the management of patients with IDH-mutant astrocytoma.

  10. Lovastatin inhibits proliferation of anaplastic thyroid cancer cells through up-regulation of p27 by interfering with the Rho/ROCK-mediated pathway.

    PubMed

    Zhong, Wen-Bin; Hsu, Sung-Po; Ho, Pei-Yin; Liang, Yu-Chih; Chang, Tien-Chun; Lee, Wen-Sen

    2011-12-01

    Previously, we demonstrated that lovastatin, a HMG-CoA reductase inhibitor, induced apoptosis, differentiation, and inhibition of invasiveness of human anaplastic thyroid carcinoma cells (ATCs). Here, we further examined the effect of lovastatin on the growth of ARO cells. Lovastatin (0-20μM) concentration-dependently decreased cell number in cultured ATC and arrested the cell at the G0/G1 phase of the cell cycle. Western blot analysis revealed that lovastatin caused an increase of the protein level of p27 and cyclin-dependent kinase (CDK)4 and a decrease of the protein level of cyclin A2, cyclin D3, and phosphorylated Rb (pRb), but did not significantly change the protein levels of p21, cyclins D1 and E, and CDK2, in ARO cells. The formation of the CDK2-p27 complex was increased and the CDK2 activity was decreased in the lovastatin-treated ARO cells. Pretreatment of ARO cells with a p27, but not p21, antisense oligonucleotide prevented the lovastatin-induced G0/G1 arrest in ARO cells. The lovastatin-induced growth inhibition and translocation of RhoA and Rac1 in ARO cells were completely prevented by mevalonate and partially by geranylgeranyl pyrophosphate. Treatment of ARO cells with Y27632, an inhibitor of Rho-associated kinase, abolished the GGPP-mediated prevention of lovastatin-induced anti-proliferation and up-regulation and prolonged degradation of p27. Taken together, these data suggest that lovastatin treatment caused a reduction of Rho geranylgeranylation, which in turn increased the expression and stability of p27, and then inhibited ARO cell proliferation. These data suggest that lovastatin merits further investigation as multipotent therapy for treatment ATC.

  11. Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population

    PubMed Central

    Zaric, Bojan; Stojsic, Vladimir; Panjkovic, Milana; Tegeltija, Dragana; Stepanov, Vanesa; Kovacevic, Tomi; Sarcev, Tatjana; Radosavljevic, Davorin; Milovancev, Aleksandar; Adamidis, Vasilis; Zarogoulidis, Paul; Hohenforst-Schmidt, Wolfgang; Trakada, Georgia; Rapti, Aggeliki; Perin, Branislav

    2016-01-01

    Introduction: The incidence of echinoderm microtubule-associated protein-like4-anaplastic lymphoma kinase (EML4-ALK) mutation among surgically treated patients with adenocarcinoma of the lung of the Eastern European ethnicity is underreported. The aim of this trial was the determination of EML4-ALK mutation frequency in investigated population, and the evaluation of correlations between lung adenocarcinoma subtype and clinical characteristics with mutation status. Patients and methods: This was a prospective trial which included 195 patients with adenocarcinoma of the lung who underwent surgical treatment. ALK mutation screening was performed by immunohistochemistry (IHC). IHC scores of 2+ and 3+ were regarded as positive. Confirmatory FISH was performed in all IHC positive and in 2:1 ratio in negative patients. Results: Overall ALK mutation rate established by IHC was 6.2%, while FISH confirmed rate of 5.1%. The FISH confirmed ALK positivity in 7.6% Hungarians, 5.5% Serbians, and 6.6% Slovakians. Acinar subtype of adenocarcinoma of the lung was significantly (p=0.02) related to EML4-ALK positive mutation status. Most of the patients were males (56.9%), smokers (50.8%), or former smokers (28.7%) with acinar (55.4%) or solid (35.9%) adenocarcinoma of the lung. Sensitivity and specificity of IHC were 100% and 98.9% respectively. Conclusions: ALK mutation rate in surgically treated patients with adenocarcinoma of the lung was found to be 6.2% by IHC and 5.1% by FISH. Acinar subtype of the adenocarcinoma of the lung was significantly related to ALK positive mutation. PMID:27994656

  12. Differential expression of alphaB-crystallin and Hsp27-1 in anaplastic thyroid carcinomas because of tumor-specific alphaB-crystallin gene (CRYAB) silencing

    PubMed Central

    Mineva, Ivelina; Gartner, Wolfgang; Hauser, Peter; Kainz, Alexander; Löffler, Michael; Wolf, Gerhard; Oberbauer, Rainer; Weissel, Michael; Wagner, Ludwig

    2005-01-01

    Expression of the small heat shock protein alphaB-crystallin in differentiated thyroid tumors has been described recently. In this study, we investigated the molecular mechanisms that affect the expression of alphaB-crystallin in benign goiters (n = 7) and highly malignant anaplastic thyroid carcinomas (ATCs) (n = 3). AlphaB-crystallin expression was compared with that of Hsp27-1. Immunoblot and quantitative real-time (RT) polymerase chain reaction revealed marked downregulation of alphaB-crystallin in all the tested ATCs and the ATC-derived cell line C-643 . In contrast, considerable expression of Hsp27-1 in benign and malignant thyroid tissue was demonstrated. Immunofluorescence analysis revealed no relevant topological differences between benign and malignant thyrocytes in the cytoplasmic staining of both proteins. Consistent and marked downregulation of TFCP2L1 was identified as one of the main mechanisms contributing to CRYAB gene silencing in ATCs. In addition, CRYAB gene promoter methylation seems to occur in distinct ATCs. In silico analysis revealed that the differential expression of alphaB-crystallin and Hsp27-1 results from differences between the alphaB-crystallin and Hsp27-1 promoter fragments (712 bp upstream from the transcriptional start site). Biological activity of the analyzed promoter element is confirmed by its heat shock inducibility. In conclusion, we demonstrate downregulation of alphaB-crystallin expression in highly dedifferentiated ATCs because of a tumor-specific transcription factor pattern. The differential expression of alphaB-crystallin and Hsp27-1 indicates functional differences between both proteins. PMID:16184762

  13. Differential expression of alphaB-crystallin and Hsp27-1 in anaplastic thyroid carcinomas because of tumor-specific alphaB-crystallin gene (CRYAB) silencing.

    PubMed

    Mineva, Ivelina; Gartner, Wolfgang; Hauser, Peter; Kainz, Alexander; Löffler, Michael; Wolf, Gerhard; Oberbauer, Rainer; Weissel, Michael; Wagner, Ludwig

    2005-01-01

    Expression of the small heat shock protein alphaB-crystallin in differentiated thyroid tumors has been described recently. In this study, we investigated the molecular mechanisms that affect the expression of alphaB-crystallin in benign goiters (n = 7) and highly malignant anaplastic thyroid carcinomas (ATCs) (n = 3). AlphaB-crystallin expression was compared with that of Hsp27-1. Immunoblot and quantitative real-time (RT) polymerase chain reaction revealed marked downregulation of alphaB-crystallin in all the tested ATCs and the ATC-derived cell line C-643 . In contrast, considerable expression of Hsp27-1 in benign and malignant thyroid tissue was demonstrated. Immunofluorescence analysis revealed no relevant topological differences between benign and malignant thyrocytes in the cytoplasmic staining of both proteins. Consistent and marked downregulation of TFCP2L1 was identified as one of the main mechanisms contributing to CRYAB gene silencing in ATCs. In addition, CRYAB gene promoter methylation seems to occur in distinct ATCs. In silico analysis revealed that the differential expression of alphaB-crystallin and Hsp27-1 results from differences between the alphaB-crystallin and Hsp27-1 promoter fragments (712 bp upstream from the transcriptional start site). Biological activity of the analyzed promoter element is confirmed by its heat shock inducibility. In conclusion, we demonstrate downregulation of alphaB-crystallin expression in highly dedifferentiated ATCs because of a tumor-specific transcription factor pattern. The differential expression of alphaB-crystallin and Hsp27-1 indicates functional differences between both proteins.

  14. The oncolytic virus dl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma

    PubMed Central

    Vastolo, Viviana; Di Somma, Sarah; Scamardella, Eloise; Gigantino, Vincenzo; Franco, Renato; Marone, Gianni; Portella, Giuseppe

    2016-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human solid tumor and current treatments are ineffective in increasing patients' survival. Thus, the development of new therapeutic approaches for ATC is needed. We have previously shown that the oncolytic adenovirus dl922-947 induces ATC cell death in vitro and tumor regression in vivo. However, the impact of dl922-947 on the pro-tumorigenic ATC microenvironment is still unknown. Since viruses are able to regulate cytokine and chemokine production from infected cells, we sought to investigate whether dl922-947 virotherapy has such effect on ATC cells, thereby modulating ATC microenvironment. dl922-947 decreased IL-8/CXCL8 and MCP-1/CCL2 production by the ATC cell lines 8505-c and BHT101-5. These results correlated with dl922-947-mediated reduction of NF-κB p65 binding to IL8 promoter in 8505-c and BHT101-5 cells and CCL2 promoter in 8505-c cells. IL-8 stimulates cancer cell proliferation, survival and invasion, and also angiogenesis. dl922-947-mediated reduction of IL-8 impaired ATC cell motility in vitro and ATC-induced angiogenesis in vitro and in vivo. We also show that dl922-947-mediated reduction of the monocyte-attracting chemokine CCL2 decreased monocyte chemotaxis in vitro and tumor macrophage density in vivo. Interestingly, dl922-947 treatment induced the switch of tumor macrophages toward a pro-inflammatory M1 phenotype, likely by increasing the expression of the pro-inflammatory cytokine interferon-γ. Altogether, we demonstrate that dl922-947 treatment re-shape the pro-tumorigenic ATC microenvironment by modulating cancer-cell intrinsic factors and the immune response. An in-depth knowledge of dl922-947-mediated effects on ATC microenvironment may help to refine ATC virotherapy in the context of cancer immunotherapy. PMID:26625205

  15. Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

    PubMed

    Morgan, Philip; Woolacott, Nerys; Biswas, Mousumi; Mebrahtu, Teumzghi; Harden, Melissa; Hodgson, Robert

    2017-03-24

    As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than £50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis

  16. Synthesis and biological evaluation of benzo[4,5]imidazo[1,2-c]pyrimidine and benzo[4,5]imidazo[1,2-a]pyrazine derivatives as anaplastic lymphoma kinase inhibitors.

    PubMed

    Tardy, Sébastien; Orsato, Alexandre; Mologni, Luca; Bisson, William H; Donadoni, Carla; Gambacorti-Passerini, Carlo; Scapozza, Leonardo; Gueyrard, David; Goekjian, Peter G

    2014-02-15

    Chromosomal translocations involving anaplastic lymphoma kinase (ALK) are the driving mutations for a range of cancers and ALK is thus considered an attractive therapeutic target. We synthesized a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines and benzo[4,5]imidazo[1,2-a]pyrazines by an aza-Graebe-Ullman reaction, followed by palladium-catalyzed cross-coupling reactions. A sequential regioselective cross-coupling route is reported for the synthesis of unsymmetrically disubstituted benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of ALK was evaluated and compound 19 in particular showed good activity against both the wild type and crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells.

  17. Thrombospondin-1 Silencing Down-Regulates Integrin Expression Levels in Human Anaplastic Thyroid Cancer Cells with BRAFV600E: New Insights in the Host Tissue Adaptation and Homeostasis of Tumor Microenvironment

    PubMed Central

    Duquette, Mark; Sadow, Peter M.; Lawler, Jack; Nucera, Carmelo

    2013-01-01

    Background and Rationale: Anaplastic thyroid cancer (ATC) is characterized by pleomorphic cells, has a poor prognosis, is highly devastating disease, and is not curable. No reliable biomarkers of metastatic potential, helpful for early diagnosis of ATC and therapeutic response have been found yet. Thrombospondin-1 (TSP-1) plays a fundamental role in cancer progression by regulating cell stromal cross-talk in the tumor microenvironment. Goals: Our goal was to understand whether TSP-1 could affect protein levels of its integrin receptors (e.g., ITGα3, α6, and β1) and cell morphology in BRAFV600E-ATC cells in vitro and in vivo. Experimental Design: Anaplastic thyroid cancer-derived cell cultures and western blotting were used to assess integrin protein expression upon TSP-1 silencing. Immunohistochemistry was performed on orthotopic primary human ATC and metastatic ATC in lung tissue to compare TSP-1 and integrin protein expression levels. Results: TSP-1 knock-down down-regulates ITGα3, α6, and β1 in BRAFV600E-human ATC cells. BRAFV600E-ATC cells with TSP-1 knock-down were rounded compared to control cells, which displayed a spread morphology. TSP-1 knock-down also reduced TSP-1, ITGα3, α6, and β1 protein expression levels in vivo in the ATC microenvironment, which is enriched in stromal and inflammatory cells. Conclusion: TSP-1 silencing causes changes in ITG levels and ATC cell morphology. The assessment of TSP-1 and ITG levels might contribute to earlier metastatic potential of BRAFV600E-positive aggressive thyroid cancers, and allow improved patient selection for clinical trials. PMID:24348463

  18. Large N

    NASA Astrophysics Data System (ADS)

    't Hooft, Gerard

    2002-09-01

    In the first part of this lecture, the 1/N expansion technique is illustrated for the case of the large-N sigma model. In large-N gauge theories, the 1/N expansion is tantamount to sorting the Feynman diagrams according to their degree of planarity, that is, the minimal genus of the plane onto which the diagram can be mapped without any crossings. This holds both for the usual perturbative expansion with respect to powers of ˜ {g}2 = g2N, as well as for the expansion of lattice theories in positive powers of 1/˜ {g}2. If there were no renormalization effects, the ˜ {g} expansion would have a finite radius of convergence. The zero-dimensional theory can be used for counting planar diagrams. It can be solved explicitly, so that the generating function for the number of diagrams with given 3-vertices and 4-vertices, can be derived exactly. This can be done for various kinds of Feynman diagrams. We end with some remarks about planar renormalization.

  19. The histological and biological spectrum of diffuse large B-cell lymphoma in the World Health Organization classification.

    PubMed

    Menon, Madhu P; Pittaluga, Stefania; Jaffe, Elaine S

    2012-01-01

    Diffuse large B-cell lymphomas (DLBCLs) are aggressive B-cell lymphomas that are clinically, pathologically, and genetically diverse, in part reflecting the functional diversity of the B-cell system. The focus in recent years has been toward incorporation of clinical features, morphology, immunohistochemistry, and ever evolving genetic data into the classification scheme. The 2008 World Health Organization classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling heralded a new era with a focus on pathways of transformation as well as a promise of more targeted therapies, directed at specific pathways. Some DLBCLs exhibit unique clinical characteristics with a predilection for specific anatomic sites; the anatomic site often reflects underlying biological distinctions. Recently, the spectrum of Epstein-Barr virus (EBV)-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression has been better characterized; most of these occur in patients of advanced age and include Epstein-Barr virus (EBV)-positive large B-cell lymphoma of the elderly. Human herpesvirus 8 is involved in the pathogenesis of primary effusion lymphoma, which can present as a "solid variant." Two borderline categories were created; one deals with tumors at the interface between classic Hodgkin lymphoma and DLBCL. The second confronts the interface between Burkitt lymphoma and DLBCL, so-called "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma" in the 2008 classification. Most cases harbor both MYC and BCL2 translocations and are highly aggressive. Another interesting entity is anaplastic lymphoma kinase-positive DLBCL, which renders itself potentially targetable by anaplastic lymphoma kinase inhibitors. Ongoing investigations at the genomic level, with both exome and whole-genome sequencing, are sure to reveal new pathways

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

    PubMed

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

    2016-12-20

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

  1. 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.

    PubMed

    Strowd, Roy E; Abuali, Inas; Ye, Xiaobu; Lu, Yao; Grossman, Stuart A

    2016-03-01

    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

  2. Instantons and Large N

    NASA Astrophysics Data System (ADS)

    Mariño, Marcos

    2015-09-01

    Preface; Part I. Instantons: 1. Instantons in quantum mechanics; 2. Unstable vacua in quantum field theory; 3. Large order behavior and Borel summability; 4. Non-perturbative aspects of Yang-Mills theories; 5. Instantons and fermions; Part II. Large N: 6. Sigma models at large N; 7. The 1=N expansion in QCD; 8. Matrix models and matrix quantum mechanics at large N; 9. Large N QCD in two dimensions; 10. Instantons at large N; Appendix A. Harmonic analysis on S3; Appendix B. Heat kernel and zeta functions; Appendix C. Effective action for large N sigma models; References; Author index; Subject index.

  3. Large displacement spherical joint

    DOEpatents

    Bieg, Lothar F.; Benavides, Gilbert L.

    2002-01-01

    A new class of spherical joints has a very large accessible full cone angle, a property which is beneficial for a wide range of applications. Despite the large cone angles, these joints move freely without singularities.

  4. Large mode radius resonators

    NASA Technical Reports Server (NTRS)

    Harris, Michael R.

    1987-01-01

    Resonator configurations permitting operation with large mode radius while maintaining good transverse mode discrimination are considered. Stable resonators incorporating an intracavity telescope and unstable resonator geometries utilizing an output coupler with a Gaussian reflectivity profile are shown to enable large radius single mode laser operation. Results of heterodyne studies of pulsed CO2 lasers with large (11mm e sup-2 radius) fundamental mode sizes are presented demonstrating minimal frequency sweeping in accordance with the theory of laser-induced medium perturbations.

  5. LARGE BUILDING RADON MANUAL

    EPA Science Inventory

    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...

  6. Large wind turbine generators

    NASA Technical Reports Server (NTRS)

    Thomas, R. L.; Donovon, R. M.

    1978-01-01

    The development associated with large wind turbine systems is briefly described. The scope of this activity includes the development of several large wind turbines ranging in size from 100 kW to several megawatt levels. A description of the wind turbine systems, their programmatic status and a summary of their potential costs is included.

  7. Large Print Bibliography, 1990.

    ERIC Educational Resources Information Center

    South Dakota State Library, Pierre.

    This bibliography lists materials that are available in large print format from the South Dakota State Library. The annotated entries are printed in large print and include the title of the material and its author, call number, publication date, and type of story or subject area covered. Some recorded items are included in the list. The entries…

  8. Large Customers (DR Sellers)

    SciTech Connect

    Kiliccot, Sila

    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

  9. Closed Large Cell Clouds

    Atmospheric Science Data Center

    2013-04-19

    article title:  Closed Large Cell Clouds in the South Pacific     ... unperturbed by cyclonic or frontal activity. When the cell centers are cloudy and the main sinking motion is concentrated at cell ...

  10. Large scale dynamic systems

    NASA Technical Reports Server (NTRS)

    Doolin, B. F.

    1975-01-01

    Classes of large scale dynamic systems were discussed in the context of modern control theory. Specific examples discussed were in the technical fields of aeronautics, water resources and electric power.

  11. Large bowel resection - discharge

    MedlinePlus

    ... 26. Read More Colon cancer Colostomy Crohn disease Intestinal obstruction Large bowel resection Ulcerative colitis Patient Instructions Bland ... Diseases Colonic Polyps Colorectal Cancer Diverticulosis and Diverticulitis Intestinal Obstruction Ulcerative Colitis Browse the Encyclopedia A.D.A. ...

  12. Large Deployable Shroud

    NASA Technical Reports Server (NTRS)

    Jacquemin, G. G.

    1987-01-01

    Preliminary design proposed for large, lightweight telescope shroud or light shield carried to orbit in single Space Shuttle cargo load. Shroud concept applied on Earth in portable, compactly storable displays or projection screens. Large telescope shroud includes four deployable masts erecting eight walls of hinged panels of polyimide film. Panels stored fanfolded before deployment and threaded on guide wires unwinding from spools and remain taut during deployment.

  13. Large electrostatic accelerators

    SciTech Connect

    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.

  14. [Pulmonary large cell carcinoma contiguous to bullae with massive bullous hematoma and hemoptysis; with special reference to 20 cases of Japanese reports].

    PubMed

    Shindo, G; Endo, T; Onda, M; Shimada, T; Inou, T; Hiruta, H

    2005-08-01

    A 50-year-old man with continuous hemosputa and large hematoma of left upper lobe contiguous to bilateral emphysematous bullous disease was admitted for surgery to stop hemorrhage and to resect left lung hematoma and multiple bullae. Bullectomy and neodymium yttrium aluminum garnet (Nd-YAG) laser irradiation to bullae of left upper lobe performed successfully with maximum preserved pulmonary function of it. Pathological examination, however, revealed anaplastic carcinoma inside bulla of S(1+2)c with minimal invasion into adhered parietal pleura (p 3). Left upper lobectomy was carried out with complete mediastinal lymph node dissection (ND 2 b). The final pathological diagnosis was large cell carcinoma of left S(1+2)c with the staging pT3N0M0 and stage II. The patient lives actively in daily life more than 7 years without any recurrence. Clinical analysis of Japanese 20 cases of lung carcinoma with initial signs of hemosputa and/or hemoptysis contiguous to emphysematous bullae elucidate following important facts. Hemosputa and hemoptysis play important role for early finding and diagnosis of lung cancer contiguous to bullous disease, especially in patients of early clinical stage with or without computed tomography (CT) exams and promise to better surgical prognosis and survivals as compared with non hemosputa ones.

  15. Large-Scale Disasters

    NASA Astrophysics Data System (ADS)

    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.

  16. Death Writ Large

    ERIC Educational Resources Information Center

    Kastenbaum, Robert

    2004-01-01

    Mainstream thanatology has devoted its efforts to improving the understanding, care, and social integration of people who are confronted with life-threatening illness or bereavement. This article suggests that it might now be time to expand the scope and mission to include large-scale death and death that occurs through complex and multi-domain…

  17. Developing Large CAI Packages.

    ERIC Educational Resources Information Center

    Reed, Mary Jac M.; Smith, Lynn H.

