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Sample records for alk-negative anaplastic large

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

    PubMed Central

    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 evolutionof 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. PMID:23923082

  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. PMID:23923082

  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. PMID:27079579

  4. Genetics of Anaplastic Large Cell Lymphoma

    PubMed Central

    Zeng, Yu; Feldman, Andrew L.

    2016-01-01

    Anaplastic large cell lymphoma (ALCL) comprises a group of T-cell non-Hodgkin lymphomas unified by common morphologic and immunophenotypic characteristics, but with a spectrum of clinical presentations and behaviors. Early identification of anaplastic lymphoma kinase (ALK) gene rearrangements in some ALCLs led to recognition of ALK as an important diagnostic and prognostic biomarker, and a key driver of ALCL pathobiology. Rearrangements and other genetic abnormalities of ALK subsequently were identified in diverse other human malignancies. Recent clinical, pathologic, and genetic data have begun to shed light on ALK-negative ALCLs, revealing significant heterogeneity within this more ill-defined entity. PMID:26104084

  5. Anaplastic Large Cell Lymphoma Associated With Breast Implants

    PubMed Central

    Ravi-Kumar, Shalini; Sanaei, Omid; Vasef, Mohammad; Rabinowitz, Ian; Fekrazad, Mohammad Houman

    2012-01-01

    A forty two years old woman with a history of bilateral breast augmentation for cosmetic reasons was presented for poor healing of the surgical site. Tissue and periprosthetic fluid were removed from the wound site revealing an atypical lymphoid infiltrate. Subsequently the patient developed axillary lymph adenopathy. Excisional biopsy was performed. Flow cytometry was non-diagnostic. She continued to heal poorly and eventually had removal of implant during a simple mastectomy. A nodular area in the breast specimen showed ALK negative anaplastic large cell lymphoma (ALCL). The patient was treated in the private section, with only a pathology consultation being done at our institution (Figures 1-3). PMID:25734041

  6. CD30-Positive Anaplastic Lymphoma Kinase-Negative Systemic Anaplastic Large-Cell Lymphoma in a 9-Year-Old Boy

    PubMed Central

    Kim, Jeong Eun; Oh, Eui Hyun; Ro, Young Suck

    2016-01-01

    Anaplastic large-cell lymphoma (ALCL) is a CD30-positive T-cell/null-cell lymphoma that is clinically classified into either primary cutaneous ALCL or systemic ALCL (S-ALCL) sub-types. Because 90% of childhood S-ALCL cases are anaplastic lymphoma kinase (ALK)-positive, there is a lack of data on ALK-negative S-ALCL cases among pediatric patients. Herein, we report a rare case of ALK-negative S-ALCL in a 9-year-old Korean boy who initially presented with itchy erythematous maculopapules and an erosive nodule on the trunk area. We emphasize the need of high index of suspicion of an underlying malignant disease in the presence of refractory eczematous lesions. PMID:27274637

  7. CD30-Positive Anaplastic Lymphoma Kinase-Negative Systemic Anaplastic Large-Cell Lymphoma in a 9-Year-Old Boy.

    PubMed

    Kim, Jeong Eun; Oh, Eui Hyun; Ro, Young Suck; Ko, Joo Yeon

    2016-06-01

    Anaplastic large-cell lymphoma (ALCL) is a CD30-positive T-cell/null-cell lymphoma that is clinically classified into either primary cutaneous ALCL or systemic ALCL (S-ALCL) sub-types. Because 90% of childhood S-ALCL cases are anaplastic lymphoma kinase (ALK)-positive, there is a lack of data on ALK-negative S-ALCL cases among pediatric patients. Herein, we report a rare case of ALK-negative S-ALCL in a 9-year-old Korean boy who initially presented with itchy erythematous maculopapules and an erosive nodule on the trunk area. We emphasize the need of high index of suspicion of an underlying malignant disease in the presence of refractory eczematous lesions. PMID:27274637

  8. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts.

    PubMed

    Scarfò, Irene; Pellegrino, Elisa; Mereu, Elisabetta; Kwee, Ivo; Agnelli, Luca; Bergaggio, Elisa; Garaffo, Giulia; Vitale, Nicoletta; Caputo, Manuel; Machiorlatti, Rodolfo; Circosta, Paola; Abate, Francesco; Barreca, Antonella; Novero, Domenico; Mathew, Susan; Rinaldi, Andrea; Tiacci, Enrico; Serra, Sara; Deaglio, Silvia; Neri, Antonino; Falini, Brunangelo; Rabadan, Raul; Bertoni, Francesco; Inghirami, Giorgio; Piva, Roberto

    2016-01-14

    Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 5' RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 5' untranslated regions. PMID:26463425

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

    PubMed

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

    2015-01-01

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

  10. ETV6-NTRK3 Is Expressed in a Subset of ALK-Negative Inflammatory Myofibroblastic Tumors.

    PubMed

    Alassiri, Ali H; Ali, Rola H; Shen, Yaoqing; Lum, Amy; Strahlendorf, Caron; Deyell, Rebecca; Rassekh, Rod; Sorensen, Poul H; Laskin, Janessa; Marra, Marco; Yip, Stephen; Lee, Cheng-Han; Ng, Tony L

    2016-08-01

    Inflammatory myofibroblastic tumor (IMT) is a genetically heterogenous tumor of the viscera and soft tissues, with multiple molecular features having been demonstrated in this tumor type. About 50% of cases harbor an anaplastic lymphoma kinase (ALK) gene rearrangement, and recent studies have described novel fusions involving the ROS1 and PDGFRβ genes in a subset of ALK-negative cases. However, the molecular features of the remaining subset of cases are not yet defined. We report a case of a large, highly aggressive IMT of the lung in a 17-year-old girl. This case was molecularly characterized through whole-genome and transcriptome sequencing. Subsequently, we investigated a cohort of 15 ALK-negative IMTs of various anatomic sites. All cases were screened using fluorescence in situ hybridization (FISH) for rearrangement of the ETV6 locus and with reverse transcription polymerase chain reaction (RT-PCR) for the ETV6-NTRK3 fusion transcript. Whole-genome and transcriptome sequencing revealed an ETV6-NTRK3 fusion transcript in our index case. This was confirmed by FISH studies for ETV6 gene rearrangement, as well as by RT-PCR. In addition, 2 additional cases in our cohort demonstrated ETV6 rearrangement by FISH. The presence of ETV6-NTRK3 fusion transcript was demonstrated by RT-PCR in one of these additional cases. In summary, we demonstrate the expression of the ETV6-NTRK3 fusion oncogene in a small subset of IMTs, lending further support to the role of oncogenic tyrosine kinases in the pathophysiology of this tumor type. Our data also further expand the growing spectrum of tumor types expressing the ETV6-NTRK3 fusion. PMID:27259007

  11. PAX5-positive T-cell Anaplastic Large Cell Lymphomas Associated with Extra Copies of the PAX5 Gene Locus

    PubMed Central

    Feldman, Andrew L; Law, Mark E; Inwards, David J; Dogan, Ahmet; McClure, Rebecca F; Macon, William R