    1983-01-01

    When developing large computer-assisted instructional (CAI) courseware packages, it is suggested that there be more attentive planning to the overall package design before actual lesson development is begun. This process has been simplified by modifying the systems approach used to develop single CAI lessons, followed by planning for the…

  18. Risks of Large Portfolios

    PubMed Central

    Fan, Jianqing; Liao, Yuan; Shi, Xiaofeng

    2014-01-01

    The risk of a large portfolio is often estimated by substituting a good estimator of the volatility matrix. However, the accuracy of such a risk estimator is largely unknown. We study factor-based risk estimators under a large amount of assets, and introduce a high-confidence level upper bound (H-CLUB) to assess the estimation. The H-CLUB is constructed using the confidence interval of risk estimators with either known or unknown factors. We derive the limiting distribution of the estimated risks in high dimensionality. We find that when the dimension is large, the factor-based risk estimators have the same asymptotic variance no matter whether the factors are known or not, which is slightly smaller than that of the sample covariance-based estimator. Numerically, H-CLUB outperforms the traditional crude bounds, and provides an insightful risk assessment. In addition, our simulated results quantify the relative error in the risk estimation, which is usually negligible using 3-month daily data. PMID:26195851

  19. Estimating Large Numbers

    ERIC Educational Resources Information Center

    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…

  20. LARGE BUILDING HVAC SIMULATION

    EPA Science Inventory

    The report discusses the monitoring and collection of data relating to indoor pressures and radon concentrations under several test conditions in a large school building in Bartow, Florida. The Florida Solar Energy Center (FSEC) used an integrated computational software, FSEC 3.0...

  1. Large, Easily Deployable Structures

    NASA Technical Reports Server (NTRS)

    Agan, W. E.

    1983-01-01

    Study of concepts for large space structures will interest those designing scaffolding, radio towers, rescue equipment, and prefabricated shelters. Double-fold, double-cell module was selected for further design and for zero gravity testing. Concept is viable for deployment by humans outside space vehicle as well as by remotely operated manipulator.

  2. Teaching Very Large Classes

    ERIC Educational Resources Information Center

    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…

  3. Teaching Large Evening Classes

    ERIC Educational Resources Information Center

    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…

  4. Risks of Large Portfolios.

    PubMed

    Fan, Jianqing; Liao, Yuan; Shi, Xiaofeng

    2015-06-01

    The risk of a large portfolio is often estimated by substituting a good estimator of the volatility matrix. However, the accuracy of such a risk estimator is largely unknown. We study factor-based risk estimators under a large amount of assets, and introduce a high-confidence level upper bound (H-CLUB) to assess the estimation. The H-CLUB is constructed using the confidence interval of risk estimators with either known or unknown factors. We derive the limiting distribution of the estimated risks in high dimensionality. We find that when the dimension is large, the factor-based risk estimators have the same asymptotic variance no matter whether the factors are known or not, which is slightly smaller than that of the sample covariance-based estimator. Numerically, H-CLUB outperforms the traditional crude bounds, and provides an insightful risk assessment. In addition, our simulated results quantify the relative error in the risk estimation, which is usually negligible using 3-month daily data.

  5. Large bouncing jets

    NASA Astrophysics Data System (ADS)

    Cardin, Karl; Weislogel, Mark

    2016-11-01

    We experimentally investigate the phenomena of large jet rebound (bounce), a mode of fluid transfer following oblique jet impacts on hydrophobic surfaces. We initially seek to describe the regimes of such jet bounce in tests conducted in the weightless environment of a drop tower. A parametric study reveals the dependence of the rebound mode on the relevant dimensionless groups such as Weber number We⊥ defined on the velocity component perpendicular to the surface. We show that significantly larger diameter jets behave similarly as much smaller jets demonstrated during previous terrestrial investigations when We⊥ 1 . For We⊥ > 1 , large jet impacts create fishbone-like structures. We also explore rebounds from nonplanar substrates. Improving our understanding of such jet rebound opens avenues for unique transport capabilities. NASA Cooperative Agreement NNX12A047A.

  6. Large area mass analyzer

    NASA Astrophysics Data System (ADS)

    Rachev, Mikhail; Srama, Ralf; Srowig, Andre; Grün, Eberhard

    2004-12-01

    A new time-of-flight spectrometer for the chemical analysis of cosmic dust particles in space has been simulated by Simion 7.0. The instrument is based upon impact ionization. This method is a reliable method for in situ dust detection and is well established. Instruments using the impact ionization flew on board of Helios and Galileo and are still in operation on board of the Ulysses and Cassini-Huygens missions. The new instrument has a large sensitive area of 0.1 m2 in order to achieve a significant number of measurements. The mass resolution M/ΔM>100 and the mass range covers the most relevant elements expected in cosmic dust. The instrument has a reflectron configuration which increases the mass resolution. Most of the ions released during the impact are focused to the detector. The ion detector consists of a large area ion-to-electron converter, an electron reflectron and a microchannel plate detector.

  7. The Universe at Large

    NASA Astrophysics Data System (ADS)

    Münch, Guido; Mampaso, Antonio; Sánchez, Francisco

    1997-11-01

    The Universe at Large presents a unique survey of key questions outstanding in contemporary astronomy and cosmology. In this timely volume, eleven of the world's greatest living astronomers and cosmologists present personal views of what problems must be addressed by future research. Allan Sandage presents a 23-point plan to reach a full understanding of the large-scale structure in the Universe; Geoffrey Burbidge looks at the future of the Quasi Steady State alternative to the Big Bang; E. Margaret Burbidge, Donald Osterbrock and Malcolm Longair discuss active galactic nuclei (AGN); Igor Novikov, Donald Lynden-Bell, Martin Rees and Rashid Sunyaev look at the physics of black holes; and Bernard Pagel and Hubert Reeves concentrate on what we don't yet understand about elements in the cosmos. This book provides a unique review of our current understanding in astronomy and cosmology and a host of profitable research ideas for graduate students and researchers.

  8. Large Magellanic Cloud

    NASA Astrophysics Data System (ADS)

    Murdin, P.

    2000-11-01

    The larger of two nearby companions of the Milky Way Galaxy that can be seen with the naked eye in the southern hemisphere sky and which are named after the Portuguese navigator, Ferdinand Magellan, who observed them in 1519 during his circumnavigation of the world. Located in the constellation of Dorado, at a distance of about 170 000 light-years, the Large Magellanic Cloud (LMC) has an overall ...

  9. Large area LED package

    NASA Astrophysics Data System (ADS)

    Goullon, L.; Jordan, R.; Braun, T.; Bauer, J.; Becker, F.; Hutter, M.; Schneider-Ramelow, M.; Lang, K.-D.

    2015-03-01

    Solid state lighting using LED-dies is a rapidly growing market. LED-dies with the needed increasing luminous flux per chip area produce a lot of heat. Therefore an appropriate thermal management is required for general lighting with LEDdies. One way to avoid overheating and shorter lifetime is the use of many small LED-dies on a large area heat sink (down to 70 μm edge length), so that heat can spread into a large area while at the same time light also appears on a larger area. The handling with such small LED-dies is very difficult because they are too small to be picked with common equipment. Therefore a new concept called collective transfer bonding using a temporary carrier chip was developed. A further benefit of this new technology is the high precision assembly as well as the plane parallel assembly of the LED-dies which is necessary for wire bonding. It has been shown that hundred functional LED-dies were transferred and soldered at the same time. After the assembly a cost effective established PCB-technology was applied to produce a large-area light source consisting of many small LED-dies and electrically connected on a PCB-substrate. The top contacts of the LED-dies were realized by laminating an adhesive copper sheet followed by LDI structuring as known from PCB-via-technology. This assembly can be completed by adding converting and light forming optical elements. In summary two technologies based on standard SMD and PCB technology have been developed for panel level LED packaging up to 610x 457 mm2 area size.

  10. The Large Area Telescope

    SciTech Connect

    Michelson, Peter F.; /KIPAC, Menlo Park /Stanford U., HEPL

    2007-11-13

    The Large Area Telescope (LAT), one of two instruments on the Gamma-ray Large Area Space Telescope (GLAST) mission, is an imaging, wide field-of-view, high-energy pair-conversion telescope, covering the energy range from {approx}20 MeV to more than 300 GeV. The LAT is being built by an international collaboration with contributions from space agencies, high-energy particle physics institutes, and universities in France, Italy, Japan, Sweden, and the United States. The scientific objectives the LAT will address include resolving the high-energy gamma-ray sky and determining the nature of the unidentified gamma-ray sources and the origin of the apparently isotropic diffuse emission observed by EGRET; understanding the mechanisms of particle acceleration in celestial sources, including active galactic nuclei, pulsars, and supernovae remnants; studying the high-energy behavior of gamma-ray bursts and transients; using high-energy gamma-rays to probe the early universe to z {ge} 6; and probing the nature of dark matter. The components of the LAT include a precision silicon-strip detector tracker and a CsI(Tl) calorimeter, a segmented anticoincidence shield that covers the tracker array, and a programmable trigger and data acquisition system. The calorimeter's depth and segmentation enable the high-energy reach of the LAT and contribute significantly to background rejection. The aspect ratio of the tracker (height/width) is 0.4, allowing a large field-of-view and ensuring that nearly all pair-conversion showers initiated in the tracker will pass into the calorimeter for energy measurement. This paper includes a description of each of these LAT subsystems as well as a summary of the overall performance of the telescope.

  11. The large pursuit rotor.

    PubMed

    Williams, L R; Grbin, I R

    1976-09-01

    The question of whether certain phenomena that occur on the conventional rotary pursuit and other small apparatus also appear on a gross motor task was examined using a large pursuit rotor that required whole-body movements. College males (n=29) were given 90 10-sec trials over three consecutive days with 30 trials of continuous practice per day. The existence of reactive inhibition, reminiscence, and warmup decrement was confirmed, indicating that common mechanisms underlie both fine and gross bodily movements. In addition, the substantial amounts of learning and the high reliabilities for performance and learning indicated that the present apparatus has considerable potential for motor-learning research.

  12. Large character sums

    NASA Astrophysics Data System (ADS)

    Granville, Andrew; Soundararajan, K.

    2007-04-01

    In 1918 Polya and Vinogradov gave an upper bound for the maximal size of character sums, which still remains the best known general estimate. One of the main results of this paper provides a substantial improvement of the Polya-Vinogradov bound for characters of odd, bounded order. In 1977 Montgomery and Vaughan showed how the Polya-Vinogradov inequality may be sharpened assuming the Generalized Riemann Hypothesis. We give a simple proof of their estimate and provide an improvement for characters of odd, bounded order. The paper also gives characterizations of the characters for which the maximal character sum is large, and it finds a hidden structure among these characters.

  13. Large Optics Technology.

    DTIC Science & Technology

    1986-05-22

    EEEEEEEEEEmhEE SENSEffl -2-5 12" 110111111 LLLo 111M1. 2 15 .1 111-= NATIONAL BUREAU OF S Mouopy *9sO9u TESI , C N LARGE OPTICS TECHNOLOGY FINAL...Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1981 !mw ’(’* 17 ABSTRACT The mirrors used in high energy laser systems...SCIENCES (GRADUATE) In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1982

  14. Large coil test facility

    SciTech Connect

    Nelms, L.W.; Thompson, P.B.

    1980-01-01

    Final design of the facility is nearing completion, and 20% of the construction has been accomplished. A large vacuum chamber, houses the test assembly which is coupled to appropriate cryogenic, electrical, instrumentation, diagnostc systems. Adequate assembly/disassembly areas, shop space, test control center, offices, and test support laboratories are located in the same building. Assembly and installation operations are accomplished with an overhead crane. The major subsystems are the vacuum system, the test stand assembly, the cryogenic system, the experimental electric power system, the instrumentation and control system, and the data aquisition system.

  15. Large right ventricular thrombus.

    PubMed

    Sousa, Carla; Almeida, Pedro; Gonçalves, Alexandra; Rodrigues, João; Rangel, Inês; Macedo, Filipe; Maciel, M Júlia

    2014-01-01

    Right ventricular thrombosis is a rare yet potentially fatal condition. It has been described in association with hypercoagulability states, autoimmune diseases and dilated cardiomyopathy. Echocardiography constitutes the election tool for diagnosis and characterization of these entities, allowing for the differentiation between the various types of thrombi. We present a case of a patient with alcoholic dilated cardiomyopathy admitted for congestive heart failure and lower respiratory infection. In the diagnostic approach, a routine echocardiography revealed a large mural right ventricular thrombus in association with severe biventricular dysfunction. The patient was proposed for anticoagulation strategy, which he refused.

  16. A large thumb mass.

    PubMed

    Shah, Amit K; Macnair, Rory; Figus, Andrea

    2012-02-01

    A 31-year-old man presented with a 5-year history of a spontaneously occurring soft tissue mass on the palmar aspect of his left non dominant thumb. Over 5 months he was having progressive difficulty flexing at the interphalangeal joint. Magnetic resonance imaging demonstrated an heterogeneously enhancing soft tissue mass likely to be either a peripheral fibromatosis or giant cell tumour of the flexor tendon (Figure 1). Intraoperatively a large neuroma in continuity with the ulnar digital nerve was found and debulked (Figure 2). The diagnosis was confirmed histologically.

  17. Large Spectral Library Problem

    SciTech Connect

    Chilton, Lawrence K.; Walsh, Stephen J.

    2008-10-03

    Hyperspectral imaging produces a spectrum or vector at each image pixel. These spectra can be used to identify materials present in the image. In some cases, spectral libraries representing atmospheric chemicals or ground materials are available. The challenge is to determine if any of the library chemicals or materials exist in the hyperspectral image. The number of spectra in these libraries can be very large, far exceeding the number of spectral channels collected in the ¯eld. Suppose an image pixel contains a mixture of p spectra from the library. Is it possible to uniquely identify these p spectra? We address this question in this paper and refer to it as the Large Spectral Library (LSL) problem. We show how to determine if unique identi¯cation is possible for any given library. We also show that if p is small compared to the number of spectral channels, it is very likely that unique identi¯cation is possible. We show that unique identi¯cation becomes less likely as p increases.

  18. Infinitely Large New Dimensions

    SciTech Connect

    Arkani-Hamed, Nima; Dimopoulos, Savas; Dvali, Gia; Kaloper, Nemanja

    1999-07-29

    We construct intersecting brane configurations in Anti-de-Sitter space localizing gravity to the intersection region, with any number n of extra dimensions. This allows us to construct two kinds of theories with infinitely large new dimensions, TeV scale quantum gravity and sub-millimeter deviations from Newton's Law. The effective 4D Planck scale M{sub Pl} is determined in terms of the fundamental Planck scale M{sub *} and the AdS radius of curvature L via the familiar relation M{sub Pl}{sup 2} {approx} M{sub *}{sup 2+n} L{sup n}; L acts as an effective radius of compactification for gravity on the intersection. Taking M{sub *} {approx} TeV and L {approx} sub-mm reproduces the phenomenology of theories with large extra dimensions. Alternately, taking M{sub *} {approx} L{sup -1} {approx} M{sub Pl}, and placing our 3-brane a distance {approx} 100M{sub Pl}{sup -1} away from the intersection gives us a theory with an exponential determination of the Weak/Planck hierarchy.

  19. Large Particle Titanate Sorbents

    SciTech Connect

    Taylor-Pashow, K.

    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. Large Quantum Gravity Effects

    NASA Astrophysics Data System (ADS)

    Angulo, María E.; Mena Marugán, Guillermo A.; Ashtekar, A.

    Linearly polarized cylindrical waves in four-dimensional vacuum gravity are mathematically equivalent to rotationally symmetric gravity coupled to a Maxwell (or Klein-Gordon) field in three dimensions. The quantization of this latter system was performed by Ashtekar and Pierri in a recent work. Employing that quantization, we obtain here a complete quantum theory which describes the four-dimensional geometry of the Einstein-Rosen waves. In particular, we construct regularized operators to represent the metric. It is shown that the results achieved by Ashtekar about the existence of important quantum gravity effects in the Einstein-Maxwell system at large distances from the symmetry axis continue to be valid from a four-dimensional point of view. The only significant difference is that, in order to admit an approximate classical description in the asymptotic region, states that are coherent in the Maxwell field need not contain a large number of photons anymore. We also analyze the metric fluctuations on the symmetry axis and argue that they are generally relevant for all of the coherent states.

  1. Contrasting Large Solar Events

    NASA Astrophysics Data System (ADS)

    Lanzerotti, Louis J.

    2010-10-01

    After an unusually long solar minimum, solar cycle 24 is slowly beginning. A large coronal mass ejection (CME) from sunspot 1092 occurred on 1 August 2010, with effects reaching Earth on 3 August and 4 August, nearly 38 years to the day after the huge solar event of 4 August 1972. The prior event, which those of us engaged in space research at the time remember well, recorded some of the highest intensities of solar particles and rapid changes of the geomagnetic field measured to date. What can we learn from the comparisons of these two events, other than their essentially coincident dates? One lesson I took away from reading press coverage and Web reports of the August 2010 event is that the scientific community and the press are much more aware than they were nearly 4 decades ago that solar events can wreak havoc on space-based technologies.

  2. Large area plasma source

    NASA Technical Reports Server (NTRS)

    Foster, John (Inventor); Patterson, Michael (Inventor)

    2008-01-01

    An all permanent magnet Electron Cyclotron Resonance, large diameter (e.g., 40 cm) plasma source suitable for ion/plasma processing or electric propulsion, is capable of producing uniform ion current densities at its exit plane at very low power (e.g., below 200 W), and is electrodeless to avoid sputtering or contamination issues. Microwave input power is efficiently coupled with an ionizing gas without using a dielectric microwave window and without developing a throat plasma by providing a ferromagnetic cylindrical chamber wall with a conical end narrowing to an axial entrance hole for microwaves supplied on-axis from an open-ended waveguide. Permanent magnet rings are attached inside the wall with alternating polarities against the wall. An entrance magnet ring surrounding the entrance hole has a ferromagnetic pole piece that extends into the chamber from the entrance hole to a continuing second face that extends radially across an inner pole of the entrance magnet ring.

  3. Large solar arrays

    NASA Technical Reports Server (NTRS)

    Crabtree, W. L.

    1980-01-01

    A spectrophotovoltaic converter, a thermophotovoltaic converter, a cassegrainian concentrator, a large silicon cell blanket, and a high flux approach are among the concepts being investigated as part of the multihundred kW solar array program for reducing the cost of photovoltaic energy in space. These concepts involve a range of technology risks, the highest risk being represented by the thermophotovoltaics and spectrophotovoltaics approaches which involve manipulation to of the incoming spectrum to enhance system efficiency. The planar array (solar blanket) has no technology risk and a moderate payback. The primary characteristics, components, and technology concerns of each of these concepts are summarized. An orbital power platform mission in the late 1980's is being used to allow a coherent technology advancement program in order to achieve a ten year life with maintenance at a capital recurring cost of $30/watt based on 1978 dollars.

  4. Large area Czochralski silicon

    NASA Technical Reports Server (NTRS)

    Rea, S. N.; Gleim, P. S.

    1977-01-01

    The overall cost effectiveness of the Czochralski process for producing large-area silicon was determined. The feasibility of growing several 12 cm diameter crystals sequentially at 12 cm/h during a furnace run and the subsequent slicing of the ingot using a multiblade slurry saw were investigated. The goal of the wafering process was a slice thickness of 0.25 mm with minimal kerf. A slice + kerf of 0.56 mm was achieved on 12 cm crystal using both 400 grit B4C and SiC abrasive slurries. Crystal growth experiments were performed at 12 cm diameter in a commercially available puller with both 10 and 12 kg melts. Several modifications to the puller hoz zone were required to achieve stable crystal growth over the entire crystal length and to prevent crystallinity loss a few centimeters down the crystal. The maximum practical growth rate for 12 cm crystal in this puller design was 10 cm/h, with 12 to 14 cm/h being the absolute maximum range at which melt freeze occurred.

  5. Very Large Scale Optimization

    NASA Technical Reports Server (NTRS)

    Vanderplaats, Garrett; Townsend, James C. (Technical Monitor)

    2002-01-01

    The purpose of this research under the NASA Small Business Innovative Research program was to develop algorithms and associated software to solve very large nonlinear, constrained optimization tasks. Key issues included efficiency, reliability, memory, and gradient calculation requirements. This report describes the general optimization problem, ten candidate methods, and detailed evaluations of four candidates. The algorithm chosen for final development is a modern recreation of a 1960s external penalty function method that uses very limited computer memory and computational time. Although of lower efficiency, the new method can solve problems orders of magnitude larger than current methods. The resulting BIGDOT software has been demonstrated on problems with 50,000 variables and about 50,000 active constraints. For unconstrained optimization, it has solved a problem in excess of 135,000 variables. The method includes a technique for solving discrete variable problems that finds a "good" design, although a theoretical optimum cannot be guaranteed. It is very scalable in that the number of function and gradient evaluations does not change significantly with increased problem size. Test cases are provided to demonstrate the efficiency and reliability of the methods and software.

  6. The large binocular telescope.

    PubMed

    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.

  7. Large Databases in Astronomy

    NASA Astrophysics Data System (ADS)

    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.

  8. Large forging manufacturing process

    DOEpatents

    Thamboo, Samuel V.; Yang, Ling

    2002-01-01

    A process for forging large components of Alloy 718 material so that the components do not exhibit abnormal grain growth includes the steps of: a) providing a billet with an average grain size between ASTM 0 and ASTM 3; b) heating the billet to a temperature of between 1750.degree. F. and 1800.degree. F.; c) upsetting the billet to obtain a component part with a minimum strain of 0.125 in at least selected areas of the part; d) reheating the component part to a temperature between 1750.degree. F. and 1800.degree. F.; e) upsetting the component part to a final configuration such that said selected areas receive no strains between 0.01 and 0.125; f) solution treating the component part at a temperature of between 1725.degree. F. and 1750.degree. F.; and g) aging the component part over predetermined times at different temperatures. A modified process achieves abnormal grain growth in selected areas of a component where desirable.

  9. Large building characterization

    SciTech Connect

    Menetrez, M.Y.; Sanchez, D.C.; Kulp, R.N.; Pyle, B.; Williamson, A.; McDonough, S.

    1994-12-31

    Buildings are characterized in this project by examining radon concentrations and indoor air quality (IAQ) levels as affected by building ventilation dynamics. IAQ data collection stations (IAQDS), for monitoring and data logging, remote switches (pressure and sail switches), and a weather station were installed. Measurements of indoor radon, carbon dioxide (CO{sub 2}), and particle concentrations; temperature; humidity; indoor to outdoor or sub-slab pressure differentials; ambient and sub-slab radon concentrations; and outdoor air intake flow rates were collected. The outdoor air intake was adjusted, and fan cycles were controlled while tracer gas measurements were taken in all zones and IAQDS data are processed. Ventilation, infiltration, mixing rates, radon entry, pressure/temperature convective driving forces, CO{sub 2} generation/decay concentrations, and IAQ levels were defined. These dynamic interacting processes characterize the behavior of this and similar large buildings. The techniques incorporated into the experimental plan are discussed with project rationale. Results and the discussion of those results are beyond the limits of this paper.