    2010-01-01

    Cell lineage is the major criterion by which lymphomas are classified. Immunohistochemistry has greatly facilitated lymphoma diagnosis by detecting expression of lineage-associated antigens. However, loss or aberrant expression of these antigens may present diagnostic challenges. Anaplastic large cell lymphoma is a T-cell lymphoma that shows morphologic and phenotypic overlap with classical Hodgkin lymphoma, a tumor of B-cell derivation. Staining for the B-cell transcription factor, PAX5, has been suggested to be helpful in this differential, as it is positive in most classical Hodgkin lymphomas, but absent in anaplastic large cell lymphomas. Herein, we report four systemic T-cell anaplastic large cell lymphomas positive for PAX5 by immunohistochemistry, with weak staining intensity similar to that seen in classical Hodgkin lymphoma. All diagnoses were confirmed by a combination of morphologic, phenotypic, and molecular criteria. Three cases were ALK-negative and one was ALK-positive. PAX5 immunohistochemistry was negative in 198 additional peripheral T-cell lymphomas, including 66 anaplastic large cell lymphomas. Unexpectedly, though PAX5 translocations were absent, all evaluable PAX5-positive anaplastic large cell lymphomas showed extra copies of the PAX5 gene locus by fluorescence in situ hybridization. In contrast, only 4% of PAX5-negative peripheral T-cell lymphomas had extra copies of PAX5. We conclude that aberrant expression of PAX5 occurs rarely in T-cell anaplastic large cell lymphomas, and may be associated with extra copies of the PAX5 gene. PAX5-positive lymphomas with morphologic features overlapping different lymphoma types should be evaluated with an extensive immunohistochemical panel and/or molecular studies to avoid diagnostic errors that could lead to inappropriate treatment. Since PAX5 overexpression causes T-cell neoplasms in experimental models, PAX5 may have contributed to lymphomagenesis in our cases. PMID:20118907

  12. microRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma

    PubMed Central

    Liu, Cuiling; Iqbal, Javeed; Teruya-Feldstein, Julie; Shen, Yulei; Dabrowska, Magdalena Julia; Dybkaer, Karen; Lim, Megan S.; Piva, Roberto; Barreca, Antonella; Pellegrino, Elisa; Spaccarotella, Elisa; Lachel, Cynthia M.; Kucuk, Can; Jiang, Chun-Sun; Hu, Xiaozhou; Bhagavathi, Sharathkumar; Greiner, Timothy C.; Weisenburger, Dennis D.; Aoun, Patricia; Perkins, Sherrie L.; McKeithan, Timothy W.; Inghirami, Giorgio

    2013-01-01

    Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[−]) ALCLs, 9 angioimmunoblastic T-cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS, and the AITL subtype of PTCL. Cases of ALK(+) ALCL and ALK(–) ALCL were interspersed in unsupervised analysis, suggesting a close relationship at the molecular level. We identified an miRNA signature of 7 miRNAs (5 upregulated: miR-512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b; 2 downregulated: miR-146a, miR-155) significantly associated with ALK(+) ALCL cases. In addition, we derived an 11-miRNA signature (4 upregulated: miR-210, miR-197, miR-191, miR-512-3p; 7 downregulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR-494) that differentiates ALK(–) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR-17∼92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway. PMID:23801630

  13. Identification of putative pathogenic microRNA and its downstream targets in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.

    PubMed

    Mehrotra, Meenakshi; Medeiros, L Jeffrey; Luthra, Rajyalakshmi; Sargent, Rachel L; Yao, Hui; Barkoh, Bedia A; Singh, Rajesh; Patel, Keyur P

    2014-10-01

    Anaplastic large cell lymphomas (ALCL) are tumors of T/null-cell lineage characterized by uniform CD30 expression. The 2008 World Health Organization classification subdivided ALCLs into 2 groups: anaplastic lymphoma kinase (ALK)-positive (established entity) and ALK-negative (proposed new entity) ALCL. The genetic basis for the pathogenesis of newly categorized ALK- ALCL is poorly understood. In this study, we used microRNA microarray analysis to identify differentially expressed microRNAs in ALK+ and ALK- ALCL. ALK- ALCL showed significantly higher expression of miR-155 (0.888 ± 0.228) compared with ALK+ ALCL (0.0565 ± 0.009) on microarray and by quantitative real-time polymerase chain reaction in ALK- ALCL compared with ALK+ ALCL (P < .05) with a strong correlation between the 2 platforms (R = 0.9, P < .0003). A novel in situ hybridization method allows direct visualization of expression patterns and relative quantitation of miR-155 (mean score, 2.3 versus 1.3; P = .01) for the first time in tissue sections of ALCL. Among computationally predicted targets of miR-155, we identified ZNF652 (r = -0.57, P = .05), BACH1 (r = 0.88, P = .02), RBAK (r = 0.81, P = .05), TRIM32 (r = 0.92, P = .01), E2F2 (r = 0.81, P = .05), and TP53INP1 (r = -0.31, P = .03) as genes whose expression by quantitative real-time polymerase chain reaction correlated significantly with the level of miR-155 in ALCL tumor tissue. PMID:25128227