  10. Large scale traffic simulations

    SciTech Connect

    Nagel, K.; Barrett, C.L. |; Rickert, M. |

    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.

  11. Large scale tracking algorithms

    SciTech Connect

    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.

  12. Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline

    PubMed Central

    Leighl, Natasha B.; Rekhtman, Natasha; Biermann, William A.; Huang, James; Mino-Kenudson, Mari; Ramalingam, Suresh S.; West, Howard; Whitlock, Sara; Somerfield, Mark R.

    2014-01-01

    Purpose The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) guideline on molecular testing for the selection of patients with lung cancer for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors was considered for endorsement. Methods American Society of Clinical Oncology (ASCO) staff reviewed the CAP/IASLC/AMP guideline for developmental rigor; an ASCO ad hoc review panel of experts reviewed the guideline content. Results The ASCO panel concurred that the recommendations are clear, thorough, and based on the most relevant scientific evidence in this content area and present options that will be acceptable to patients. The CAP/IASLC/AMP guideline comprises 37 recommendations (evidence grade A or B), expert consensus opinions, or suggestions that address the following five principal questions: (1) When should molecular testing be performed? (2) How should EGFR testing be performed? (3) How should ALK testing be performed? (4) Should other genes be routinely tested in lung adenocarcinoma? (5) How should molecular testing be implemented and operationalized? Conclusion The ASCO review panel endorses the CAP/IASLC/AMP guideline. This guideline represents an important advance toward standardization of EGFR and ALK testing practices and is of major clinical relevance in advancing the care of patients with lung cancer. In the Discussion section, the ASCO review panel highlights three evolving areas: advances in ALK testing methodology, considerations for selecting appropriate populations for molecular testing, and emergence of other targetable molecular alterations. PMID:25311215

  13. Large Binocular Telescope Project

    NASA Astrophysics Data System (ADS)

    Hill, John M.

    1997-03-01

    The large binocular telescope (LBT) project have evolved from concepts first proposed in 1985. The present partners involved in the design and construction of this 2 by 8.4 meter binocular telescope are the University of Arizona, Italy represented by the Osservatorio Astrofisico di Arcetri and the Research Corporation based in Tucson, Arizona. These three partners have committed sufficient funds to build the enclosure and the telescope populated with a single 8.4 meter optical train -- approximately 40 million dollars (1989). Based on this commitment, design and construction activities are now moving forward. Additional partners are being sought. The next mirror to be cast at the Steward Observatory Mirror Lab in the fall of 1996 will be the first borosilicate honeycomb primary for LBT. The baseline optical configuration of LBT includes wide field Cassegrain secondaries with optical foci above the primaries to provide a corrected one degree field at F/4. The infrared F/15 secondaries are a Gregorian design to allow maximum flexibility for adaptive optics. The F/15 secondaries are undersized to provide a low thermal background focal plane which is unvignetted over a 4 arcminute diameter field-of-view. The interferometric focus combining the light from the two 8.4 meter primaries will reimage two folded Gregorian focal planes to a central location. The telescope elevation structure accommodates swing arms which allow rapid interchange of the various secondary and tertiary mirrors. Maximum stiffness and minimal thermal disturbance continue to be important drivers for the detailed design of the telescope. The telescope structure accommodates installation of a vacuum bell jar for aluminizing the primary mirrors in-situ on the telescope. The detailed design of the telescope structure will be completed in 1996 by ADS Italia (Lecco) and European Industrial Engineering (Mestre). The final enclosure design is now in progress at M3 Engineering (Tucson), EIE and ADS Italia

  14. Applied large eddy simulation.

    PubMed

    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.

  15. Epstein-Barr virus-negative diffuse large B cell lymphoma with aberrant expression of CD3 and other T cell-associated antigens: report of three cases with a review of the literature.

    PubMed

    Wu, Bin; Vallangeon, Bethany; Galeotti, Jonathan; Sebastian, Siby; Rehder, Catherine; Wang, Endi

    2016-10-01

    Expression of CD3 on a mature B cell neoplasm, such as diffuse large B cell lymphoma (DLBCL), is extremely rare. When it is present, it will cause diagnostic confusion since the classification of lymphoid neoplasms is largely based on immunophenotyping to determine the cell lineage. We report three cases of DLBCL with CD3 and other T cell-associated antigens. A literature search identifies 30 additional cases of DLBCL expressing CD3, with the majority (78.6 %) displaying cytoplasmic expression, while two of our cases demonstrate membranous staining. Additionally, expression of CD3 tends to be partial and weak in both our series and the reported cases. Of the 28 cases reported in the literature that were tested for Epstein Barr Virus (EBV), 16 (57.1 %) are positive, suggesting an important role of EBV in promoting lineage ambiguity/infidelity, whereas, all three cases in our series are negative for the virus. All three cases in our series show homogeneous expression of multiple B cell specific antigens, while the reported cases show variable expression with some having B cell antigens downregulated, particularly in those cases with EBV association or anaplastic morphology. A low threshold for testing EBV status is advocated in DLBCL with phenotypic ambiguity along with panels of immunohistochemical stains and B/T cell receptor gene rearrangement analysis.

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

    PubMed

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

    2017-03-01

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

  17. Large for Gestational Age (LGA)

    MedlinePlus

    ... 5 Additional Content Medical News Large for Gestational Age (LGA) By Arthur E. Kopelman, MD, The Brody ... Newborns Birth Injury Prematurity Postmaturity Small for Gestational Age (SGA) Large for Gestational Age (LGA) Respiratory Distress ...

  18. Large for gestational age (LGA)

    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 infant is larger ...

  19. Large Deviations for Random Trees

    PubMed Central

    Heitsch, Christine

    2010-01-01

    We consider large random trees under Gibbs distributions and prove a Large Deviation Principle (LDP) for the distribution of degrees of vertices of the tree. The LDP rate function is given explicitly. An immediate consequence is a Law of Large Numbers for the distribution of vertex degrees in a large random tree. Our motivation for this study comes from the analysis of RNA secondary structures. PMID:20216937

  20. Large landslides from oceanic volcanoes

    USGS Publications Warehouse

    Holcomb, R.T.; Searle, R.C.

    1991-01-01

    Large landslides are ubiquitous around the submarine flanks of Hawaiian volcanoes, and GLORIA has also revealed large landslides offshore from Tristan da Cunha and El Hierro. On both of the latter islands, steep flanks formerly attributed to tilting or marine erosion have been reinterpreted as landslide headwalls mantled by younger lava flows. These landslides occur in a wide range of settings and probably represent only a small sample from a large population. They may explain the large volumes of archipelagic aprons and the stellate shapes of many oceanic volcanoes. Large landslides and associated tsunamis pose hazards to many islands. -from Authors

  1. Health impacts of large dams

    SciTech Connect

    Lerer, L.B.; Scudder, T.

    1999-03-01

    Large dams have been criticized because of their negative environmental and social impacts. Public health interest largely has focused on vector-borne diseases, such as schistosomiasis, associated with reservoirs and irrigation projects. Large dams also influence health through changes in water and food security, increases in communicable diseases, and the social disruption caused by construction and involuntary resettlement. Communities living in close proximity to large dams often do not benefit from water transfer and electricity generation revenues. A comprehensive health component is required in environmental and social impact assessments for large dam projects.

  2. Factors associated with sinus bradycardia during crizotinib treatment: a retrospective analysis of two large-scale multinational trials (PROFILE 1005 and 1007).

    PubMed

    Ou, Sai-Hong Ignatius; Tang, Yiyun; Polli, Anna; Wilner, Keith D; Schnell, Patrick

    2016-04-01

    Decreases in heart rate (HR) have been described in patients receiving crizotinib. We performed a large retrospective analysis of HR changes during crizotinib therapy. HRs from vital-sign data for patients with anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer enrolled in PROFILE 1005 and the crizotinib arm of PROFILE 1007 were analyzed. Sinus bradycardia (SB) was defined as HR <60 beats per minute (bpm). Magnitude and timing of HR changes were assessed. Potential risk factors for SB were investigated by logistic regression analysis. Progression-free survival (PFS) was evaluated according to HR decrease by <20 versus ≥ 20 bpm within the first 50 days of starting treatment. For the 1053 patients analyzed, the mean maximum postbaseline HR decrease was 25 bpm (standard deviation 15.8). Overall, 441 patients (41.9%) had at least one episode of postbaseline SB. The mean precrizotinib treatment HR was significantly lower among patients with versus without postbaseline SB (82.2 bpm vs. 92.6 bpm). The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. PFS was comparable among patients with or without HR decrease of ≥ 20 bpm within the first 50 days of starting crizotinib. Decrease in HR is very common among patients on crizotinib. The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. This is the first large-scale report investigating the association between treatment with a tyrosine kinase inhibitor and the development of bradycardia. HRs should be closely monitored during crizotinib treatment.

  3. Large Extremity Peripheral Nerve Repair

    DTIC Science & Technology

    2015-10-01

    regeneration using our approach with an acellular nerve allograft to be equivalent to standard autograft repair in rodent models. An ongoing large animal ...be clinically acceptable for use in the animal studies in Aim 2. The anatomy of HAM is shown pictorially in Figure 7. In vivo, the epithelial...product. Given that the large animal studies with large caliber nerves in Aim 3 will use AxoGuard we feel that the single layer SIS material is totally

  4. Querying Large Biological Network Datasets

    ERIC Educational Resources Information Center

    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.…

  5. Students' Perceptions of Large Classes.

    ERIC Educational Resources Information Center

    Wulff, Donald H.; And Others

    1987-01-01

    Students' perceptions of instruction in large classes are summarized, based on standardized questionnaires administered in lower-division large classes. Students' ratings of classes and responses to open-ended questions are discussed in terms of content and amount learned, specific instructional dimensions, and evaluation processes. (MLW)

  6. Team Learning in Large Classes.

    ERIC Educational Resources Information Center

    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…

  7. Sharpen Your Skills: Large Type.

    ERIC Educational Resources Information Center

    Knisely, Phyllis

    1983-01-01

    Three short articles about large type transcribing are provided for braille transcribers and teachers of the visually handicapped. The first article explains section IV-B-2 of the National Braille Association Manual for Large Type Transcribing. The second article presents the results of a survey on the kinds of typewriters, types of…

  8. Sharpen Your Skills: Large Type.

    ERIC Educational Resources Information Center

    Knisely, Phillis; Wickham, Marian

    1984-01-01

    Three short articles about large type transcribing are provided for braille transcribers and teachers of the visually handicapped. The first article lists general suggestions for simple typewriter maintenance. The second article reviews the guidelines for typing fractions in large type for mathematics exercises. The third article describes a…

  9. Measuring happiness in large population

    NASA Astrophysics Data System (ADS)

    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.

  10. Large engines and vehicles, 1958

    NASA Technical Reports Server (NTRS)

    1978-01-01

    During the mid-1950s, the Air Force sponsored work on the feasibility of building large, single-chamber engines, presumably for boost-glide aircraft or spacecraft. In 1956, the Army missile development group began studies of large launch vehicles. The possibilities opened up by Sputnik accelerated this work and gave the Army an opportunity to bid for the leading role in launch vehicles. The Air Force had the responsibility for the largest ballistic missiles and hence a ready-made base for extending their capability for spaceflight. During 1958, actions taken to establish a civilian space agency, and the launch vehicle needs seen by its planners, added a third contender to the space vehicle competition. These activities during 1958 are examined as to how they resulted in the initiation of a large rocket engine and the first large launch vehicle.

  11. Personalized Teaching in Large Classes.

    ERIC Educational Resources Information Center

    Silvia, Evelyn M.; Hom, Carole L.

    1996-01-01

    Refutes the assumption that large classes must be impersonal, characterized by lecture style, and presented in a theorem-proof-example format. Discusses successful strategies for space use, classroom management, and collecting student feedback. (DDR)

  12. Large Extremity Peripheral Nerve Repair

    DTIC Science & Technology

    2015-10-01

    approach with an acellular nerve allograft to be equivalent to standard autograft repair in rodent models. An ongoing large animal validation study...the animal studies in Aim 2. The anatomy of HAM is shown pictorially in Figure 7. In vivo, the epithelial layer is in contact with the amniotic...AxoGuard and Oasis SIS products are manufactured by Cook Medical. AxoGuard is simply a multi-layered SIS product. Given that the large animal studies with

  13. Large Extremity Peripheral Nerve Repair

    DTIC Science & Technology

    2015-10-01

    in rodent models. An ongoing large animal validation study will pave the way for human studies of this technology. 15. SUBJECT TERMS 16. SECURITY...to be clinically acceptable for use in the animal studies in Aim 2. The anatomy of HAM is shown pictorially in Figure 7. In vivo, the epithelial... animal studies with large caliber nerves in Aim 3 will use AxoGuard we feel that the single layer SIS material is totally appropriate for these small

  14. Laparoscopic Management of Large Myomas

    PubMed Central

    Sinha, Rakesh; Sundaram, Meenakshi

    2009-01-01

    The objective of this article is to review the different techniques that have been adopted for removal of large myomas laparoscopically. We have also quoted literature about the impact of myomas on Pregnancy and obstetrical outcome and the effect of laparoscopic myomectomy on the same. Technical modifications to remove large myomas have been described along with methods to reduce intraoperative bleeding. This comprehensive review describes all possibilities of laparoscopic myomectomy irrespective of size, site and number. PMID:22442517

  15. Does Yellowstone need large fires

    SciTech Connect

    Romme, W.H. ); Turner, M.G.; Gardner, R.H.; Hargrove, W.W. )

    1994-06-01

    This paper synthesizes several studies initiated after the 1988 Yellowstone fires, to address the question whether the ecological effects of large fires differ qualitatively as well as quantitatively from small fires. Large burn patches had greater dominance and contagion of burn severity classes, and a higher proportion of crown fire. Burned aspen stands resprouted vigorously over an extensive area, but heavy ungulate browsing prevented establishment of new tree-sized stems. A burst of sexual reproduction occurred in forest herbs that usually reproduce vegetatively, and new aspen clones became established from seed - a rare event in this region. We conclude that the effects of large fires are qualitatively different, but less dramatically so than expected.

  16. Phenomenology of Large Nc QCD

    NASA Astrophysics Data System (ADS)

    Lebed, Richard F.

    1999-09-01

    These lectures are designed to introduce the methods and results of large N c QCD in a presentation intended for nuclear and particle physicists alike. Beginning with definitions and motivations of the approach, we demonstrate that all quark and gluon Feynman diagrams are organized into classes based on powers of 1/N c. We then show that this result can be translated into definite statements about mesons and baryons containing arbitrary numbers of constituents. In the mesons, numerous well-known phenomenological properties follow as immediate consequences of simply counting powers of N c, while for the baryons, quantitative large N c analyses of masses and other properties are seen to agree with experiment, even when large” N c is set equal to its observed value of 3. Large N c reasoning is also used to explain some simple features of nuclear interactions.

  17. Large-scale structural optimization

    NASA Technical Reports Server (NTRS)

    Sobieszczanski-Sobieski, J.

    1983-01-01

    Problems encountered by aerospace designers in attempting to optimize whole aircraft are discussed, along with possible solutions. Large scale optimization, as opposed to component-by-component optimization, is hindered by computational costs, software inflexibility, concentration on a single, rather than trade-off, design methodology and the incompatibility of large-scale optimization with single program, single computer methods. The software problem can be approached by placing the full analysis outside of the optimization loop. Full analysis is then performed only periodically. Problem-dependent software can be removed from the generic code using a systems programming technique, and then embody the definitions of design variables, objective function and design constraints. Trade-off algorithms can be used at the design points to obtain quantitative answers. Finally, decomposing the large-scale problem into independent subproblems allows systematic optimization of the problems by an organization of people and machines.

  18. Pictures of Tethys' large crater.

    NASA Technical Reports Server (NTRS)

    1981-01-01

    This series of Voyager 2 pictures of Tethys shows its distinctive large crater, 400 kilometers (250 miles) in diameter, as it rotates toward the termination and limb of this satellite of Saturn. These images were obtained at four-hour intervals beginning late Aug. 24 and ending early the next day; the distances were 1.1 million km. (670,000 mi.), 826,000 km. (510,000 mi.) and 680,000 km. (420,000 mi.), respectively. The crater, the remnant of a large impact, has a central peak and several concentric rings. Some grooves radiating from the center may be formed of material thrown from the crater during the impact. The bottom frame, with the crater in profile, reveals that its floor has risen back to the spherical shape of the satellite, unlike the large crater seen on Tethys sister moon Mimas. The Voyager project is managed for NASA by the Jet Propulsion Laboratory, Pasadena, Calif.

  19. Inflating with large effective fields

    SciTech Connect

    Burgess, C.P.; Cicoli, M.; Quevedo, F.; Williams, M. E-mail: mcicoli@ictp.it E-mail: mwilliams@perimeterinsititute.ca

    2014-11-01

    We re-examine large scalar fields within effective field theory, in particular focussing on the issues raised by their use in inflationary models (as suggested by BICEP2 to obtain primordial tensor modes). We argue that when the large-field and low-energy regimes coincide the scalar dynamics is most effectively described in terms of an asymptotic large-field expansion whose form can be dictated by approximate symmetries, which also help control the size of quantum corrections. We discuss several possible symmetries that can achieve this, including pseudo-Goldstone inflatons characterized by a coset G/H (based on abelian and non-abelian, compact and non-compact symmetries), as well as symmetries that are intrinsically higher dimensional. Besides the usual trigonometric potentials of Natural Inflation we also find in this way simple large-field power laws (like V ∝ φ{sup 2}) and exponential potentials, V(φ) = ∑{sub k}V{sub x}e{sup −kφ/M}. Both of these can describe the data well and give slow-roll inflation for large fields without the need for a precise balancing of terms in the potential. The exponential potentials achieve large r through the limit |η| || ε and so predict r ≅ (8/3)(1-n{sub s}); consequently n{sub s} ≅ 0.96 gives r ≅ 0.11 but not much larger (and so could be ruled out as measurements on r and n{sub s} improve). We examine the naturalness issues for these models and give simple examples where symmetries protect these forms, using both pseudo-Goldstone inflatons (with non-abelian non-compact shift symmetries following familiar techniques from chiral perturbation theory) and extra-dimensional models.

  20. Management of large hepatocellular carcinoma.

    PubMed

    Amarapurkar, D N

    2004-04-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. There is increasing incidence of HCC in India. More than 70% of HCC are not suitable for curative treatment. Majority of the HCCs are large when diagnosed all over the world. There is no standard treatment for large HCCs. Different palliative treatments like arterial embolization/chemoembolization, intraarterial lipoidol chemotherapy, hormonal compounds like tamoxifene, octerotide systemic chemotherapy, immuno therapy with interferon, internal radiation with 131I or 99Yttrium. Arterial chemoembolization is the treatment of choice with proved efficacy in selected group of patients. The newer modalities and strategies need to be tried in controlled randomized trials.

  1. Large inert-gas thrusters

    NASA Technical Reports Server (NTRS)

    Kaufman, H. R.; Robinson, R. S.

    1981-01-01

    Using present technology as a starting point, performance predictions were made for large thrusters. The optimum beam diameter for maximum thruster efficiency was determined for a range of specific impulse. This optimum beam diameter varied greatly with specific impulse, from about 0.6 m at 3000 seconds (and below) to about 4 m at 10,000 seconds with argon, and from about 0.6 m at 2,000 seconds (and below) to about 12 m at 10,000 seconds with Xe. These beams sizes would require much larger thrusters than those presently available, but would offer substantial complexity and cost reductions for large electric propulsion systems.

  2. Ideas for Managing Large Classes.

    ERIC Educational Resources Information Center

    Kabel, Robert L.

    1983-01-01

    Describes management strategies used in a large kinetics/industrial chemistry course. Strategies are designed to make instruction in such classes more efficient and effective. Areas addressed include homework assignment, quizzes, final examination, grading and feedback, and rewards for conducting the class in the manner described. (JN)

  3. Galaxy clustering on large scales.

    PubMed Central

    Efstathiou, G

    1993-01-01

    I describe some recent observations of large-scale structure in the galaxy distribution. The best constraints come from two-dimensional galaxy surveys and studies of angular correlation functions. Results from galaxy redshift surveys are much less precise but are consistent with the angular correlations, provided the distortions in mapping between real-space and redshift-space are relatively weak. The galaxy two-point correlation function, rich-cluster two-point correlation function, and galaxy-cluster cross-correlation function are all well described on large scales ( greater, similar 20h-1 Mpc, where the Hubble constant, H0 = 100h km.s-1.Mpc; 1 pc = 3.09 x 10(16) m) by the power spectrum of an initially scale-invariant, adiabatic, cold-dark-matter Universe with Gamma = Omegah approximately 0.2. I discuss how this fits in with the Cosmic Background Explorer (COBE) satellite detection of large-scale anisotropies in the microwave background radiation and other measures of large-scale structure in the Universe. PMID:11607400

  4. Large gap magnetic suspension system

    NASA Technical Reports Server (NTRS)

    Abdelsalam, Moustafa K.; Eyssa, Y. M.

    1991-01-01

    The design of a large gap magnetic suspension system is discussed. Some of the topics covered include: the system configuration, permanent magnet material, levitation magnet system, superconducting magnets, resistive magnets, superconducting levitation coils, resistive levitation coils, levitation magnet system, and the nitrogen cooled magnet system.

  5. Making Large Classes More Interactive.

    ERIC Educational Resources Information Center

    Brenner, John

    2000-01-01

    Describes the method of using prompts to allow students to have more "voice" in a large class. The prompt assignment requires students to respond anonymously to a statement that concerns the chapter being discussed in the class. Discusses how the Internet has allowed more freedom with the prompts. Puts forth some student responses to the…

  6. Fermi's Large Area Telescope (LAT)

    NASA Video Gallery

    Fermi’s Large Area Telescope (LAT) is the spacecraft’s main scientificinstrument. This animation shows a gamma ray (purple) entering the LAT,where it is converted into an electron (red) and a...

  7. The very large hadron collider

    SciTech Connect

    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.

  8. Large pure intracranial vagal schwannoma.

    PubMed

    Gazzeri, Roberto; Galarza, Marcelo; Costanzo, De Bonis; Carotenuto, Vincenzo; D'Angelo, Vincenzo

    2009-04-01

    We report a patient with a large, pure intracranial vagal schwannoma, compressing the medulla who presented with essential hypertension. Based on this and on previous cases, we suggest that a differentiation of pure intracranial schwannomas (subtype A1) from intracranial schwannomas with some extension in the jugular foramen (type A) should be used.