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

    ClinicalTrials.gov

    2016-09-01

    Anaplastic Large Cell Lymphoma, ALK-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

  15. Anaplastic large cell lymphoma in paediatric and young adult patients.

    PubMed

    Turner, Suzanne D; Lamant, Laurence; Kenner, Lukas; Brugières, Laurence

    2016-05-01

    Anaplastic large cell lymphoma (ALCL) is a heterogeneous disease of debateable origin that, in children, is largely anaplastic lymphoma kinase (ALK) positive with aberrant ALK activity induced following the formation of chromosomal translocations. Whilst the survival rates for this disease are relatively high, a significant proportion (20-40%) of patients suffer disease relapse, in some cases on multiple occasions and therefore suffer the toxic side-effects of combination chemotherapy. Traditionally, patients are treated with a combination of agents although recent data from relapse patients have suggested that low risk patients might benefit from single agent vinblastine and, going forward, the addition of ALK inhibitors to the therapeutic regimen may have beneficial consequences. There are also a plethora of other drugs that might be advantageous to patients with ALCL and many of these have been identified through laboratory research although the decision as to which drugs to implement in trials will not be trivial. PMID:26913827

  16. 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

  17. 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

  18. [Breast implant-associated anaplastic large-cell lymphoma].

    PubMed

    Jarjis, Reem Dina; Matzen, Steen Henrik

    2015-11-23

    Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare entity. Due to the lack of awareness of BIA-ALCL, patients with prior history of breast implants who present with non-specific implant-related complications might experience a delay in diagnosis and appropriate treatment of this distinct condition. There are still no evidence-based guidelines on how this condition should be diagnosed, treated or followed because of the rarity of available data. We review current literature in order to raise awareness and discuss management options of this unique clinical entity. PMID:26617170

  19. Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation

    PubMed Central

    Merkel, Olaf; Hamacher, Frank; Griessl, Robert; Grabner, Lisa; Schiefer, Ana-Iris; Prutsch, Nicole; Baer, Constance; Egger, Gerda; Schlederer, Michaela; Krenn, Peter William; Hartmann, Tanja Nicole; Simonitsch-Klupp, Ingrid; Plass, Christoph; Staber, Philipp Bernhard; Moriggl, Richard; Turner, Suzanne D; Greil, Richard; Kenner, Lukas

    2015-01-01

    Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK+). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK−), which is characterized by a worse prognosis. We found that ALCL ALK−, in contrast to ALCL ALK+, lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK+ cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK−, we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK− and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID:25820993

  20. Sarcomatoid variant of ALK- anaplastic large cell lymphoma involving multiple lymph nodes and both lungs with production of proinflammatory cytokines: report of a case and review of literature

    PubMed Central

    Yu, Lu; Yan, Lin Li; Yang, Shou Jing

    2014-01-01

    Sarcomatoid variant of anaplastic large cell lymphoma (ALCL) is one of the rarest histologic variants of ALCL that consists of large, bizarre, often spindle-shaped, neoplastic cells resembling a soft tissue sarcoma. We report here such a case of ALCL with both pulmonary and multiple nodal involvement in a 47-year-old woman who initially presented with fever, cough, sputum, itching skin, and weight loss. The initial transbronchial lung biopsy showed discohesive pleomorphic malignant cells in a strong inflammatory milieu reminiscent of inflammatory malignant fibrous histiocytoma (MFH). Subsequent cervical lymph node biopsy revealed a spindle cell sarcoma predominantly composed of plump spindle and oval neoplastic cells in interweaving fascicles, with sparse inflammatory infiltrates, resembling pleomorphic-storiform type of MFH. However, these tumor cells in the lung and node lesions revealed essentially similar immunohistochemical features that were positive for CD30, EMA, TIA-1, granzyme B, and fascin, but negative for anaplastic lymphoma kinase (ALK), and T- or B-lineage-specific marker. The spindled cells stains diffuse strong positive for smooth muscle actin (SMA), along with vimentin. Further studies showed that the tumor produced large quantities of the proinflammatory cytokines interleukin-2 (IL-2), IL-6, and IL-8, which we believe may contribute to the pathogenesis of sarcomatoid transformation of this tumor, and was associated with the patient’s inflammatory symptoms. To the best of our knowledge, this is the first reported case of sarcomatoid variant of ALK-negative ALCL with null cell phenotype and in situ production of proinflammatory cytokines presenting as multiple nodes and pulmonary involvement. PMID:25197351

  1. Anaplastic Large Cell Lymphoma Involving Anterior Segment of the Eye

    PubMed Central

    Park, Choul Yong; Hwang, Sang Won; Kim, Do Yeun; Huh, Hee Jin

    2014-01-01

    A 36-year-old woman was diagnosed with anaplastic large cell lymphoma (ALCL) by excisional biopsy of a left frontal skin lesion. During the first cycle of chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), the patient complained of right ocular pain and inflammation. Cytologic examination using aqueous humor revealed atypical lymphocytes, suggesting intraocular ALCL involvement. Acute angle closure developed in the anterior chamber due to rapid progression of ALCL, causing pupillary block. Laser and surgical interventions were attempted but failed to relieve the pupillary block. Finally, radiation therapy resolved the pupillary block to restore the anterior chamber and normalize intraocular pressure. This is the first case in the English literature of ALCL involving the iris to cause acute secondary angle closure. PMID:24505208

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

    PubMed

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

    2016-07-01

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

  3. Rapidly Progressive Acute Pustular Secondary Cutaneous Anaplastic Large Cell Lymphoma.

    PubMed

    Mordorski, Breanne; Friedman, Adam; Han, George

    2016-09-01

    Cutaneous anaplastic large cell lymphoma (ALCL) is an uncommon diagnosis that may either present as a primary cutaneous process or develop secondary to systemic disease. It is imperative to distinguish between these two entities due to differences in treatment recommendations and prognosis. Here, their salient features will be reviewed. It is also important that clinicians recognize atypical clinical morphologies of cutaneous ALCL, including pustular lesions, which may masquerade as infectious or other inflammatory conditions, thereby delaying the onset of treatment. In this report, we present a case of secondary cutaneous ALCL associated with an atypical pustular morphology and an aggressive, fatal course.

    J Drugs Dermatol. 2016;15(9):1132-1135. PMID:27602978

  4. 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

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

    PubMed Central

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

    2015-01-01

    Introduction: Anaplastic large cell lymphoma is a subset of non-Hodgkin lymphoma and an unusual disease in children. Case Presentation: Herein we have reported a 7- year- old girl with a large necrotic skin ulcer on the chest caused by systemic form of anaplastic large-cell lymphoma and simultaneous active toxoplasmosis diagnosed by PCR on lymph node specimen. There were few reports showing a role for toxoplasma infection to cause some malignancies such as lymphoma in adults. Conclusions: Based to our knowledge, this has been the first report of simultaneous systemic anaplastic large cell lymphoma and active toxoplasmosis, documented by positive PCR on tissue biopsy in a child. This case report has suggested more attention to the accompanying Toxoplasma gondii infection as a probable cause of some types of lymphomas. PMID:26478795