  9. Energy conservation in large buildings

    NASA Astrophysics Data System (ADS)

    Rosenfeld, A.; Hafemeister, D.

    1985-11-01

    As energy prices rise, newly energy aware designers use better tools and technology to create energy efficient buildings. Thus the U.S. office stock (average age 20 years) uses 250 kBTU/ft2 of resource energy, but the guzzler of 1972 uses 500 (up×2), and the 1986 ASHRAE standards call for 100-125 (less than 25% of their 1972 ancestors). Surprisingly, the first real cost of these efficient buildings has not risen since 1972. Scaling laws are used to calculate heat gains and losses of buildings to obtain the ΔT(free) which can be as large as 15-30 °C (30-60 °F) for large buildings. The net thermal demand and thermal time constants are determined for the Swedish Thermodeck buildings which need essentially no heat in the winter and no chillers in summer. The BECA and other data bases for large buildings are discussed. Off-peak cooling for large buildings is analyzed in terms of saving peak-electrical power. By downsizing chillers and using cheaper, off-peak power, cost-effective thermal storage in new commercial buildings can reduce U.S. peak power demands by 10-20 GW in 15 years. A further potential of about 40 GW is available from adopting partial thermal storage and more efficient air conditioners in existing buildings.

  10. Large deviations and portfolio optimization

    NASA Astrophysics Data System (ADS)

    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.

  11. Large deviations in Taylor dispersion

    NASA Astrophysics Data System (ADS)

    Kahlen, Marcel; Engel, Andreas; Van den Broeck, Christian

    2017-01-01

    We establish a link between the phenomenon of Taylor dispersion and the theory of empirical distributions. Using this connection, we derive, upon applying the theory of large deviations, an alternative and much more precise description of the long-time regime for Taylor dispersion.

  12. Pesa Large Red Dry Bean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Released in 2006, Pesa was derived from the single cross Rojo x Kablanketi made in Dec-Jan 1992-93. The parent ‘Rojo’ is a large red-seeded cultivar released by SUA in 1997. It has I bc-12 resistance to BCMV and BCMNV, resistance to the prevalent races of ALS, and moderate resistance to CBB, and H...

  13. The physics of large eruptions

    NASA Astrophysics Data System (ADS)

    Gudmundsson, Agust

    2015-04-01

    Based on eruptive volumes, eruptions can be classified as follows: small if the volumes are from less than 0.001 km3 to 0.1 km3, moderate if the volumes are from 0.1 to 10 km3, and large if the volumes are from 10 km3 to 1000 km3 or larger. The largest known explosive and effusive eruptions have eruptive volumes of 4000-5000 km3. The physics of small to moderate eruptions is reasonably well understood. For a typical mafic magma chamber in a crust that behaves as elastic, about 0.1% of the magma leaves the chamber (erupted and injected as a dyke) during rupture and eruption. Similarly, for a typical felsic magma chamber, the eruptive/injected volume during rupture and eruption is about 4%. To provide small to moderate eruptions, chamber volumes of the order of several tens to several hundred cubic kilometres would be needed. Shallow crustal chambers of these sizes are common, and deep-crustal and upper-mantle reservoirs of thousands of cubic kilometres exist. Thus, elastic and poro-elastic chambers of typical volumes can account for small to moderate eruptive volumes. When the eruptions become large, with volumes of tens or hundreds of cubic kilometres or more, an ordinary poro-elastic mechanism can no longer explain the eruptive volumes. The required sizes of the magma chambers and reservoirs to explain such volumes are simply too large to be plausible. Here I propose that the mechanics of large eruptions is fundamentally different from that of small to moderate eruptions. More specifically, I suggest that all large eruptions derive their magmas from chambers and reservoirs whose total cavity-volumes are mechanically reduced very much during the eruption. There are two mechanisms by which chamber/reservoir cavity-volumes can be reduced rapidly so as to squeeze out much of, or all, their magmas. One is piston-like caldera collapse. The other is graben subsidence. During large slip on the ring-faults/graben-faults the associated chamber/reservoir shrinks in volume

  14. Large space structure damping design

    NASA Technical Reports Server (NTRS)

    Pilkey, W. D.; Haviland, J. K.

    1983-01-01

    Several FORTRAN subroutines and programs were developed which compute complex eigenvalues of a damped system using different approaches, and which rescale mode shapes to unit generalized mass and make rigid bodies orthogonal to each other. An analytical proof of a Minimum Constrained Frequency Criterion (MCFC) for a single damper is presented. A method to minimize the effect of control spill-over for large space structures is proposed. The characteristic equation of an undamped system with a generalized control law is derived using reanalysis theory. This equation can be implemented in computer programs for efficient eigenvalue analysis or control quasi synthesis. Methods to control vibrations in large space structure are reviewed and analyzed. The resulting prototype, using electromagnetic actuator, is described.

  15. Structural qualification of large spacecraft

    NASA Technical Reports Server (NTRS)

    Wada, Ben K.

    1986-01-01

    Over the past twenty-five (25) years of the space program, the major challenge in the structural qualification of the primary structure has shifted from conducting a test that simulated the environment to accurately predicting the structural member loads in flight. Once the flight loads are avaliable, a number of different test methods are used to qualify the structure by subjecting it to the proper loads. The qualification challenge for future large spacecraft will be to adequately predict its dynamic characteristic in space to assure that it can be controlled to meet the mission objectives. A new test concept that may allow acquisition of modal data by ground tests for verification of mathematical models of large flexible space structures which can't be ground tested by conventional methods is discussed.

  16. Development of large rotorcraft transmissions

    NASA Technical Reports Server (NTRS)

    Samanich, N. E.; Drago, R. J.; Mack, J. C.

    1984-01-01

    The U.S. Army Heavy Lift Helicopter (HLH) represents a large rotorcraft which was developed by an American aerospace company. In the early 1970's with the HLH Advanced Technology Components (ATC) program, the development of large rotorcraft transmission and drive systems was started. Failures in the spiral bevel gearing were experienced in tests because the employed method of analysis had not considered the effect of rim bending. Consequently, new gears with strengthened rims were designed and fabricated. For a more accurate prediction of the load capacity of the gears, an extensive Finite Element Method (FEM) system was developed. The U.S. Army's XCH-62 HLH aft rotor transmission was finally successfully tested at full design torque and speed. A description of the test program is provided, and the analytical program is discussed. The analytical phase includes the development of a preprocessing program which aids in the review of calculated FEM stresses.

  17. Large aperture Fresnel telescopes/011

    SciTech Connect

    Hyde, R.A., LLNL

    1998-07-16

    At Livermore we`ve spent the last two years examining an alternative approach towards very large aperture (VLA) telescopes, one based upon transmissive Fresnel lenses rather than on mirrors. Fresnel lenses are attractive for VLA telescopes because they are launchable (lightweight, packagable, and deployable) and because they virtually eliminate the traditional, very tight, surface shape requirements faced by reflecting telescopes. Their (potentially severe) optical drawback, a very narrow spectral bandwidth, can be eliminated by use of a second (much smaller) chromatically-correcting Fresnel element. This enables Fresnel VLA telescopes to provide either single band ({Delta}{lambda}/{lambda} {approximately} 0.1), multiple band, or continuous spectral coverage. Building and fielding such large Fresnel lenses will present a significant challenge, but one which appears, with effort, to be solvable.

  18. Large Capacity Missile Carrier (CMX)

    DTIC Science & Technology

    1993-12-01

    is examined. It is included that the benefits of the large number of additional missiles provided by the CMX more than offsets the lost capability of...project was to exercise the ship design process from the requirements setting phase through the preliminary design, including design analysis. The...Navy to meet the challenges ensuing from this assumed global scenario. The Student Design Team was tasked to develop scenarios for the deployment of the

  19. Collapse of large vapor bubbles

    NASA Technical Reports Server (NTRS)

    Tegart, J.; Dominick, S.

    1982-01-01

    The refilling of propellant tanks while in a low-gravity environment requires that entrapped vapor bubbles be collapsed by increasing the system pressure. Tests were performed to verify the mechanism of collapse for these large vapor bubbles with the thermodynamic conditions, geometry, and boundary conditions being those applicable to propellant storage systems. For these conditions it was found that conduction heat transfer determined the collapse rate, with the specific bubble geometry having a significant influence.

  20. Simulating cosmic reionization: how large a volume is large enough?

    NASA Astrophysics Data System (ADS)

    Iliev, Ilian T.; Mellema, Garrelt; Ahn, Kyungjin; Shapiro, Paul R.; Mao, Yi; Pen, Ue-Li

    2014-03-01

    We present the largest-volume (425 Mpc h-1 = 607 Mpc on a side) full radiative transfer simulation of cosmic reionization to date. We show that there is significant additional power in density fluctuations at very large scales. We systematically investigate the effects this additional power has on the progress, duration and features of reionization and on selected reionization observables. We find that comoving volume of ˜100 Mpc h-1 per side is sufficient for deriving a convergent mean reionization history, but that the reionization patchiness is significantly underestimated. We use jackknife splitting to quantify the convergence of reionization properties with simulation volume. We find that sub-volumes of ˜100 Mpc h-1 per side or larger yield convergent reionization histories, except for the earliest times, but smaller volumes of ˜50 Mpc h-1 or less are not well converged at any redshift. Reionization history milestones show significant scatter between the sub-volumes, as high as Δz ˜ 1 for ˜50 Mpc h-1 volumes. If we only consider mean-density sub-regions the scatter decreases, but remains at Δz ˜ 0.1-0.2 for the different size sub-volumes. Consequently, many potential reionization observables like 21-cm rms, 21-cm PDF skewness and kurtosis all show good convergence for volumes of ˜200 Mpc h-1, but retain considerable scatter for smaller volumes. In contrast, the three-dimensional 21-cm power spectra at large scales (k < 0.25 h Mpc-1) do not fully converge for any sub-volume size. These additional large-scale fluctuations significantly enhance the 21-cm fluctuations, which should improve the prospects of detection considerably, given the lower foregrounds and greater interferometer sensitivity at higher frequencies.

  1. Large Component Removal/Disposal

    SciTech Connect

    Wheeler, D. M.

    2002-02-27

    This paper describes the removal and disposal of the large components from Maine Yankee Atomic Power Plant. The large components discussed include the three steam generators, pressurizer, and reactor pressure vessel. Two separate Exemption Requests, which included radiological characterizations, shielding evaluations, structural evaluations and transportation plans, were prepared and issued to the DOT for approval to ship these components; the first was for the three steam generators and one pressurizer, the second was for the reactor pressure vessel. Both Exemption Requests were submitted to the DOT in November 1999. The DOT approved the Exemption Requests in May and July of 2000, respectively. The steam generators and pressurizer have been removed from Maine Yankee and shipped to the processing facility. They were removed from Maine Yankee's Containment Building, loaded onto specially designed skid assemblies, transported onto two separate barges, tied down to the barges, th en shipped 2750 miles to Memphis, Tennessee for processing. The Reactor Pressure Vessel Removal Project is currently under way and scheduled to be completed by Fall of 2002. The planning, preparation and removal of these large components has required extensive efforts in planning and implementation on the part of all parties involved.

  2. Aberrant expression of the dendritic cell marker TNFAIP2 by the malignant cells of Hodgkin lymphoma and primary mediastinal large B-cell lymphoma distinguishes these tumor types from morphologically and phenotypically similar lymphomas.

    PubMed

    Kondratiev, Svetlana; Duraisamy, Sekhar; Unitt, Christine L; Green, Michael R; Pinkus, Geraldine S; Shipp, Margaret A; Kutok, Jeffery L; Drapkin, Ronny I; Rodig, Scott J

    2011-10-01

    Tumor necrosis factor-α-inducible protein-2 (TNFAIP2) is a protein upregulated in cultured cells treated with tumor necrosis factor α (TNF), but its expression in normal and neoplastic tissues remains largely unknown. Here, we use standard immunohistochemical techniques to demonstrate that TNFAIP2 is normally expressed by follicular dendritic cells, interdigitating dendritic cells, and macrophages but not by lymphoid cells in secondary lymphoid tissues. Consistent with this expression pattern, we found strong TNFAIP2 staining of tumor cells in 4 of 4 cases (100%) of follicular dendritic cell sarcoma and in 3 of 3 cases (100%) of histiocytic sarcoma. Although TNFAIP2 is not expressed by the small and intermediate-sized neoplastic B cells comprising follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, or marginal zone lymphoma, we observed strong TNFAIP2 staining of the large, neoplastic cells in 31 of 31 cases (100%) of classical Hodgkin lymphoma, in 12 of 12 cases (100%) of nodular lymphocyte-predominant Hodgkin lymphoma, and in 27 of 31 cases (87%) of primary mediastinal (thymic) large B-cell lymphoma. In contrast, TNFAIP2 was expressed by malignant cells in only 2 of 45 cases (4%) of diffuse large B-cell lymphoma, not otherwise specified, in 2 of 18 cases (11%) of Burkitt lymphoma, and in 1 of 19 cases (5%) of anaplastic large cell lymphoma. Further analysis indicates that TNFAIP2, as a single diagnostic marker, is more sensitive (sensitivity=87%) and specific (specificity=96%) than TRAF1, nuclear cRel, or CD23 for distinguishing the malignant B cells of primary mediastinal (thymic) large B-cell lymphoma from those of its morphologic and immunophenotypic mimic, diffuse large B-cell lymphoma, not otherwise specified. Thus, TNFAIP2 may serve as a useful new marker of dendritic and histiocytic sarcomas, the aberrant expression of which in the malignant cells of classical Hodgkin lymphoma and primary mediastinal (thymic) large B-cell lymphoma

  3. TURP for BPH. How large is too large?

    PubMed

    Persu, C; Georgescu, D; Arabagiu, I; Cauni, V; Moldoveanu, C; Geavlete, P

    2010-01-01

    BPH remains one of the most common diseases that the urologist has to manage. The last decade brought numerous new techniques, aiming to improve the minimally invasive approach to BPH, but, for the moment, none had changed the place of TURP as the gold standard treatment for medium sized prostates. Based on a large personal experience, the authors present a study in which TURP is used for prostates over 80 ml, the cutoff point set by the guidelines of the European Association of Urology. The rationale for this study is that many situations require minimally invasive treatment, based on the express request of the patient, other conditions that makes open surgery very difficult or impossible, or the need for a quick discharge in an overcrowded service. The aim of the study was to prove that TURP is safe and effective even in larger prostates. The technique used is basically the classic one, with minor tactical alterations in some cases. Some cases required a two-stage approach, but offered good functional results after the first stage. The results proved that, with a good technique, a skilled urologist might achieve the same results by using TURP or open surgery for large sized prostates.

  4. TURP for BPH. How Large is Too Large?

    PubMed Central

    Georgescu, D; Arabagiu, I; Cauni, V; Moldoveanu, C; Geavlete, P

    2010-01-01

    BPH remains one of the most common disease that the urologist has to manage. The last decade brought numerous new techniques, aiming to improve the minimally invasive approach to BPH, but none had, for the moment, changed the place of TURP as the gold standard treatment for medium sized prostates. Based on a large personal experience, the authors present a study in which TURP is used for prostates over 80ml, the cutoff point set by the guidelines of the European Association of Urology. The rationale for this study is that many situations require minimally invasive treatment, based on the express request of the patient, other conditions that makes open surgery very difficult or impossible, or the need for a quick discharge in an overcrowded service. The aim of the study was to prove that TURP is safe and effective even in larger prostates. The technique used is basically the classic one, with minor tactical alterations in some cases. Some cases required a two-stage approach, but offered good functional results after the first stage. The results proved that, with a good technique, a skilled urologist might achieve the same results by using TURP or open surgery for large sized prostates. PMID:21254734

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

    NASA Astrophysics Data System (ADS)

    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

  6. Large-bore pipe decontamination

    SciTech Connect

    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.

  7. Foreshock occurrence before large earthquakes

    USGS Publications Warehouse

    Reasenberg, P.A.

    1999-01-01

    Rates of foreshock occurrence involving shallow M ??? 6 and M ??? 7 mainshocks and M ??? 5 foreshocks were measured in two worldwide catalogs over ???20-year intervals. The overall rates observed are similar to ones measured in previous worldwide and regional studies when they are normalized for the ranges of magnitude difference they each span. The observed worldwide rates were compared to a generic model of earthquake clustering based on patterns of small and moderate aftershocks in California. The aftershock model was extended to the case of moderate foreshocks preceding large mainshocks. Overall, the observed worldwide foreshock rates exceed the extended California generic model by a factor of ???2. Significant differences in foreshock rate were found among subsets of earthquakes defined by their focal mechanism and tectonic region, with the rate before thrust events higher and the rate before strike-slip events lower than the worldwide average. Among the thrust events, a large majority, composed of events located in shallow subduction zones, had a high foreshock rate, while a minority, located in continental thrust belts, had a low rate. These differences may explain why previous surveys have found low foreshock rates among thrust events in California (especially southern California), while the worldwide observations suggests the opposite: California, lacking an active subduction zone in most of its territory, and including a region of mountain-building thrusts in the south, reflects the low rate apparently typical for continental thrusts, while the worldwide observations, dominated by shallow subduction zone events, are foreshock-rich. If this is so, then the California generic model may significantly underestimate the conditional probability for a very large (M ??? 8) earthquake following a potential (M ??? 7) foreshock in Cascadia. The magnitude differences among the identified foreshock-mainshock pairs in the Harvard catalog are consistent with a uniform

  8. the Large Aperture GRB Observatory

    SciTech Connect

    Bertou, Xavier

    2009-04-30

    The Large Aperture GRB Observatory (LAGO) aims at the detection of high energy photons from Gamma Ray Bursts (GRB) using the single particle technique (SPT) in ground based water Cherenkov detectors (WCD). To reach a reasonable sensitivity, high altitude mountain sites have been selected in Mexico (Sierra Negra, 4550 m a.s.l.), Bolivia (Chacaltaya, 5300 m a.s.l.) and Venezuela (Merida, 4765 m a.s.l.). We report on the project progresses and the first operation at high altitude, search for bursts in 6 months of preliminary data, as well as search for signal at ground level when satellites report a burst.

  9. Large block test status report

    SciTech Connect

    Wilder, D.G.; Lin, W.; Blair, S.C.

    1997-08-26

    This report is intended to serve as a status report, which essentially transmits the data that have been collected to date on the Large Block Test (LBT). The analyses of data will be performed during FY98, and then a complete report will be prepared. This status report includes introductory material that is not needed merely to transmit data but is available at this time and therefore included. As such, this status report will serve as the template for the future report, and the information is thus preserved.

  10. LHC: The Large Hadron Collider

    ScienceCinema

    Lincoln, Don

    2016-07-12

    The Large Hadron Collider (or LHC) is the world’s most powerful particle accelerator. In 2012, scientists used data taken by it to discover the Higgs boson, before pausing operations for upgrades and improvements. In the spring of 2015, the LHC will return to operations with 163% the energy it had before and with three times as many collisions per second. It’s essentially a new and improved version of itself. In this video, Fermilab’s Dr. Don Lincoln explains both some of the absolutely amazing scientific and engineering properties of this modern scientific wonder.

  11. Large holograms in traveling exhibitions

    NASA Astrophysics Data System (ADS)

    Christakis, Anne-Marie

    1994-01-01

    The presentation of large holograms in travelling exhibitions has always posed problems, mainly due to lack of space. The Museum of Holography was consequently required to develop, with Jean-Francois Moreau, display consoles which are light, affordable and completely detachable. In a permanent exposition at the Forum des Halles in Paris, the Museum displays a room with 22 holograms, each measuring 1 m X 1 m, in a structure designed by the architect Fabien Vienne. The different systems used by the Museum are presented here.

  12. Radiative transport in large arteries

    PubMed Central

    Ruh, Dominic; Subramanian, Sivaraman; Theodor, Michael; Zappe, Hans; Seifert, Andreas

    2013-01-01

    A refined model for the photon energy distribution in a living artery is established by solving the radiative transfer equation in a cylindrical geometry, using the Monte Carlo method. Combining this model with the most recent experimental values for the optical properties of flowing blood and the biomechanics of a blood-filled artery subject to a pulsatile pressure, we find that the optical intensity transmitted through large arteries decreases linearly with increasing arterial distension. This finding provides a solid theoretical foundation for measuring photoplethysmograms. PMID:24466476

  13. Aeroacoustics of large wind turbines

    NASA Technical Reports Server (NTRS)

    Hubbard, Harvey H.; Shepherd, Kevin P.

    1991-01-01

    This paper reviews published information on aerodynamically generated noise from large horizontal axis wind turbines operated for electric power generation. Methods are presented for predicting both the discrete frequency rotational noise components and the broadband noise components, and results are compared with measurements. Refraction effects that result in the formation of high-frequency shadow zones in the upwind direction and channeling effects for the low frequencies in the downwind direction are illustrated. Special topics such as distributed source effects in prediction and the role of building dynamics in perception are also included.

  14. Large spin systematics in CFT

    NASA Astrophysics Data System (ADS)

    Alday, Luis F.; Bissi, Agnese; Lukowski, Tomasz

    2015-11-01

    Using conformal field theory (CFT) arguments we derive an infinite number of constraints on the large spin expansion of the anomalous dimensions and structure constants of higher spin operators. These arguments rely only on analyticity, unitarity, crossing-symmetry and the structure of the conformal partial wave expansion. We obtain results for both, perturbative CFT to all order in the perturbation parameter, as well as non-perturbatively. For the case of conformal gauge theories this provides a proof of the reciprocity principle to all orders in perturbation theory and provides a new "reciprocity" principle for structure constants. We argue that these results extend also to non-conformal theories.

  15. LHC: The Large Hadron Collider

    SciTech Connect

    Lincoln, Don

    2015-03-04

    The Large Hadron Collider (or LHC) is the world’s most powerful particle accelerator. In 2012, scientists used data taken by it to discover the Higgs boson, before pausing operations for upgrades and improvements. In the spring of 2015, the LHC will return to operations with 163% the energy it had before and with three times as many collisions per second. It’s essentially a new and improved version of itself. In this video, Fermilab’s Dr. Don Lincoln explains both some of the absolutely amazing scientific and engineering properties of this modern scientific wonder.

  16. Mobile Platform for Large Structures

    NASA Technical Reports Server (NTRS)

    Wesselski, C. J.; Schneider, W. C.

    1987-01-01

    Proposed platform moves forward and in reverse, turns left and right, and changes planes. Mobile-platform concept proposed to move remote manipulators, workers, or other loads over truss panels on large structures. Platform moves at constant speed so does not cause swinging motion in hanging loads and overstress remote-manipulator arms. Transferred around corners to adjacent panels. Platform rides on sprocketed guide pins extending from structure at truss joints. Set of orthogonal tracks under platform slides on pins, which have enlarged heads to interlock with tracks. At least three tracks engage at least three pins at any position on panel so platform adequately and stably supported.

  17. Large-Scale Sequence Comparison.

    PubMed

    Lal, Devi; Verma, Mansi

    2017-01-01

    There are millions of sequences deposited in genomic databases, and it is an important task to categorize them according to their structural and functional roles. Sequence comparison is a prerequisite for proper categorization of both DNA and protein sequences, and helps in assigning a putative or hypothetical structure and function to a given sequence. There are various methods available for comparing sequences, alignment being first and foremost for sequences with a small number of base pairs as well as for large-scale genome comparison. Various tools are available for performing pairwise large sequence comparison. The best known tools either perform global alignment or generate local alignments between the two sequences. In this chapter we first provide basic information regarding sequence comparison. This is followed by the description of the PAM and BLOSUM matrices that form the basis of sequence comparison. We also give a practical overview of currently available methods such as BLAST and FASTA, followed by a description and overview of tools available for genome comparison including LAGAN, MumMER, BLASTZ, and AVID.

  18. Mesoscale Ocean Large Eddy Simulations

    NASA Astrophysics Data System (ADS)

    Pearson, Brodie; Fox-Kemper, Baylor; Bachman, Scott; Bryan, Frank

    2015-11-01

    The highest resolution global climate models (GCMs) can now resolve the largest scales of mesoscale dynamics in the ocean. This has the potential to increase the fidelity of GCMs. However, the effects of the smallest, unresolved, scales of mesoscale dynamics must still be parametrized. One such family of parametrizations are mesoscale ocean large eddy simulations (MOLES), but the effects of including MOLES in a GCM are not well understood. In this presentation, several MOLES schemes are implemented in a mesoscale-resolving GCM (CESM), and the resulting flow is compared with that produced by more traditional sub-grid parametrizations. Large eddy simulation (LES) is used to simulate flows where the largest scales of turbulent motion are resolved, but the smallest scales are not resolved. LES has traditionally been used to study 3D turbulence, but recently it has also been applied to idealized 2D and quasi-geostrophic (QG) turbulence. The MOLES presented here are based on 2D and QG LES schemes.

  19. Large aperture diffractive space telescope

    DOEpatents

    Hyde, Roderick A.

    2001-01-01

    A large (10's of meters) aperture space telescope including two separate spacecraft--an optical primary objective lens functioning as a magnifying glass and an optical secondary functioning as an eyepiece. The spacecraft are spaced up to several kilometers apart with the eyepiece directly behind the magnifying glass "aiming" at an intended target with their relative orientation determining the optical axis of the telescope and hence the targets being observed. The objective lens includes a very large-aperture, very-thin-membrane, diffractive lens, e.g., a Fresnel lens, which intercepts incoming light over its full aperture and focuses it towards the eyepiece. The eyepiece has a much smaller, meter-scale aperture and is designed to move along the focal surface of the objective lens, gathering up the incoming light and converting it to high quality images. The positions of the two space craft are controlled both to maintain a good optical focus and to point at desired targets which may be either earth bound or celestial.

  20. Damping characterization in large structures

    NASA Technical Reports Server (NTRS)

    Eke, Fidelis O.; Eke, Estelle M.

    1991-01-01

    This research project has as its main goal the development of methods for selecting the damping characteristics of components of a large structure or multibody system, in such a way as to produce some desired system damping characteristics. The main need for such an analytical device is in the simulation of the dynamics of multibody systems consisting, at least partially, of flexible components. The reason for this need is that all existing simulation codes for multibody systems require component-by-component characterization of complex systems, whereas requirements (including damping) often appear at the overall system level. The main goal was met in large part by the development of a method that will in fact synthesize component damping matrices from a given system damping matrix. The restrictions to the method are that the desired system damping matrix must be diagonal (which is almost always the case) and that interbody connections must be by simple hinges. In addition to the technical outcome, this project contributed positively to the educational and research infrastructure of Tuskegee University - a Historically Black Institution.

  1. Large amplitude drop shape oscillations

    NASA Technical Reports Server (NTRS)

    Trinh, E. H.; Wang, T. G.

    1982-01-01

    An experimental study of large amplitude drop shape oscillation was conducted in immiscible liquids systems and with levitated free liquid drops in air. In liquid-liquid systems the results indicate the existence of familiar characteristics of nonlinear phenomena. The resonance frequency of the fundamental quadrupole mode of stationary, low viscosity Silicone oil drops acoustically levitated in water falls to noticeably low values as the amplitude of oscillation is increased. A typical, experimentally determined relative frequency decrease of a 0.5 cubic centimeters drop would be about 10% when the maximum deformed shape is characterized by a major to minor axial ratio of 1.9. On the other hand, no change in the fundamental mode frequency could be detected for 1 mm drops levitated in air. The experimental data for the decay constant of the quadrupole mode of drops immersed in a liquid host indicate a slight increase for larger oscillation amplitudes. A qualitative investigation of the internal fluid flows for such drops revealed the existence of steady internal circulation within drops oscillating in the fundamental and higher modes. The flow field configuration in the outer host liquid is also significantly altered when the drop oscillation amplitude becomes large.

  2. Historical challenge of large lenses

    NASA Astrophysics Data System (ADS)

    Johnson, Kevin L.

    2002-02-01

    To present a full account of the developments in the manufacture of large lenses one needs to address wider issues rather than just provide a catalogue of technological progress. The advances in glass manufacture and improvement in optical techniques have to be considered in relation to the cultural, social and economic factors that have determined where, how and why large lens manufacture developed in specific countries. The challenge facing historians trying to tackle this technological theme, is that it is often poorly documented and little is preserved in the historical records. Until relatively recent times, opticians have concealed their methods, trade secrecy being an important economic strategy. To provide an example, it should be noted that although William Herschel produced the best optics and telescopes of the day, he published practically nothing about his methods. What has been gleaned of his techniques has only been uncovered by careful study of surviving manuscript sources and measurement of his surviving optics. Such was William's personal knowledge, that his son John had to take instruction from his father to refurbish William Herschel's 20-foot telescope. This training gave John tacit knowledge of William's methods and allowed him to successfully undertake his cape observations in the Southern Hemisphere. In spite of the shortcomings of the historical record, historians can give a measured account of the developments of lens optics by studying surviving telescopes and their optics.

  3. Large phased-array radars

    SciTech Connect

    Brookner, D.E.

    1988-12-15

    Large phased-array radars can play a very important part in arms control. They can be used to determine the number of RVs being deployed, the type of targeting of the RVs (the same or different targets), the shape of the deployed objects, and possibly the weight and yields of the deployed RVs. They can provide this information at night as well as during the day and during rain and cloud covered conditions. The radar can be on the ground, on a ship, in an airplane, or space-borne. Airborne and space-borne radars can provide high resolution map images of the ground for reconnaissance, of anti-ballistic missile (ABM) ground radar installations, missile launch sites, and tactical targets such as trucks and tanks. The large ground based radars can have microwave carrier frequencies or be at HF (high frequency). For a ground-based HF radar the signal is reflected off the ionosphere so as to provide over-the-horizon (OTH) viewing of targets. OTH radars can potentially be used to monitor stealth targets and missile traffic.

  4. Large scale cluster computing workshop

    SciTech Connect

    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.

  5. Large data centers interconnect bottlenecks.

    PubMed

    Ghiasi, Ali

    2015-02-09

    Large data centers interconnect bottlenecks are dominated by the switch I/O BW and the front panel BW as a result of pluggable modules. To overcome the front panel BW and the switch ASIC BW limitation one approach is to either move the optics onto the mid-plan or integrate the optics into the switch ASIC. Over the last 4 years, VCSEL based optical engines have been integrated into the packages of large-scale HPC routers, moderate size Ethernet switches, and even FPGA's. Competing solutions based on Silicon Photonics (SiP) have also been proposed for integration into HPC and Ethernet switch packages but with better integration path through the use of TSV (Through Silicon Via) stack dies. Integrating either VCSEL or SiP based optical engines into complex ASIC package that operates at high temperatures, where the required reliability is not trivial, one should ask what is the technical or the economic advantage before embarking on such a complex integration. High density Ethernet switches addressing data centers currently in development are based on 25G NRZ signaling and QSFP28 optical module that can support up to 3.6 Tb of front panel bandwidth.

  6. Infrastructure for large space telescopes

    NASA Astrophysics Data System (ADS)

    MacEwen, Howard A.; Lillie, Charles F.

    2016-10-01

    It is generally recognized (e.g., in the National Aeronautics and Space Administration response to recent congressional appropriations) that future space observatories must be serviceable, even if they are orbiting in deep space (e.g., around the Sun-Earth libration point, SEL2). On the basis of this legislation, we believe that budgetary considerations throughout the foreseeable future will require that large, long-lived astrophysics missions must be designed as evolvable semipermanent observatories that will be serviced using an operational, in-space infrastructure. We believe that the development of this infrastructure will include the design and development of a small to mid-sized servicing vehicle (MiniServ) as a key element of an affordable infrastructure for in-space assembly and servicing of future space vehicles. This can be accomplished by the adaptation of technology developed over the past half-century into a vehicle approximately the size of the ascent stage of the Apollo Lunar Module to provide some of the servicing capabilities that will be needed by very large telescopes located in deep space in the near future (2020s and 2030s). We specifically address the need for a detailed study of these servicing requirements and the current proposals for using presently available technologies to provide the appropriate infrastructure.

  7. Histotripsy Liquefaction of Large Hematomas.

    PubMed

    Khokhlova, Tatiana D; Monsky, Wayne L; Haider, Yasser A; Maxwell, Adam D; Wang, Yak-Nam; Matula, Thomas J

    2016-07-01

    Intra- and extra-muscular hematomas result from repetitive injury as well as sharp and blunt limb trauma. The clinical consequences can be serious, including debilitating pain and functional deficit. There are currently no short-term treatment options for large hematomas, only lengthy conservative treatment. The goal of this work was to evaluate the feasibility of a high intensity focused ultrasound (HIFU)-based technique, termed histotripsy, for rapid (within a clinically relevant timeframe of 15-20 min) liquefaction of large volume (up to 20 mL) extra-vascular hematomas for subsequent fine-needle aspiration. Experiments were performed using in vitro extravascular hematoma phantoms-fresh bovine blood poured into 50 mL molds and allowed to clot. The resulting phantoms were treated by boiling histotripsy (BH), cavitation histotripsy (CH) or a combination in a degassed water tank under ultrasound guidance. Two different transducers operating at 1 MHz and 1.5 MHz with f-number = 1 were used. The liquefied lysate was aspirated and analyzed by histology and sized in a Coulter Counter. The peak instantaneous power to achieve BH was lower than (at 1.5 MHz) or equal to (at 1 MHz) that which was required to initiate CH. Under the same exposure duration, BH-induced cavities were one and a half to two times larger than the CH-induced cavities, but the CH-induced cavities were more regularly shaped, facilitating easier aspiration. The lysates contained a small amount of debris larger than 70 μm, and 99% of particulates were smaller than 10 μm. A combination treatment of BH (for initial debulking) and CH (for liquefaction of small residual fragments) yielded 20 mL of lysate within 17.5 minutes of treatment and was found to be most optimal for liquefaction of large extravascular hematomas.

  8. Large Space Antenna Systems Technology, 1984

    NASA Technical Reports Server (NTRS)

    Boyer, W. J. (Compiler)

    1985-01-01

    Mission applications for large space antenna systems; large space antenna structural systems; materials and structures technology; structural dynamics and control technology, electromagnetics technology, large space antenna systems and the Space Station; and flight test and evaluation were examined.

  9. Large amplitude relativistic plasma waves

    SciTech Connect

    Coffey, Timothy

    2010-05-15

    Relativistic, longitudinal plasma oscillations are studied for the case of a simple water bag distribution of electrons having cylindrical symmetry in momentum space with the axis of the cylinder parallel to the velocity of wave propagation. The plasma is required to obey the relativistic Vlasov-Poisson equations, and solutions are sought in the wave frame. An exact solution for the plasma density as a function of the electrostatic field is derived. The maximum electric field is presented in terms of an integral over the known density. It is shown that when the perpendicular momentum is neglected, the maximum electric field approaches infinity as the wave phase velocity approaches the speed of light. It is also shown that for any nonzero perpendicular momentum, the maximum electric field will remain finite as the wave phase velocity approaches the speed of light. The relationship to previously published solutions is discussed as is some recent controversy regarding the proper modeling of large amplitude relativistic plasma waves.

  10. Large-scale Digitoxin Intoxication

    PubMed Central

    Lely, A. H.; Van Enter, C. H. J.

    1970-01-01

    Because of an error in the manufacture of digoxin tablets a large number of patients took tablets that contained 0·20 mg. of digitoxin and 0·05 mg. of digoxin instead of the prescribed 0·25 mg. of digoxin. The symptoms are described of 179 patients who took these tablets and suffered from digitalis intoxication. Of these patients, 125 had taken the faultily composed tablets for more than three weeks. In 48 patients 105 separate disturbances in rhythm or in atrioventricular conduction were observed on the electrocardiogram. Extreme fatigue and serious eye conditions were observed in 95% of the patients. Twelve patients had a transient psychosis. Extensive ophthalmological observations indicated that the visual complaints were most probably caused by a transient retrobulbar neuritis. PMID:5273245

  11. Large area pulsed solar simulator

    NASA Technical Reports Server (NTRS)

    Kruer, Mark A. (Inventor)

    1999-01-01

    An advanced solar simulator illuminates the surface a very large solar array, such as one twenty feet by twenty feet in area, from a distance of about twenty-six feet with an essentially uniform intensity field of pulsed light of an intensity of one AMO, enabling the solar array to be efficiently tested with light that emulates the sun. Light modifiers sculpt a portion of the light generated by an electrically powered high power Xenon lamp and together with direct light from the lamp provide uniform intensity illumination throughout the solar array, compensating for the square law and cosine law reduction in direct light intensity, particularly at the corner locations of the array. At any location within the array the sum of the direct light and reflected light is essentially constant.

  12. Gyrodampers for large space structures

    NASA Technical Reports Server (NTRS)

    Aubrun, J. N.; Margulies, G.

    1979-01-01

    The problem of controlling the vibrations of a large space structures by the use of actively augmented damping devices distributed throughout the structure is addressed. The gyrodamper which consists of a set of single gimbal control moment gyros which are actively controlled to extract the structural vibratory energy through the local rotational deformations of the structure, is described and analyzed. Various linear and nonlinear dynamic simulations of gyrodamped beams are shown, including results on self-induced vibrations due to sensor noise and rotor imbalance. The complete nonlinear dynamic equations are included. The problem of designing and sizing a system of gyrodampers for a given structure, or extrapolating results for one gyrodamped structure to another is solved in terms of scaling laws. Novel scaling laws for gyro systems are derived, based upon fundamental physical principles, and various examples are given.

  13. LARGE BLOCK TEST STATUS REPORT

    SciTech Connect

    Wilder, D. G.; Blair, S. C.; Buscheck, T.; Carloson, R. C.; Lee, K.; Meike, A.; Ramirez, J. L.; Sevougian, D.

    1997-08-26

    This report is intended to serve as a status report, which essentially transmits the data that have been collected to date on the Large Block Test (LBT). The analyses of data will be performed during FY98, and then a complete report will be prepared. This status report includes introductory material that is not needed merely to transmit data but is available at this time and therefore included. As such, this status report will serve as the template for the future report, and the information is thus preserved. The United States Department of Energy (DOE) is investigatinq the suitability of Yucca Mountain (YM) as a potential site for the nation's first high-level nuclear waste repository. As shown in Fig. 1-1, the site is located about 120 km northwest of Las Vegas, Nevada, in an area of uninhabited desert.

  14. Adaptive Optics for Large Telescopes

    SciTech Connect

    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.

  15. Black rings at large D

    NASA Astrophysics Data System (ADS)

    Tanabe, Kentaro

    2016-02-01

    We study the effective theory of slowly rotating black holes at the infinite limit of the spacetime dimension D. This large D effective theory is obtained by integrating the Einstein equation with respect to the radial direction. The effective theory gives equations for non-linear dynamical deformations of a slowly rotating black hole by effective equations. The effective equations contain the slowly rotating Myers-Perry black hole, slowly boosted black string, non-uniform black string and black ring as stationary solutions. We obtain the analytic solution of the black ring by solving effective equations. Furthermore, by perturbation analysis of effective equations, we find a quasinormal mode condition of the black ring in analytic way. As a result we confirm that thin black ring is unstable against non-axisymmetric perturbations. We also include 1 /D corrections to the effective equations and discuss the effects by 1 /D corrections.

  16. Large area mercuric iodide photodetectors

    SciTech Connect

    Iwanczyk, J.S.; Dabrowski, A.J.; Markakis, J.M.; Ortale, C.; Schnepple, W.F.

    1984-02-01

    Results of an investigation of large area mercuric iodide (HgI/sub 2/) photodetectors are reported. Different entrance contacts were studied, including semitransparent metallic films and conductive liquids. Theoretical calculations of electronic noise of these photodetectors were compared with experimental results. HgI/sub 2/ photodetectors with active area up to 4 cm/sup 2/ were matched with NaI(Tl) and CsI(Tl) scintillation crystals and were evaluated as gamma-radiation spectrometers. Energy resolution of 9.3% for gamma radiation of 511 keV with a CsI(Tl) scintillator and energy resolution of 9.0% for gamma radiation of 622 keV with a NaI(Tl) scintillator have been obtained.

  17. Large Aperture Scintillometer Intercomparison Study

    NASA Astrophysics Data System (ADS)

    Kleissl, J.; Gomez, J.; Hong, S.-H.; Hendrickx, J. M. H.; Rahn, T.; Defoor, W. L.

    2008-07-01

    Two field studies with six large aperture scintillometers (LASs) were performed using horizontal and slant paths. The accuracy of this novel and increasingly popular technique for measuring sensible heat fluxes was quantified by comparing measurements from different instruments over nearly identical transects. Random errors in LAS measurements were small, since correlation coefficients between adjacent measurements were greater than 0.995. However, for an ideal set-up differences in linear regression slopes of up to 21% were observed with typical inter-instrument differences of 6%. Differences of 10% are typical in more realistic measurement scenarios over homogeneous natural vegetation and different transect heights and locations. Inaccuracies in the optics, which affect the effective aperture diameter, are the most likely explanation for the observed differences.

  18. OSIRIS Large Guaranteed Time Programs

    NASA Astrophysics Data System (ADS)

    Cepa, J.; Bongiovanni, A.; Ramón-Pérez, M.; Pérez García, A. M.; Alfaro, E. J.; Castaneda, H. O.; Cervino, M.; Gallego, J.; González, J. J.; González-Serrano, J. I.; Lara-López, M. A.; Pérez-Martínez, R.; Pintos-Castro, I.; Sánchez-Portal, M.; Bland-Hawthorn, J.; Jones, D. H.

    2017-03-01

    The status of OTELO and Lockman SpReSO surveys, the two large guaranteed time programs currently under way using OSIRIS at the 10.4m GTC is presented. The OTELO project, designed to detect the main optical emission lines from Hα to Lyα at redshifts from 0.4 through 7, is the deepest emission line survey to date, with unprecedented sensitivity in the detection of small equivalent widths. Lockman SpReSO is aimed to obtaining optical spectra, up to 24.5 AB magnitudes, in the central 24×24 square arcminutes of the Lockman Hole field, which has been observed with ROSAT and XMM–Newton at the highest depth. Lockman SpReSO mainly targets Far Infrared sources detected with the Herschel Space Observatory.

  19. Large exotropia after retrobulbar anesthesia

    PubMed Central

    Kim, Chung-Hwan; Kim, Ungsoo Samuel

    2016-01-01

    A 67-year-old woman complained of horizontal diplopia shortly following bilateral cataract surgery with intraocular lens implantation performed under retrobulbar anesthesia. Retrobulbar anesthesia was administered at an inferotemporal injection site using 1 cc lidocaine hydrochloride 2% mixed with bupivacaine hydrochloride 0.5%. The initial ophthalmologic evaluation showed a 12-prism diopter (PD) exotropia, and ocular motility evaluation revealed marked limitation of adduction without vertical limitation. One year after cataract surgery, the exodeviation increased up to 60 PD. The patient underwent an 8.0-mm recession of the right lateral rectus and a 6.0-mm recession of the left lateral rectus. Both lateral rectus muscles were biopsied, and biopsy revealed dense fibrous connective tissue without viable muscular cells. The lateral rectus muscle might be injured by retrobulbar anesthesia, and it could induce large exotropia. PMID:26953032

  20. Large Aperture Electrostatic Dust Detector

    SciTech Connect

    C.H. Skinner, R. Hensley, and A.L Roquemore

    2007-10-09

    Diagnosis and management of dust inventories generated in next-step magnetic fusion devices is necessary for their safe operation. A novel electrostatic dust detector, based on a fine grid of interlocking circuit traces biased to 30 or 50 ν has been developed for the detection of dust particles on remote surfaces in air and vacuum environments. Impinging dust particles create a temporary short circuit and the resulting current pulse is recorded by counting electronics. Up to 90% of the particles are ejected from the grid or vaporized suggesting the device may be useful for controlling dust inventories. We report measurements of the sensitivity of a large area (5x5 cm) detector to microgram quantities of dust particles and review its applications to contemporary tokamaks and ITER.

  1. Large and small photovoltaic powerplants

    NASA Astrophysics Data System (ADS)

    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.

  2. Sweetwater, Texas Large N Experiment

    NASA Astrophysics Data System (ADS)

    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.

  3. Large hole rotary drill performance

    SciTech Connect

    Workman, J.L.; Calder, P.N.

    1996-12-31

    Large hole rotary drilling is one of the most common methods of producing blastholes in open pit mining. Large hole drilling generally refers to diameters from 9 to 17 inch (229 to 432 mm), however a considerable amount of rotary drilling is done in diameters from 6{1/2} to 9 inch (165 to 229 mm). These smaller diameters are especially prevalent in gold mining and quarrying. Rotary drills are major mining machines having substantial capital cost. Drill bit costs can also be high, depending on the bit type and formation being drilled. To keep unit costs low the drills must perform at a high productivity level. The most important factor in rotary drilling is the penetration rate. This paper discusses the factors affecting penetration rate. An empirical factor in rotary drilling is the penetration rate. This paper discusses the factors affecting penetration rate. An empirical factor is given for calculating the penetration rate based on rock strength, pulldown weight and the RPM. The importance of using modern drill performance monitoring systems to calibrate the penetration equation for specific rock formations is discussed. Adequate air delivered to the bottom of the hole is very important to achieving maximum penetration rates. If there is insufficient bailing velocity cuttings will not be transported from the bottom of the hole rapidly enough and the penetration rate is very likely to decrease. An expression for the balancing air velocity is given. The amount by which the air velocity must exceed the balancing velocity for effective operation is discussed. The effect of altitude on compressor size is also provided.

  4. Low Cost Large Space Antennas

    NASA Technical Reports Server (NTRS)

    Chmielewski, Artur B.; Freeland, Robert

    1997-01-01

    The mobile communication community could significantly benefit from the availability of low-cost, large space-deployable antennas. A new class of space structures, called inflatable deployable structures, will become an option for this industry in the near future. This new technology recently made significant progress with respect to reducing the risk of flying large inflatable structures in space. This progress can be attributed to the successful space flight of the Inflatable Antenna Experiment in May of 1996, which prompted the initiation of the NASA portion of the joint NASA/DOD coordinated Space Inflatables Program, which will develop the technology to be used in future mobile communications antennas along with other users. The NASA/DOD coordinated Space Inflatables Program was initiated in 1997 as a direct result of the Inflatable Antenna Experiment. The program adds a new NASA initiative to a substantial DOD program that involves developing a series of ground test hardware, starting with 3 meter diameter units and advancing the manufacturing techniques to fabricate a 25 meter ground demonstrator unit with surface accuracy exceeding the requirements for mobile communication applications. Simultaneously, the program will be advancing the state of the art in several important inflatable technology areas, such as developing rigidizable materials for struts and tori and investigating thin film technology issues, such as application of coatings, property measurement and materials processing and assembly techniques. A very important technology area being addressed by the program is deployment control techniques. The program will sponsor activities that will lead to understanding the effects of material strain energy release, residual air in the stowed structure, and the design of the launch restraint and release system needed to control deployment dynamics. Other technology areas directly applicable to developing inflatable mobile communication antennas in the near

  5. Large-Scale Information Systems

    SciTech Connect

    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.

  6. Large optical field enhancement for nanotips with large opening angles

    NASA Astrophysics Data System (ADS)

    Thomas, Sebastian; Wachter, Georg; Lemell, Christoph; Burgdörfer, Joachim; Hommelhoff, Peter

    2015-06-01

    We theoretically investigate the dependence of the enhancement of optical near-fields at nanometric tips on the shape, size, and material of the tip. We confirm the strong dependence of the field enhancement factor on the radius of curvature. In addition, we find a surprisingly strong increase of field enhancement with increasing opening angle of the nanotips. For gold and tungsten nanotips in the experimentally relevant parameter range (radius of curvature ≥slant 5 nm at 800 nm laser wavelength), we obtain field enhancement factors of up to ∼ 35 for Au and ∼ 12 for W for large opening angles. We confirm this strong dependence on the opening angle for many other materials featuring a wide variety in their dielectric response. For dielectrics, the opening angle dependence is traced back to the electrostatic force of the induced surface charge at the tip shank. For metals, the plasmonic response strongly increases the field enhancement and shifts the maximum field enhancement to smaller opening angles.

  7. Large and small volcanic eruptions

    NASA Astrophysics Data System (ADS)

    Gudmundsson, Agust; Mohajeri, Nahid

    2013-04-01

    Despite great progress in volcanology in the past decades, we still cannot make reliable forecasts as to the likely size (volume, mass) of an eruption once it has started. Empirical data collected from volcanoes worldwide indicates that the volumes (or masses) of eruptive materials in volcanic eruptions are heavy-tailed. This means that most of the volumes erupted from a given magma chamber are comparatively small. Yet, the same magma chamber can, under certain conditions, squeeze out large volumes of magma. To know these conditions is of fundamental importance for forecasting the likely size of an eruption. Thermodynamics provides the basis for understanding the elastic energy available to (i) propagate an injected dyke from the chamber and to the surface to feed an eruption, and (ii) squeeze magma out of the chamber during the eruption. The elastic energy consists of two main parts: first, the strain energy stored in the volcano before magma-chamber rupture and dyke injection, and, second, the work done through displacement of the flanks of the volcano (or the margins of a rift zone) and the expansion and shrinkage of the magma chamber itself. Other forms of energy in volcanoes - thermal, seismic, kinetic - are generally important but less so for squeezing magma out of a chamber during an eruption. Here we suggest that for (basaltic) eruptions in rift zones the strain energy is partly related to minor doming above the reservoir, and partly to stretching of the rift zone before rupture. The larger the reservoir, the larger is the stored strain energy before eruption. However, for the eruption to be really large, the strain energy has to accumulate in the entire crustal segment above the reservoir and there will be additional energy input into the system during the eruption which relates to the displacements of the boundary of the rift-zone segment. This is presumably why feeder dykes commonly propagate laterally at the surface following the initial fissure

  8. Large Volcanic Rises on Venus

    NASA Technical Reports Server (NTRS)

    Smrekar, Suzanne E.; Kiefer, Walter S.; Stofan, Ellen R.

    1997-01-01

    Large volcanic rises on Venus have been interpreted as hotspots, or the surface manifestation of mantle upwelling, on the basis of their broad topographic rises, abundant volcanism, and large positive gravity anomalies. Hotspots offer an important opportunity to study the behavior of the lithosphere in response to mantle forces. In addition to the four previously known hotspots, Atla, Bell, Beta, and western Eistla Regiones, five new probable hotspots, Dione, central Eistla, eastern Eistla, Imdr, and Themis, have been identified in the Magellan radar, gravity and topography data. These nine regions exhibit a wider range of volcano-tectonic characteristics than previously recognized for venusian hotspots, and have been classified as rift-dominated (Atla, Beta), coronae-dominated (central and eastern Eistla, Themis), or volcano-dominated (Bell, Dione, western Eistla, Imdr). The apparent depths of compensation for these regions ranges from 65 to 260 km. New estimates of the elastic thickness, using the 90 deg and order spherical harmonic field, are 15-40 km at Bell Regio, and 25 km at western Eistla Regio. Phillips et al. find a value of 30 km at Atla Regio. Numerous models of lithospheric and mantle behavior have been proposed to interpret the gravity and topography signature of the hotspots, with most studies focusing on Atla or Beta Regiones. Convective models with Earth-like parameters result in estimates of the thickness of the thermal lithosphere of approximately 100 km. Models of stagnant lid convection or thermal thinning infer the thickness of the thermal lithosphere to be 300 km or more. Without additional constraints, any of the model fits are equally valid. The thinner thermal lithosphere estimates are most consistent with the volcanic and tectonic characteristics of the hotspots. Estimates of the thermal gradient based on estimates of the elastic thickness also support a relatively thin lithosphere (Phillips et al.). The advantage of larger estimates of

  9. Large Block Test Final Report

    SciTech Connect

    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

  10. Large-scale PACS implementation.

    PubMed

    Carrino, J A; Unkel, P J; Miller, I D; Bowser, C L; Freckleton, M W; Johnson, T G

    1998-08-01

    The transition to filmless radiology is a much more formidable task than making the request for proposal to purchase a (Picture Archiving and Communications System) PACS. The Department of Defense and the Veterans Administration have been pioneers in the transformation of medical diagnostic imaging to the electronic environment. Many civilian sites are expected to implement large-scale PACS in the next five to ten years. This presentation will related the empirical insights gleaned at our institution from a large-scale PACS implementation. Our PACS integration was introduced into a fully operational department (not a new hospital) in which work flow had to continue with minimal impact. Impediments to user acceptance will be addressed. The critical components of this enormous task will be discussed. The topics covered during this session will include issues such as phased implementation, DICOM (digital imaging and communications in medicine) standard-based interaction of devices, hospital information system (HIS)/radiology information system (RIS) interface, user approval, networking, workstation deployment and backup procedures. The presentation will make specific suggestions regarding the implementation team, operating instructions, quality control (QC), training and education. The concept of identifying key functional areas is relevant to transitioning the facility to be entirely on line. Special attention must be paid to specific functional areas such as the operating rooms and trauma rooms where the clinical requirements may not match the PACS capabilities. The printing of films may be necessary for certain circumstances. The integration of teleradiology and remote clinics into a PACS is a salient topic with respect to the overall role of the radiologists providing rapid consultation. A Web-based server allows a clinician to review images and reports on a desk-top (personal) computer and thus reduce the number of dedicated PACS review workstations. This session

  11. Phase II Pediatric Study With Dabrafenib in HGG Patients

    ClinicalTrials.gov

    2017-02-13

    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

  12. Anthropogenic Triggering of Large Earthquakes

    NASA Astrophysics Data System (ADS)

    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.

  13. Large cities are less green.

    PubMed

    Oliveira, Erneson A; Andrade, José S; Makse, Hernán A

    2014-02-28

    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 CO2 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 CO2 emissions and city population with average allometric exponent β = 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. Metropolitan Statistical Area (MSA). Specifically, MSAs display isometric scaling emissions and we argue that this discrepancy is due to the overestimation of MSA areas. The results suggest that allometric studies based on administrative boundaries to define cities may suffer from endogeneity bias.

  14. Large Angle Satellite Attitude Maneuvers

    NASA Technical Reports Server (NTRS)

    Cochran, J. E.; Junkins, J. L.

    1975-01-01

    Two methods are proposed for performing large angle reorientation maneuvers. The first method is based upon Euler's rotation theorem; an arbitrary reorientation is ideally accomplished by rotating the spacecraft about a line which is fixed in both the body and in space. This scheme has been found to be best suited for the case in which the initial and desired attitude states have small angular velocities. The second scheme is more general in that a general class of transition trajectories is introduced which, in principle, allows transfer between arbitrary orientation and angular velocity states. The method generates transition maneuvers in which the uncontrolled (free) initial and final states are matched in orientation and angular velocity. The forced transition trajectory is obtained by using a weighted average of the unforced forward integration of the initial state and the unforced backward integration of the desired state. The current effort is centered around practical validation of this second class of maneuvers. Of particular concern is enforcement of given control system constraints and methods for suboptimization by proper selection of maneuver initiation and termination times. Analogous reorientation strategies which force smooth transition in angular momentum and/or rotational energy are under consideration.

  15. Large Eddy Simulations in Astrophysics

    NASA Astrophysics Data System (ADS)

    Schmidt, Wolfram

    2015-12-01

    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 dynamic 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 adaptive mesh refinement (AMR) simulations. Moreover, the notion of shear-improved models for in-homogeneous and non-stationary turbulence is introduced. Finally, applications of LES to turbulent combustion in thermonuclear supernovae, star formation and feedback in galaxies, and cosmological structure formation are reviewed.

  16. Chemotaxis of large granular lymphocytes

    SciTech Connect

    Pohajdak, B.; Gomez, J.; Orr, F.W.; Khalil, N.; Talgoy, M.; Greenberg, A.H.

    1986-01-01

    The hypothesis that large granular lymphocytes (LGL) are capable of directed locomotion (chemotaxis) was tested. A population of LGL isolated from discontinuous Percoll gradients migrated along concentration gradients of N-formyl-methionyl-leucyl-phenylalanine (f-MLP), casein, and C5a, well known chemoattractants for polymorphonuclear leukocytes and monocytes, as well as interferon-..beta.. and colony-stimulating factor. Interleukin 2, tuftsin, platelet-derived growth factor, and fibronectin were inactive. Migratory responses were greater in Percoll fractions with the highest lytic activity and HNK-1/sup +/ cells. The chemotactic response to f-MLP, casein, and C5a was always greater when the chemoattractant was present in greater concentration in the lower compartment of the Boyden chamber. Optimum chemotaxis was observed after a 1 hr incubation that made use of 12 ..mu..m nitrocellulose filters. LGL exhibited a high degree of nondirected locomotion when allowed to migrate for longer periods (> 2 hr), and when cultured in vitro for 24 to 72 hr in the presence or absence of IL 2 containing phytohemagluttinin-conditioned medium. LGL chemotaxis to f-MLP could be inhibited in a dose-dependent manner by the inactive structural analog CBZ-phe-met, and the RNK tumor line specifically bound f-ML(/sup 3/H)P, suggesting that LGL bear receptors for the chemotactic peptide.

  17. Large boulders at landing site

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Large boulders are visible in this enlargement of pictures taken by the Imager for Mars Pathfinder (IMP) lander camera on July 4, 1997. The landing site is in the dry flood channel named Ares Valles. The boulders probably represent deposits from one of the catastrophic floods that carved the ancient channel. Between the rocks is brownish windblown soil. The gray-tan sky results from dust particles in the atmosphere.

    Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars over the next ten years. Mars Global Surveyor, already en route, arrives at Mars on September 11 to begin a two year orbital reconnaissance of the planet's composition, topography, and climate. Additional orbiters and landers will follow every 26 months.

    Mars Pathfinder was developed and managed by the Jet Propulsion Laboratory (JPL) for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  18. Facilitating Navigation Through Large Archives

    NASA Technical Reports Server (NTRS)

    Shelton, Robert O.; Smith, Stephanie L.; Troung, Dat; Hodgson, Terry R.

    2005-01-01

    Automated Visual Access (AVA) is a computer program that effectively makes a large collection of information visible in a manner that enables a user to quickly and efficiently locate information resources, with minimal need for conventional keyword searches and perusal of complex hierarchical directory systems. AVA includes three key components: (1) a taxonomy that comprises a collection of words and phrases, clustered according to meaning, that are used to classify information resources; (2) a statistical indexing and scoring engine; and (3) a component that generates a graphical user interface that uses the scoring data to generate a visual map of resources and topics. The top level of an AVA display is a pictorial representation of an information archive. The user enters the depicted archive by either clicking on a depiction of subject area cluster, selecting a topic from a list, or entering a query into a text box. The resulting display enables the user to view candidate information entities at various levels of detail. Resources are grouped spatially by topic with greatest generality at the top layer and increasing detail with depth. The user can zoom in or out of specific sites or into greater or lesser content detail.

  19. Large Scale Magnetostrictive Valve Actuator

    NASA Technical Reports Server (NTRS)

    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.

  20. How large should whales be?

    PubMed

    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.

  1. Anthropogenic triggering of large earthquakes.

    PubMed

    Mulargia, Francesco; Bizzarri, Andrea

    2014-08-26

    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. Control of large space structures

    NASA Technical Reports Server (NTRS)

    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.

  3. Anthropogenic Triggering of Large Earthquakes

    PubMed Central

    Mulargia, Francesco; Bizzarri, Andrea

    2014-01-01

    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. PMID:25156190

  4. Large cities are less green

    NASA Astrophysics Data System (ADS)

    Oliveira, Erneson A.; Andrade, José S.; Makse, Hernán A.

    2014-02-01

    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 CO2 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 CO2 emissions and city population with average allometric exponent β = 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. Metropolitan Statistical Area (MSA). Specifically, MSAs display isometric scaling emissions and we argue that this discrepancy is due to the overestimation of MSA areas. The results suggest that allometric studies based on administrative boundaries to define cities may suffer from endogeneity bias.

  5. Natural Selection in Large Populations

    NASA Astrophysics Data System (ADS)

    Desai, Michael

    2011-03-01

    I will discuss theoretical and experimental approaches to the evolutionary dynamics and population genetics of natural selection in large populations. In these populations, many mutations are often present simultaneously, and because recombination is limited, selection cannot act on them all independently. Rather, it can only affect whole combinations of mutations linked together on the same chromosome. Methods common in theoretical population genetics have been of limited utility in analyzing this coupling between the fates of different mutations. In the past few years it has become increasingly clear that this is a crucial gap in our understanding, as sequence data has begun to show that selection appears to act pervasively on many linked sites in a wide range of populations, including viruses, microbes, Drosophila, and humans. I will describe approaches that combine analytical tools drawn from statistical physics and dynamical systems with traditional methods in theoretical population genetics to address this problem, and describe how experiments in budding yeast can help us directly observe these evolutionary dynamics.

  6. Disorder in large- N theories

    NASA Astrophysics Data System (ADS)

    Aharony, Ofer; Komargodski, Zohar; Yankielowicz, Shimon

    2016-04-01

    We consider Euclidean Conformal Field Theories perturbed by quenched disorder, namely by random fluctuations in their couplings. Such theories are relevant for second-order phase transitions in the presence of impurities or other forms of disorder. Theories with quenched disorder often flow to new fixed points of the renormalization group. We begin with disorder in free field theories. Imry and Ma showed that disordered free fields can only exist for d > 4. For d > 4 we show that disorder leads to new fixed points which are not scale-invariant. We then move on to large- N theories (vector models or gauge theories in the `t Hooft limit). We compute exactly the beta function for the disorder, and the correlation functions of the disordered theory. We generalize the results of Imry and Ma by showing that such disordered theories exist only when disorder couples to operators of dimension Δ > d/4. Sometimes the disordered fixed points are not scale-invariant, and in other cases they have unconventional dependence on the disorder, including non-trivial effects due to irrelevant operators. Holography maps disorder in conformal theories to stochastic differential equations in a higher dimensional space. We use this dictionary to reproduce our field theory results. We also study the leading 1 /N corrections, both by field theory methods and by holography. These corrections are particularly important when disorder scales with the number of degrees of freedom.

  7. Large optics inspection, tilting, and washing stand

    DOEpatents

    Ayers, Marion Jay; Ayers, Shannon Lee

    2012-10-09

    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.

  8. Large optics inspection, tilting, and washing stand

    DOEpatents

    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.

  9. Ultra-Large Solar Sail

    NASA Technical Reports Server (NTRS)

    Burton, Rodney; Coverstone, Victoria

    2009-01-01

    UltraSail is a next-generation ultra-large (km2 class) sail system. Analysis of the launch, deployment, stabilization, and control of these sails shows that high-payload-mass fractions for interplanetary and deep-space missions are possible. UltraSail combines propulsion and control systems developed for formation-flying microsatellites with a solar sail architecture to achieve controllable sail areas approaching 1 km2. Electrically conductive CP-1 polyimide film results in sail subsystem area densities as low as 5 g/m2. UltraSail produces thrust levels many times those of ion thrusters used for comparable deep-space missions. The primary innovation involves the near-elimination of sail-supporting structures by attaching each blade tip to a formation- flying microsatellite, which deploys the sail and then articulates the sail to provide attitude control, including spin stabilization and precession of the spin axis. These microsatellite tips are controlled by microthrusters for sail-film deployment and mission operations. UltraSail also avoids the problems inherent in folded sail film, namely stressing, yielding, or perforating, by storing the film in a roll for launch and deployment. A 5-km long by 2 micrometer thick film roll on a mandrel with a 1 m circumference (32 cm diameter) has a stored thickness of 5 cm. A 5 m-long mandrel can store a film area of 25,000 m2, and a four-blade system has an area of 0.1 sq km.

  10. Temporal Large-Eddy Simulation

    NASA Technical Reports Server (NTRS)

    Pruett, C. D.; Thomas, B. C.

    2004-01-01

    In 1999, Stolz and Adams unveiled a subgrid-scale model for LES based upon approximately inverting (defiltering) the spatial grid-filter operator and termed .the approximate deconvolution model (ADM). Subsequently, the utility and accuracy of the ADM were demonstrated in a posteriori analyses of flows as diverse as incompressible plane-channel flow and supersonic compression-ramp flow. In a prelude to the current paper, a parameterized temporal ADM (TADM) was developed and demonstrated in both a priori and a posteriori analyses for forced, viscous Burger's flow. The development of a time-filtered variant of the ADM was motivated-primarily by the desire for a unifying theoretical and computational context to encompass direct numerical simulation (DNS), large-eddy simulation (LES), and Reynolds averaged Navier-Stokes simulation (RANS). The resultant methodology was termed temporal LES (TLES). To permit exploration of the parameter space, however, previous analyses of the TADM were restricted to Burger's flow, and it has remained to demonstrate the TADM and TLES methodology for three-dimensional flow. For several reasons, plane-channel flow presents an ideal test case for the TADM. Among these reasons, channel flow is anisotropic, yet it lends itself to highly efficient and accurate spectral numerical methods. Moreover, channel-flow has been investigated extensively by DNS, and a highly accurate data base of Moser et.al. exists. In the present paper, we develop a fully anisotropic TADM model and demonstrate its utility in simulating incompressible plane-channel flow at nominal values of Re(sub tau) = 180 and Re(sub tau) = 590 by the TLES method. The TADM model is shown to perform nearly as well as the ADM at equivalent resolution, thereby establishing TLES as a viable alternative to LES. Moreover, as the current model is suboptimal is some respects, there is considerable room to improve TLES.

  11. The Large Binocular Telescope Project

    NASA Astrophysics Data System (ADS)

    Hill, J. M.

    1994-12-01

    The Large Binocular Telescope (LBT) Project has evolved from concepts first proposed in 1985. The present partners involved in the design and construction of this 2 x 8.4 meter binocular telescope are the University of Arizona, Italy represented by the Osservatorio Astronomico di Arcetri and the Research Corporation based in Tucson. These three partners have committed sufficient funds to build the enclosure and the telescope populated with a single 8.4 meter optical train --- approximately 40 million dollars (1989). Based on this commitment, design and construction activities are now moving forward. Additional partners are being sought. The next mirror to be cast at the Steward Observatory Mirror Lab in late fall 1995 will be the first borosilicate honeycomb primary for LBT. The baseline optical configuration of LBT includes wide field Cassegrain secondaries with optical foci above the primaries to provide a corrected one degree field at F/4. The infrared F/15 secondaries are a Gregorian design to allow maximum flexibility for adaptive optics. The F/15 secondaries are undersized to provide a low thermal background focal plane which is unvignetted over a 4 arcminute diameter field-of-view. The interferometric focus combining the light from the two 8.4 meter primaries will reimage two folded Gregorian focal planes to a central location. The telescope elevation structure accommodates swing arms which allow rapid interchange of the various secondary and tertiary mirrors. Maximum stiffness and minimal thermal disturbance continue to be important drivers for the detailed design of the telescope. The telescope structure accommodates installation of a vacuum bell jar for aluminizing the primary mirrors in-situ on the telescope. The detailed design of the telescope structure will be completed in 1995 by ADS Italia (Lecco) and European Industrial Engineering (Mestre). The final enclosure design is now in progress at M3 Engineering (Tucson) and ADS Italia. Construction

  12. The Large Binocular Telescope Project

    NASA Astrophysics Data System (ADS)

    Hill, J. M.

    1995-05-01

    The Large Binocular Telescope (LBT) Project has evolved from concepts first proposed in 1985. The present partners involved in the design and construction of this 2 x 8.4 meter binocular telescope are the University of Arizona, Italy represented by the Osservatorio Astrofisico di Arcetri and the Research Corporation based in Tucson. These three partners have committed sufficient funds to build the enclosure and the telescope populated with a single 8.4 meter optical train --- approximately 40 million dollars (1989). Based on this commitment, design and construction activities are now moving forward. Additional partners are being sought. The next mirror to be cast at the Steward Observatory Mirror Lab in spring of 1996 will be the first borosilicate honeycomb primary for LBT. The baseline optical configuration of LBT includes wide field Cassegrain secondaries with optical foci above the primaries to provide a corrected one degree field at F/4. The infrared F/15 secondaries are a Gregorian design to allow maximicrons flexibility for adaptive optics. The F/15 secondaries are undersized to provide a low thermal background focal plane which is unvignetted over a 4 arcminute diameter field-of-view. The interferometric focus combining the light from the two 8.4 meter primaries will reimage two folded Gregorian focal planes to a central location. The telescope elevation structure accommodates swing arms which allow rapid interchange of the various secondary and tertiary mirrors. Maximicrons stiffness and minimal thermal disturbance continue to be important drivers for the detailed design of the telescope. The telescope structure accommodates installation of a vacuum bell jar for aluminizing the primary mirrors in-situ on the telescope. The detailed design of the telescope structure will be completed in 1995 by ADS Italia (Lecco) and European Industrial Engineering (Mestre). The final enclosure design is now in progress at M3 Engineering (Tucson) and ADS Italia

  13. Large capacity temporary visual memory

    PubMed Central

    Endress, Ansgar D.; Potter, Mary C.

    2014-01-01

    Visual working memory (WM) capacity is thought to be limited to three or four items. However, many cognitive activities seem to require larger temporary memory stores. Here, we provide evidence for a temporary memory store with much larger capacity than past WM capacity estimates. Further, based on previous WM research, we show that a single factor — proactive interference — is sufficient to bring capacity estimates down to the range of previous WM capacity estimates. Participants saw a rapid serial visual presentation (RSVP) of 5 to 21 pictures of familiar objects or words presented at rates of 4/s or 8/s, respectively, and thus too fast for strategies such as rehearsal. Recognition memory was tested with a single probe item. When new items were used on all trials, no fixed memory capacities were observed, with estimates of up to 9.1 retained pictures for 21-item lists, and up to 30.0 retained pictures for 100-item lists, and no clear upper bound to how many items could be retained. Further, memory items were not stored in a temporally stable form of memory, but decayed almost completely after a few minutes. In contrast, when, as in most WM experiments, a small set of items was reused across all trials, thus creating proactive interference among items, capacity remained in the range reported in previous WM experiments. These results show that humans have a large-capacity temporary memory store in the absence of proactive interference, and raise the question of whether temporary memory in everyday cognitive processing is severely limited as in WM experiments, or has the much larger capacity found in the present experiments. PMID:23937181

  14. Large Alluvial Fans on Mars

    NASA Technical Reports Server (NTRS)

    Moore, Jeffrey M.; Howard, Alan D.

    2004-01-01

    Several dozen distinct alluvial fans, 10 to greater than 40 km long downslope are observed exclusively in highlands craters. Within a search region between 0 deg. and 30 deg. S, alluvial fan-containing craters were only found between 18 and 29 S, and they all occur at around plus or minus 1 km of the MOLA-defined Martian datum. Within the study area they are not randomly distributed but instead form three distinct clusters. Fans typically descend greater than 1 km from where they disgorge from their alcoves. Longitudinal profiles show that their surfaces are very slightly concave with a mean slope of 2 degrees. Many fans exhibit very long, narrow low-relief ridges radially oriented down-slope, often branching at their distal ends, suggestive of distributaries. Morphometric data for 31 fans was derived from MOLA data and compared with terrestrial fans with high-relief source areas, terrestrial low gradient alluvial ramps in inactive tectonic settings, and older Martian alluvial ramps along crater floors. The Martian alluvial fans generally fall on the same trends as the terrestrial alluvial fans, whereas the gentler Martian crater floor ramps are similar in gradient to the low relief terrestrial alluvial surfaces. For a given fan gradient, Martian alluvial fans generally have greater source basin relief than terrestrial fans in active tectonic settings. This suggests that the terrestrial source basins either yield coarser debris or have higher sediment concentrations than their Martian counterpoints. Martian fans and Basin and Range fans have steeper gradients than the older Martian alluvial ramps and terrestrial low relief alluvial surfaces, which is consistent with a supply of coarse sediment. Martian fans are relatively large and of low gradient, similar to terrestrial fluvial fans rather than debris flow fans. However, gravity scaling uncertainties make the flow regime forming Martian fans uncertain. Martian fans, at least those in Holden crater, apparently

  15. Large springs of east Tennessee

    USGS Publications Warehouse

    Sun, Pao-chang P.; Criner, J.H.; Poole, J.L.

    1963-01-01

    Springs constitute an important source of water in east Tennessee, and many individual springs are capable of supplying the large quantities needed for municipal and industrial supplies. Most of the springs in east Tennessee issue from solution openings and fractured and faulted zones in limestone and dolomite of the Knox Group, Chickamauga Limestone, and Conasauga Group. The ability of these rocks to yield a sustained flow of water to springs is dependent on a system of interconnected openings through which water can infiltrate from the land surface and move to points of natural discharge. Ninety springs were selected for detailed study, and 84 of these are analyzed in terms of magnitude and variability of discharge. Of the 84 springs analyzed, 4 flow at an average rate of 10 to 100 cfs (cubic feet per second), 62 at an average rate of 1 to 10 cfs, and 18 at an average rate of 1 cfs or less. Of the 90 springs, 75 are variable in their discharge; that is, the ratio of their fluctuations to their average discharges exceeds 100 percent. Mathematical analysis of the flow recession curve of Mill Spring near Jefferson City shows that the hydrologic system contributing to the flow of the spring has an effective capacity of about 70 million cubic feet of water. The rate of depletion of this volume of water, in the absence of significant precipitation, averages 0.0056 cfs per day between the time when the hydrologic system is full and the time when the spring ceases to flow. From such a curve it is possible to determine at any time the residual volume of water remaining in the system and the expected rate of decrease in discharge from that time to cessation of flow. Correlation of discharge measurements of 22 springs with those of Mill Spring shows that rough approximations of discharge can be projected for springs for which few measurements are available. Seventeen of the springs analyzed in this manner show good correlation with Mill Spring: that is, their coefficients

  16. The Very Large Ecological Array

    NASA Astrophysics Data System (ADS)

    Hamilton, M. P.; Dawson, T. E.; Thompson, S. E.

    2011-12-01

    Regional climatic change and variability is expected to alter the boundary conditions to which ecosystems and landscapes are subject. Unambiguously identifying how these changes alter the biophysics of ecosystems or the phenology or behavior of individual organisms, however, remains challenging due to the complexity and heterogeneity of real landscapes. One of the aims of the Very Large Ecological Array (VeLEA) - a landscape-scale distributed wireless environmental monitoring system under deployment at the University of California, Blue Oak Ranch Reserve (Mount Hamilton Range, Santa Clara County, California) - is to allow a sufficiently fine-resolution understanding of spatial and temporal variability in the landscape that such changes can be reliably quantified. The VeLEA is structured around two wireless mesh radio networks, with solar-powered nodes spaced by up to 2 miles. This allows widely distributed arrays of instrumentation to be deployed over hundreds to thousands of hectares. The first network supports ten weather stations (recording barometric pressure, temperature, humidity, wind, rainfall, total solar radiation and leaf wetness), along with sixty nodes measuring humidity and air temperature at 1m above ground. Future deployments will extend the network to include soil moisture, soil temperature, piezometric head and streamflow across the site. The second network supports an array of 10 networked cameras providing real-time viewing and time-lapse recording of animal behavior, vegetation phenology and aquatic variability. An important goal of the VeLEA project is to optimize the deployment of wireless nodes with respect to spatial and temporal variation at the site. Preliminary data obtained from the initial deployments are being used to characterize spatial and temporal variability across the site and to investigate mechanistic and statistical methods for interpolating and up-scaling that data. Observing and characterizing such spatio

  17. Experiments with large enclosed ecosystems.

    PubMed

    Davies, J M; Gamble, J C

    1979-08-08

    conclusion that the levels of mercury found in surface waters around the coast of the U.K. (0.001--0.022 microgram Hg/l) are one or two orders of magnitude below the levels at which a response of the biological population can be demonstrated. The usefulness of large scale enclosed ecosystems for further pollution research is discussed and it is concluded that those facilities that provided a link between the water column and the sediments would be most useful since they would (1) enable estimates to be made of the flux rates of pollutants from the water column to the sediments; and (2) allow experiments to be carried out with the pollutant in contact with sediment in its natural form.

  18. Large space systems technology, 1981. [conferences

    NASA Technical Reports Server (NTRS)

    Boyer, W. J. (Compiler)

    1982-01-01

    A total systems approach including structures, analyses, controls, and antennas is presented as a cohesive, programmatic plan for large space systems. Specifically, program status, structures, materials, and analyses, and control of large space systems are addressed.

  19. Ixabepilone in Treating Patients With Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2014-05-07

    Anaplastic Large Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma

  20. Large Space Antenna Systems Technology, 1984

    NASA Technical Reports Server (NTRS)

    Boyer, W. J. (Compiler)

    1985-01-01

    Papers are presented which provide a comprehensive review of space missions requiring large antenna systems and of the status of key technologies required to enable these missions. Topic areas include mission applications for large space antenna systems, large space antenna structural systems, materials and structures technology, structural dynamics and control technology, electromagnetics technology, large space antenna systems and the space station, and flight test and evaluation.

  1. 27 CFR 19.915 - Large plants.

    Code of Federal Regulations, 2010 CFR

    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...

  2. Large Devaluations and the Real Exchange Rate

    ERIC Educational Resources Information Center

    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…

  3. Large variable conductance heat pipe. Transverse header

    NASA Technical Reports Server (NTRS)

    Edelstein, F.

    1975-01-01

    The characteristics of gas-loaded, variable conductance heat pipes (VCHP) are discussed. The difficulties involved in developing a large VCHP header are analyzed. The construction of the large capacity VCHP is described. A research project to eliminate some of the problems involved in large capacity VCHP operation is explained.

  4. SOME TRAINING IMPLICATIONS OF LARGE SHELTERS.

    ERIC Educational Resources Information Center

    BEND, EMIL

    BASED LARGELY ON AIR RESEARCH ON SHELTER MANAGEMENT SIMULATION, AN ANALYSIS WAS MADE OF THE IMPACT OF THE LARGE, COMPLEX SHELTER ON SHELTER MANAGEMENT TRAINING NEEDS. THE LARGE SHELTER REQUIRES THE TYPE OF LEADERSHIP THAT ONLY THOSE WHO ALREADY HAVE SUPERVISORY SKILLS CAN SUPPLY. SUCH PEOPLE ARE NEITHER ATTRACTED NOR HELPED BY THE USUAL SHELTER…

  5. Large space systems technology, 1980, volume 1

    NASA Technical Reports Server (NTRS)

    Kopriver, F., III (Compiler)

    1981-01-01

    The technological and developmental efforts in support of the large space systems technology are described. Three major areas of interests are emphasized: (1) technology pertient to large antenna systems; (2) technology related to large space systems; and (3) activities that support both antenna and platform systems.

  6. Large Space Systems Technology, Part 2, 1981

    NASA Technical Reports Server (NTRS)

    Boyer, W. J. (Compiler)

    1982-01-01

    Four major areas of interest are covered: technology pertinent to large antenna systems; technology related to the control of large space systems; basic technology concerning structures, materials, and analyses; and flight technology experiments. Large antenna systems and flight technology experiments are described. Design studies, structural testing results, and theoretical applications are presented with accompanying validation data. These research studies represent state-of-the art technology that is necessary for the development of large space systems. A total systems approach including structures, analyses, controls, and antennas is presented as a cohesive, programmatic plan for large space systems.

  7. Survey on large scale system control methods

    NASA Technical Reports Server (NTRS)

    Mercadal, Mathieu

    1987-01-01

    The problem inherent to large scale systems such as power network, communication network and economic or ecological systems were studied. The increase in size and flexibility of future spacecraft has put those dynamical systems into the category of large scale systems, and tools specific to the class of large systems are being sought to design control systems that can guarantee more stability and better performance. Among several survey papers, reference was found to a thorough investigation on decentralized control methods. Especially helpful was the classification made of the different existing approaches to deal with large scale systems. A very similar classification is used, even though the papers surveyed are somehow different from the ones reviewed in other papers. Special attention is brought to the applicability of the existing methods to controlling large mechanical systems like large space structures. Some recent developments are added to this survey.

  8. Force Sensor for Large Robot Arms

    NASA Technical Reports Server (NTRS)

    Bejczy, A. K.; Primus, H. C.; Scheinman, V. D.

    1985-01-01

    Modified Maltese-cross force sensor larger and more sensitive than earlier designs. Measures inertial forces and torques exerted on large robot arms during free movement as well as those exerted by claw on manipulated objects. Large central hole of sensor allows claw drive mounted inside arm instead of perpendicular to its axis, eliminating potentially hazardous projection. Originally developed for Space Shuttle, sensor finds applications in large industrial robots.

  9. Global Behavior in Large Scale Systems

    DTIC Science & Technology

    2013-12-05

    Sinopoli, and J. Moura, “ Distributed detection over time varying networks: Large deviations analysis,” in Communication, Control , and Computing...and J. Moura, “ Distributed detection via gaussian running consensus : Large deviations asymptotic analysis,” Signal Processing, IEEE Transactions on... Distributed detection via Gaussian running consensus : large deviations asymptotic analysis,” IEEE Transactions on Signal Processing, vol. 59, no. 9, pp

  10. How Large Are Large Classes? Lancaster-Leeds Language Learning in Large Classes Research Project Report No. 4.

    ERIC Educational Resources Information Center

    Coleman, Hywel

    This report confirms anecdotal evidence that language teachers do find large classes to be problematic, collates data on class sizes in various parts of the world, and investigates the possibility of defining a large class, at least from the teachers'points of view. The first section is introductory. The second presents findings of a small-scale…

  11. What is a large-scale dynamo?

    NASA Astrophysics Data System (ADS)

    Nigro, G.; Pongkitiwanichakul, P.; Cattaneo, F.; Tobias, S. M.

    2017-01-01

    We consider kinematic dynamo action in a sheared helical flow at moderate to high values of the magnetic Reynolds number (Rm). We find exponentially growing solutions which, for large enough shear, take the form of a coherent part embedded in incoherent fluctuations. We argue that at large Rm large-scale dynamo action should be identified by the presence of structures coherent in time, rather than those at large spatial scales. We further argue that although the growth rate is determined by small-scale processes, the period of the coherent structures is set by mean-field considerations.

  12. Scalar gain interpretation of large order filters

    NASA Technical Reports Server (NTRS)

    Mason, Paul A. C.; Mook, D. Joseph

    1993-01-01

    A technique is developed which demonstrates how to interpret a large fully-populated filter gain matrix as a set of scalar gains. The inverse problem is also solved, namely, how to develop a large-order filter gain matrix from a specified set of scalar gains. Examples are given to illustrate the method.

  13. Evaluating Large-Scale Interactive Radio Programmes

    ERIC Educational Resources Information Center

    Potter, Charles; Naidoo, Gordon

    2009-01-01

    This article focuses on the challenges involved in conducting evaluations of interactive radio programmes in South Africa with large numbers of schools, teachers, and learners. It focuses on the role such large-scale evaluation has played during the South African radio learning programme's development stage, as well as during its subsequent…

  14. Getting Active in the Large Lecture

    ERIC Educational Resources Information Center

    Huerta, Juan Carlos

    2007-01-01

    The benefits of active learning are well documented; nonetheless, the implementation of active learning strategies can be challenging in large lecture environments. The project will examine the research supporting active learning, present the implementation of simple active learning techniques in large lecture classes, and provide evidence to test…

  15. World atlas of large optical telescopes

    NASA Technical Reports Server (NTRS)

    Meszaros, S. P.

    1979-01-01

    By 1980 there will be approximately 100 large optical telescopes in the world with mirror or lens diameters of one meter (39 inches) and larger. This atlas gives information on these telescopes and shows their locations on continent-sized maps. Observatory locations considered suitable for the construction of future large telescopes are also shown.

  16. Implementing Large Projects in Software Engineering Courses

    ERIC Educational Resources Information Center

    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…

  17. LARGE AND GREAT RIVERS: NEW ASSESSMENT TOOLS

    EPA Science Inventory

    The Ecological Exposure Research Division has been conducting research to support the development of the next generation of bioassessment and monitoring tools for large and great rivers. Focus has largely been on the development of standardized protocols for the traditional indi...

  18. Collaborative Working for Large Digitisation Projects

    ERIC Educational Resources Information Center

    Yeates, Robin; Guy, Damon

    2006-01-01

    Purpose: To explore the effectiveness of large-scale consortia for disseminating local heritage via the web. To describe the creation of a large geographically based cultural heritage consortium in the South East of England and management lessons resulting from a major web site digitisation project. To encourage the improved sharing of experience…

  19. Generically large nongaussianity in small multifield inflation

    SciTech Connect

    Bramante, Joseph

    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.

  20. Large Scale Metal Additive Techniques Review

    SciTech Connect

    Nycz, Andrzej; Adediran, Adeola I; Noakes, Mark W; Love, Lonnie J

    2016-01-01

    In recent years additive manufacturing made long strides toward becoming a main stream production technology. Particularly strong progress has been made in large-scale polymer deposition. However, large scale metal additive has not yet reached parity with large scale polymer. This paper is a review study of the metal additive techniques in the context of building large structures. Current commercial devices are capable of printing metal parts on the order of several cubic feet compared to hundreds of cubic feet for the polymer side. In order to follow the polymer progress path several factors are considered: potential to scale, economy, environment friendliness, material properties, feedstock availability, robustness of the process, quality and accuracy, potential for defects, and post processing as well as potential applications. This paper focuses on current state of art of large scale metal additive technology with a focus on expanding the geometric limits.

  1. Environmental effects and large space systems

    NASA Technical Reports Server (NTRS)

    Garrett, H. B.

    1981-01-01

    When planning large scale operations in space, environmental impact must be considered in addition to radiation, spacecraft charging, contamination, high power and size. Pollution of the atmosphere and space is caused by rocket effluents and by photoelectrons generated by sunlight falling on satellite surfaces even light pollution may result (the SPS may reflect so much light as to be a nuisance to astronomers). Large (100 Km 2) structures also will absorb the high energy particles that impinge on them. Altogether, these effects may drastically alter the Earth's magnetosphere. It is not clear if these alterations will in any way affect the Earth's surface climate. Large structures will also generate large plasma wakes and waves which may cause interference with communications to the vehicle. A high energy, microwave beam from the SPS will cause ionospheric turbulence, affecting UHF and VHF communications. Although none of these effects may ultimately prove critical, they must be considered in the design of large structures.

  2. Testing Large Structures in the Field

    NASA Technical Reports Server (NTRS)

    James, George; Carne, Thomas G.

    2009-01-01

    Field testing large structures creates unique challenges such as limited choices for boundary conditions and the fact that natural excitation sources cannot be removed. Several critical developments in field testing of large structures are reviewed, including: step relaxation testing which has been developed into a useful technique to apply large forces to operational systems by careful windowing; the capability of large structures testing with free support conditions which has been expanded by implementing modeling of the support structure; natural excitation which has been developed as a viable approach to field testing; and the hybrid approach which has been developed to allow forces to be estimated in operating structures. These developments have increased the ability to extract information from large structures and are highlighted in this presentation.

  3. Large Eddy Simulation of a Turbulent Jet

    NASA Technical Reports Server (NTRS)

    Webb, A. T.; Mansour, Nagi N.

    2001-01-01

    Here we present the results of a Large Eddy Simulation of a non-buoyant jet issuing from a circular orifice in a wall, and developing in neutral surroundings. The effects of the subgrid scales on the large eddies have been modeled with the dynamic large eddy simulation model applied to the fully 3D domain in spherical coordinates. The simulation captures the unsteady motions of the large-scales within the jet as well as the laminar motions in the entrainment region surrounding the jet. The computed time-averaged statistics (mean velocity, concentration, and turbulence parameters) compare well with laboratory data without invoking an empirical entrainment coefficient as employed by line integral models. The use of the large eddy simulation technique allows examination of unsteady and inhomogeneous features such as the evolution of eddies and the details of the entrainment process.

  4. Large structures and tethers working group

    NASA Technical Reports Server (NTRS)

    Murphy, G.; Garrett, H.; Samir, U.; Barnett, A.; Raitt, J.; Sullivan, J.; Katz, I.

    1986-01-01

    The Large Structures and Tethers Working Group sought to clarify the meaning of large structures and tethers as they related to space systems. Large was assumed to mean that the characteristic length of the structure was greater than one of such relevant plasma characteristics as ion gyroradius or debey length. Typically, anything greater than or equal to the Shuttle dimensions was considered large. It was agreed that most large space systems that the tether could be better categorized as extended length, area, or volume structures. The key environmental interactions were then identified in terms of these three categories. In the following Working Group summary, these categories and the related interactions are defined in detail. The emphasis is on how increases in each of the three spatial dimensions uniquely determine the interactions with the near-Earth space environment. Interactions with the environments around the other planets and the solar wind were assumed to be similar or capable of being extrapolated from the near-Earth results. It should be remembered in the following that the effects on large systems do not just affect specific technologies but will quite likely impact whole missions. Finally, the possible effects of large systems on the plasma environment, although only briefly discussed, were felt to be of potentially great concern.

  5. Very Large System Dynamics Models - Lessons Learned

    SciTech Connect

    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.

  6. Experimental Simulations of Large-Scale Collisions

    NASA Technical Reports Server (NTRS)

    Housen, Kevin R.

    2002-01-01

    This report summarizes research on the effects of target porosity on the mechanics of impact cratering. Impact experiments conducted on a centrifuge provide direct simulations of large-scale cratering on porous asteroids. The experiments show that large craters in porous materials form mostly by compaction, with essentially no deposition of material into the ejecta blanket that is a signature of cratering in less-porous materials. The ratio of ejecta mass to crater mass is shown to decrease with increasing crater size or target porosity. These results are consistent with the observation that large closely-packed craters on asteroid Mathilde appear to have formed without degradation to earlier craters.

  7. Large area perovskite solar cell module

    NASA Astrophysics Data System (ADS)

    Cai, Longhua; Liang, Lusheng; Wu, Jifeng; Ding, Bin; Gao, Lili; Fan, Bin

    2017-01-01

    The recent dramatic rise in power conversion efficiencies (PCE) of perovskite solar cells has triggered intense research worldwide. However, their practical development is hampered by poor stability and low PCE values with large areas devices. Here, we developed a gas-pumping method to avoid pinholes and eliminate local structural defects over large areas of perovskite film, even for 5 × 5 cm2 modules, the PCE reached 10.6% and no significant degradation was found after 140 days of outdoor testing. Our approach enables the realization of high performance large-area PSCs for practical application.

  8. The next generation very large array

    NASA Astrophysics Data System (ADS)

    McKinnon, Mark; Carilli, Chris; Beasley, Tony

    2016-07-01

    The North American astronomical community is considering a future large area radio array optimized to perform imaging of thermal emission down to milliarcsecond scales. This `Next Generation Very Large Array' would entail ten times the effective collecting area of the Jansky Very Large Array, operate from 1GHz to 115GHz, with ten times longer baselines (300km) providing milliarcsecond resolution, and include a dense core on kilometer scales for high surface brightness imaging. The preliminary design, capabilities, and some of the priority science goals of the instrument are summarized.

  9. The Amateurs' Love Affair with Large Datasets

    NASA Astrophysics Data System (ADS)

    Price, Aaron; Jacoby, S. H.; Henden, A.

    2006-12-01

    Amateur astronomers are professionals in other areas. They bring expertise from such varied and technical careers as computer science, mathematics, engineering, and marketing. These skills, coupled with an enthusiasm for astronomy, can be used to help manage the large data sets coming online in the next decade. We will show specific examples where teams of amateurs have been involved in mining large, online data sets and have authored and published their own papers in peer-reviewed astronomical journals. Using the proposed LSST database as an example, we will outline a framework for involving amateurs in data analysis and education with large astronomical surveys.

  10. Adaptive Control Of Large Vibrating, Rotating Structures

    NASA Technical Reports Server (NTRS)

    Bayard, David S.

    1991-01-01

    Globally convergent theoretical method provides for adaptive set-point control of orientation of, along with suppression of the vibrations of, large structure. Method utilizes inherent passivity properties of structure to attain mathematical condition essential to adaptive convergence on commanded set point. Maintains stability and convergence in presence of errors in mathematical model of dynamics of structure and actuators. Developed for controlling attitudes of large, somewhat flexible spacecraft, also useful in such terrestrial applications as controlling movable bridges or suppressing earthquake vibrations in bridges, buildings, and other large structures.

  11. Performance of large inert-gas thrusters

    NASA Technical Reports Server (NTRS)

    Kaufman, H. R.

    1981-01-01

    The performance of large inert-gas thrusters is predicted based on present knowledge of ion optics performance and discharge chamber operation. Calculated performance data are given for argon and xenon propellants. The effect of varying propellant utilization and thruster diameter is discussed and the optimum choice of beam diameter for very large systems is indicated for low, intermediate, and high specific impulses. Optimum discharge chamber depths are also specified. Although detailed design considerations may modify the predictions, the general trends indicated should still be useful for directing future technology efforts and evaluating mission studies involving large thrusters.

  12. Model for repetitive cycles of large earthquakes

    SciTech Connect

    Newman, W.I.; Knopoff, L.

    1983-04-01

    The theory of the fusion of small cracks into large ones reproduces certain features also observed in the clustering of earthquake sequences. By modifying our earlier model to take into account the stress release associated with the occurrence of large earthquakes, we obtain repetitive periodic cycles of large earthquakes. A preliminary conclusion is that a combination of the stress release or elastic rebound mechanism plus time delays in the fusion process are sufficient to destabilize the crack populations and, ultimately, give rise to repetitive episodes of seismicity.

  13. Learning to build large structures in space

    NASA Technical Reports Server (NTRS)

    Hagler, T.; Patterson, H. G.; Nathan, C. A.

    1977-01-01

    The paper examines some of the key technologies and forms of construction know-how that will have to be developed and tested for eventual application to building large structures in space. Construction of a shuttle-tended space construction/demonstration platform would comprehensively demonstrate large structure technology, develop construction capability, and furnish a construction platform for a variety of operational large structures. Completion of this platform would lead to demonstrations of the Satellite Power System (SPS) concept, including microwave transmission, fabrication of 20-m-deep beams, conductor installation, rotary joint installation, and solar blanket installation.

  14. Environmental interaction implications for large space systems

    NASA Technical Reports Server (NTRS)

    Miller, E.; Fischbein, W.; Stauber, M. C.; Suh, P. K.

    1979-01-01

    Large Space Systems (LSS) comprise a new class of spacecraft, the design and performance of which may be seriously affected by a variety of environmental interactions. The special concerns associated with spacecraft charging and plasma interactions from the LSS designer's viewpoint are addressed. Survivability of these systems under combined solar U.V., particle radiation and repeated electrical discharges is of primary importance. Additional questions regard the character of electrical discharges over very large areas, the effects of high current/voltage systems and magnitude of induced structural disturbances. A concept is described for a large scale experiment platform.

  15. Laparoscopic management of large ureteral fibroepithelial polyp.

    PubMed

    Kijvikai, Kittinut; Maynes, Lincoln J; Herrell, S Duke

    2007-08-01

    Fibroepithelial polyps of the ureter are rare benign mesothelial tumors. Most polyps are small; however, very rare large polyps have also been reported. Currently, most investigators encourage endoscopic management in these patients. Nevertheless, endoscopic resection can be difficult in patients with a long or large polypoid lesion. We describe our experience and laparoscopic technique for treatment of a symptomatic 42-year-old woman who presented with a 17-cm-long fibroepithelial polyp in the proximal ureter associated with ureteral obstruction. To our knowledge, this is the first reported case of laparoscopic management of a large ureteral fibroepithelial polyp.

  16. Experimental verification of a large flexible manipulator

    NASA Technical Reports Server (NTRS)

    Lee, Jac Won; Huggins, James D.; Book, Wayne J.

    1988-01-01

    A large experimental lightweight manipulator would be useful for material handling, for welding, or for ultrasonic inspection of a large structure, such as an airframe. The flexible parallel link mechanism is designed for high rigidity without increasing weight. This constrained system is analyzed by singular value decomposition of the constraint Jacobian matrix. A verification of the modeling using the assumed mode method is presented. Eigenvalues and eigenvectors of the linearized model are compared to the measured system natural frequencies and their associated mode shapes. The modeling results for large motions are compared to the time response data from the experiments. The hydraulic actuator is verified.

  17. Communication architecture for large geostationary platforms

    NASA Technical Reports Server (NTRS)

    Bond, F. E.

    1979-01-01

    Large platforms have been proposed for supporting multipurpose communication payloads to exploit economy of scale, reduce congestion in the geostationary orbit, provide interconnectivity between diverse earth stations, and obtain significant frequency reuse with large multibeam antennas. This paper addresses a specific system design, starting with traffic projections in the next two decades and discussing tradeoffs and design approaches for major components including: antennas, transponders, and switches. Other issues explored are selection of frequency bands, modulation, multiple access, switching methods, and techniques for servicing areas with nonuniform traffic demands. Three-major services are considered: a high-volume trunking system, a direct-to-user system, and a broadcast system for video distribution and similar functions. Estimates of payload weight and d.c. power requirements are presented. Other subjects treated are: considerations of equipment layout for servicing by an orbit transfer vehicle, mechanical stability requirements for the large antennas, and reliability aspects of the large number of transponders employed.

  18. Large Meteor Tracked over Northeast Alabama

    NASA Video Gallery

    On the evening of May 18, NASA all-sky meteor cameras located at NASA’s Marshall Space Flight Center and at the Walker County Science Center near Chickamauga, Ga. tracked the entry of a large meteo...

  19. Large, horizontal-axis wind turbines

    NASA Technical Reports Server (NTRS)

    Linscott, B. S.; Perkins, P.; Dennett, J. T.

    1984-01-01

    Development of the technology for safe, reliable, environmentally acceptable large wind turbines that have the potential to generate a significant amount of electricity at costs competitive with conventional electric generating systems are presented. In addition, these large wind turbines must be fully compatible with electric utility operations and interface requirements. There are several ongoing large wind system development projects and applied research efforts directed toward meeting the technology requirements for utility applications. Detailed information on these projects is provided. The Mod-O research facility and current applied research effort in aerodynamics, structural dynamics and aeroelasticity, composite and hybrid composite materials, and multiple system interaction are described. A chronology of component research and technology development for large, horizontal axis wind turbines is presented. Wind characteristics, wind turbine economics, and the impact of wind turbines on the environment are reported. The need for continued wind turbine research and technology development is explored. Over 40 references are sited and a bibliography is included.

  20. Large-scale regions of antimatter

    SciTech Connect

    Grobov, A. V. Rubin, S. G.

    2015-07-15

    Amodified mechanism of the formation of large-scale antimatter regions is proposed. Antimatter appears owing to fluctuations of a complex scalar field that carries a baryon charge in the inflation era.

  1. Remotely controlled large container disposal methodology

    SciTech Connect

    Amir, S.J.

    1994-09-01

    Remotely Handled Large Containers (RHLC), also called drag-off boxes, have been used at the Hanford Site since the 1940s to dispose of large pieces of radioactively contaminated equipment. These containers are typically large steel-reinforced concrete boxes, which weigh as much as 40 tons. Because large quantities of high-dose waste can produce radiation levels as high as 200 mrem/hour at 200 ft, the containers are remotely handled (either lifted off the railcar by crane or dragged off with a cable). Many of the existing containers do not meet existing structural and safety design criteria and some of the transportation requirements. The drag-off method of pulling the box off the railcar using a cable and a tractor is also not considered a safe operation, especially in view of past mishaps.

  2. Gravitational waves and large field inflation

    NASA Astrophysics Data System (ADS)

    Linde, Andrei

    2017-02-01

    According to the famous Lyth bound, one can confirm large field inflation by finding tensor modes with sufficiently large tensor-to-scalar ratio r. Here we will try to answer two related questions: is it possible to rule out all large field inflationary models by not finding tensor modes with r above some critical value, and what can we say about the scale of inflation by measuring r? However, in order to answer these questions one should distinguish between two different definitions of the large field inflation and three different definitions of the scale of inflation. We will examine these issues using the theory of cosmological α-attractors as a convenient testing ground.

  3. Bipartite Graphs of Large Clique-Width

    NASA Astrophysics Data System (ADS)

    Korpelainen, Nicholas; Lozin, Vadim V.

    Recently, several constructions of bipartite graphs of large clique-width have been discovered in the literature. In the present paper, we propose a general framework for developing such constructions and use it to obtain new results on this topic.

  4. Large & Small: Exploring the Laws of Nature

    ERIC Educational Resources Information Center

    Creutz, E.

    1976-01-01

    Illustrates how both large entities (such as stars and galaxies) and small entities (such as fundamental particles) obey the same physical laws. Discusses quantum mechanics, Newton's laws, and general relativity. (MLH)

  5. Have Large Dams Altered Extreme Precipitation Patterns?

    NASA Astrophysics Data System (ADS)

    Hossain, Faisal; Jeyachandran, Indumathi; Pielke, Roger

    2009-12-01

    Dams and their impounded waters are among the most common civil infrastructures, with a long heritage of modern design and operations experience. In particular, large dams, defined by the International Commission on Large Dams (ICOLD) as having a height greater than 15 meters from the foundation and holding a reservoir volume of more than 3 million cubic meters, have the potential to vastly transform local climate, landscapes, regional economics, and urbanization patterns. In the United States alone, about 75,000 dams are capable of storing a volume of water equaling almost 1 year's mean runoff of the nation [Graf, 1999]. The World Commission on Dams (WCD) reports that at least 45,000 large dams have been built worldwide since the 1930s. These sheer numbers raise the question of the extent to which large dams and their impounded waters alter patterns that would have been pervasive had the dams not been built.

  6. Retroperitoneoscopic partial adrenalectomy for large adrenocortical oncocytoma.

    PubMed

    Modi, Pranjal; Goel, Rajiv; Kadam, Gaurang

    2007-04-01

    A young woman had mild hypertension, and on evaluation, a large tumor arising from the right adrenal gland was found. The tumor was hormonally inactive. Retroperitoneoscopic partial adrenalectomy was carried out. The histopathology report described adrenocortical oncocytoma.

  7. Decontamination of large components-test case

    SciTech Connect

    Mancini, A.; Bosco, B.

    1996-12-31

    The rising per-cubic-foot burial costs, together with the trend toward standardized above-ground burial sites, provides the basis for seeking an alternative to direct burial of large components. Large contaminated components such as steam generators can be safely dismantled and decontaminated for free release, metals recycle, and volume reduction. This grand-scale disposal technology will prove to be an economical and ecological alternative to direct burial or interim storage. Yankee Atomic Electric Company (YAEC) in Bolton, operators and decommissioners of the Yankee Nuclear Power Station in Rowe, Massachusetts, has teamed with Frank W Hake Associates in Memphis, TN, to decontaminate a large component as a test case. The large component is YAEC`s reactor pressure vessel head (RPVH). The 79 100 lb RPVH is surface contaminated with 0.7 Ci (1500 mR/h contact) resulting from 32 yr of operating in a 2000 psi, 530{degrees}F pressurized water reactor environment.

  8. Large Space Antenna Systems Technology, part 1

    NASA Technical Reports Server (NTRS)

    Lightner, E. B. (Compiler)

    1983-01-01

    A compilation of the unclassified papers presented at the NASA Conference on Large Space Antenna Systems Technology covers the following areas: systems, structures technology, control technology, electromagnetics, and space flight test and evaluation.

  9. Large Area Synthesis of 2D Materials

    NASA Astrophysics Data System (ADS)

    Vogel, Eric

    Transition metal dichalcogenides (TMDs) have generated significant interest for numerous applications including sensors, flexible electronics, heterostructures and optoelectronics due to their interesting, thickness-dependent properties. Despite recent progress, the synthesis of high-quality and highly uniform TMDs on a large scale is still a challenge. In this talk, synthesis routes for WSe2 and MoS2 that achieve monolayer thickness uniformity across large area substrates with electrical properties equivalent to geological crystals will be described. Controlled doping of 2D semiconductors is also critically required. However, methods established for conventional semiconductors, such as ion implantation, are not easily applicable to 2D materials because of their atomically thin structure. Redox-active molecular dopants will be demonstrated which provide large changes in carrier density and workfunction through the choice of dopant, treatment time, and the solution concentration. Finally, several applications of these large-area, uniform 2D materials will be described including heterostructures, biosensors and strain sensors.

  10. Cosmogenic Nuclides Study of Large Iron Meteorites

    NASA Astrophysics Data System (ADS)

    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.

  11. Peripheral T-Cell Lymphoma

    MedlinePlus

    ... consists of a group of rare and usually aggressive (fast-growing) NHLs that develop from mature T- ... also be involved. This group of PTCLs is aggressive and requires combination chemotherapy upon diagnosis. Anaplastic Large ...

  12. A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer

    ClinicalTrials.gov

    2017-04-04

    Non-Small Cell Lung Cancer (ALK-positive); Non-Small Cell Lung Cancer (c-Met Dependent); Non-Small Cell Lung Cancer (ROS Marker Positive); Systemic Anaplastic Large-Cell Lymphoma; Advanced Malignancies (Except Leukemia)

  13. The large bowel--a supplementary rumen?

    PubMed

    Argenzio, R A; Stevens, C E

    1984-01-01

    The rumen and the mammalian large intestine are similar in many respects. Microbial protein appears to be synthesized and degraded in the digesta of both organs in a comparable manner. The VFA end-products of carbohydrate fermentation are produced in similar concentrations. Digesta pH is maintained with buffer added by the saliva or ileal fluid, HCO3 released into the lumen and rapid absorption of the organic acids. VFA are absorbed at equivalent rates by rumen epithelium and large intestinal mucosa. Over-production of VFA produces similar adverse effects. There is a considerable amount of species variation in the relative length and volume as well as the extent of sacculation of the large intestine. The caecum is the primary site for retention of digesta and microbial fermentation in the large intestine of rabbits, rodents and a few other species. However, the proximal colon is the major site of retention and fermentation in most mammals. Absorptions of Na and VFA appear to account for absorption of most of the water removed during passage of digesta through the large intestine. A relatively slow rate of Na absorption and release of HCO3 appears to provide the fluid and buffering capacity needed for efficient microbial digestion in the rumen and in the large intestine of some species. A more rapid absorption of Na by the large intestine of other species would aid in the conservation of Na and water. The many similarities between the large intestine and the rumen suggest that further comparison can provide additional information on both the function and diseases of these two organs. The rumen has proved to be accessible to a variety of procedures useful for the study of microbial digestive processes and its epithelium has provided a non-glandular tissue for studies of inorganic ion transport as well as the transport and metabolism of VFA. Comparative studies of the large intestine also can provide a better understanding of the functions and malfunctions of the

  14. Very Large Arrays of Bipolar Electrodes

    DTIC Science & Technology

    2013-01-01

    Array-based chemical and biosensors are necessary for detection of WMDs. • At present there are no viable, large-scale electrochemical array...Mavre, John A. Crooks, Byoung-Yong Chang, Richard M. Crooks, Kwok-Fan Chow. A Large-Scale, Wireless Electrochemical Bipolar Electrode Microarray, Journal...Wireless Electrochemical DNA Microarray Sensor, Journal of the American Chemical Society, (06 2008): 7544. doi: 10.1021/ja802013q 05/30/2013 17.00 Rahul

  15. Optical iconic filters for large class recognition.

    PubMed

    Casasent, D; Mahalamobis, A

    1987-06-01

    Approaches are advanced for pattern recognition when a large number of classes must be identified. Multilevel encoded multiple-iconic filters are considered for this problem. Hierarchical arrangements of iconic filters and/or preprocessing stages are described. A theoretical basis for the sidelobe level and noise effects of filters designed for large class problems is advanced. Experimental data are provided for an optical character recognition case study.

  16. Algorithms for Large-Scale Astronomical Problems

    DTIC Science & Technology

    2013-08-01

    release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Modern astronomical datasets are getting larger and larger, which already include...of data, which raises the following question: How can we use modern computer science techniques to help astronomers better analyze large datasets? To...indexing and sorting further reduce the processing time of user queries.  We processed large data using modern distributed computing frameworks

  17. On large N solution of ABJM theory

    NASA Astrophysics Data System (ADS)

    Suyama, Takao

    2010-07-01

    We investigate the large N limit of the expectation value W(λ) of a BPS Wilson loop in ABJM theory, using an integral expression of the partition function obtained recently by Kapustin et al. Certain saddle-point equations provide the correct perturbative expansion of W(λ). The large λ behavior of W(λ) is also obtained from the saddle-point equations. The result is consistent with AdS/CFT correspondence.

  18. Large diameter carbon-boron fiber

    NASA Technical Reports Server (NTRS)

    Veltri, R. D.; Jacob, B. A.; Galasso, F. S.

    1975-01-01

    Investigations concerned with a development of large-diameter carbon fibers are considered, taking into account the employment of vapor deposition techniques. In the experiments a carbon monofilament substrate is used together with reacting gases which consist of combinations of hydrogen, methane, and boron trichloride. It is found that the described approach can be used to obtain a large-diameter carbon filament containing boron. The filament has reasonable strength and modulus properties.

  19. Large-scale cortical networks and cognition.

    PubMed

    Bressler, S L

    1995-03-01

    The well-known parcellation of the mammalian cerebral cortex into a large number of functionally distinct cytoarchitectonic areas presents a problem for understanding the complex cortical integrative functions that underlie cognition. How do cortical areas having unique individual functional properties cooperate to accomplish these complex operations? Do neurons distributed throughout the cerebral cortex act together in large-scale functional assemblages? This review examines the substantial body of evidence supporting the view that complex integrative functions are carried out by large-scale networks of cortical areas. Pathway tracing studies in non-human primates have revealed widely distributed networks of interconnected cortical areas, providing an anatomical substrate for large-scale parallel processing of information in the cerebral cortex. Functional coactivation of multiple cortical areas has been demonstrated by neurophysiological studies in non-human primates and several different cognitive functions have been shown to depend on multiple distributed areas by human neuropsychological studies. Electrophysiological studies on interareal synchronization have provided evidence that active neurons in different cortical areas may become not only coactive, but also functionally interdependent. The computational advantages of synchronization between cortical areas in large-scale networks have been elucidated by studies using artificial neural network models. Recent observations of time-varying multi-areal cortical synchronization suggest that the functional topology of a large-scale cortical network is dynamically reorganized during visuomotor behavior.

  20. Large area monolithic organic solar cells

    NASA Astrophysics Data System (ADS)

    Jin, Hui; Tao, Cheng; Hambsch, Mike; Pivrikas, Almantas; Velusamy, Marappan; Aljada, Muhsen; Zhang, Yuliang; Burn, Paul L.; Meredith, Paul

    2012-11-01

    Although efficiencies of > 10% have recently been achieved in laboratory-scale organic solar cells, these competitive performance figures are yet to be translated to large active areas and geometries relevant for viable manufacturing. One of the factors hindering scale-up is a lack of knowledge of device physics at the sub-module level, particularly cell architecture, electrode geometry and current collection pathways. A more in depth understanding of how photocurrent and photovoltage extraction can be optimised over large active areas is urgently needed. Another key factor suppressing conversion efficiencies in large area cells is the relatively high sheet resistance of the transparent conducting anode - typically indium tin oxide. Hence, to replace ITO with alternative transparent conducting anodes is also a high priority on the pathway to viable module-level organic solar cells. In our paper we will focus on large area devices relevant to sub-module scales - 5 cm × 5 cm monolithic geometry. We have applied a range of experimental techniques to create a more comprehensive understanding of the true device physics that could help make large area, monolithic organic solar cells more viable. By employing this knowledge, a novel transparent anode consisting of molybdenum oxide (MoOx) and silver (Ag) is developed to replace ITO and PEDOT-free large area solar cell sub-modules, acting as both a transparent window and hole-collecting electrode. The proposed architecture and anode materials are well suited to high throughput, low cost all-solution processing.