  6. Primary anaplastic large cell lymphoma of trachea with subcutaneous emphysema and progressive dyspnea.

    PubMed

    Khodadad, K; Karimi, S; Arab, M; Esfahani-Monfared, Z

    2011-01-01

    Primary anaplastic large cell lymphoma of the trachea is a rare tumor. Common complaints are dyspnea and cough that could mimic a partially refractory asthma in some cases. We report a 16-year-old female with an anaplastic large cell lymphoma (null cell type) in which tracheal involvement was presented with life-threatening airway obstruction and subcutaneous emphysema. After debulking the tumor by endobronchial curettage, the patient was treated with chemotherapy followed by local radiotherapy. She had no evidence of local or distant recurrence after 25 months. Primary anaplastic large cell lymphoma of the trachea is a rare life-threatening disease. Nevertheless, this condition has a good prognosis if diagnosed immediately and treated with chemotherapy and radiotherapy. PMID:22198193

  7. A Case of Lymphomatoid Papulosis Occurred Simultaneously with Ki-1-Positive Anaplastic Large Cell Lymphoma

    PubMed Central

    Lee, Nam-Su; Cha, Sang-Woo; Hong, Su-Jin; Shin, Won-Yong; Lee, Gyu-Taeg; Jeon, Jin-Woo; Won, Jong-Ho; Baick, Seung-Ho; Hong, Dae-Sik; Park, Hee-Sook

    1997-01-01

    Lymphomatoid papulosis (LyP) is a chronic self-healing skin eruption that is clinically benign but histologically mimics a malignant lymphoma. However, lymphomatoid papulosis with anaplastic large cell lymphoma responds poorly to medical treatments, including chemotherapies. We experienced a 60-year-old male patient with lymphomatoid papulosis occurred simultaneously with relapsed Ki-1-positive anaplastic large cell lymphoma who was treated with salvage chemotherapy but, unfortunately, failed to be rescued. We report it with a review of the literature. PMID:9159045

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

    PubMed Central

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

    2016-01-01

    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. PMID:27158575

  9. 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

  10. Pediatric anaplastic large cell lymphoma misdiagnosed as multiple organ abscesses: a case report and literature review.

    PubMed

    Yang, Wenmin; Zuo, Yunlong; Yang, Yiyu; Tao, Jianping; Hong, Jie; Wu, Zhiyuan; Chen, Feiyan; Dang, Run; Liang, Yufeng; Li, Yang; Liu, Dabo

    2015-01-01

    We report the case of a 6-year-old male with fever, left maxillofacial swelling, cervical and mediastinal masses, and lymphadenopathy who developed respiratory failure and shock caused by tracheal compression and superior vena cava reflux disorder. The initial diagnosis was maxillary sinus, cervical, and mediastinal abscesses. Initial treatments included maxillary sinus abscess resection, neck abscess incision drainage, and antibiotics. Anaplastic large cell lymphoma (ALCL) was diagnosed ultimately according to pathological and immunohistochemical examination of cervical lesion biopsy tissue. We analyze the reasons for misdiagnosis by comparing clinical and pathological features of ALCL to other systemic illnesses that cause lymphadenopathy. PMID:26770602

  11. Novel Technique for Sampling of Breast Implant–associated Seroma in Anaplastic Large Cell Lymphoma

    PubMed Central

    T’Kindt, Johan; Mertens, Marianne; Colpaert, Steven D. M.

    2016-01-01

    Summary: We describe a novel technique for the sampling of breast implant–associated seroma. Using a blunt-tip lipofilling cannula, we have the freedom of movement to sample all fluid collections and prevent the misfortunes of damaging the implant. Also, we have demonstrated the inability of the Coleman style I lipofilling cannula to perforate a silicone breast implant. This practical and reliable technique will prove to be useful in managing the breast implant–associated seroma, especially with the rising incidence of the anaplastic large cell lymphoma, where the sampling of seroma is mandatory. PMID:27200250

  12. Pediatric anaplastic large cell lymphoma misdiagnosed as multiple organ abscesses: a case report and literature review

    PubMed Central

    Yang, Wenmin; Zuo, Yunlong; Yang, Yiyu; Tao, Jianping; Hong, Jie; Wu, Zhiyuan; Chen, Feiyan; Dang, Run; Liang, Yufeng; Li, Yang; Liu, Dabo

    2015-01-01

    We report the case of a 6-year-old male with fever, left maxillofacial swelling, cervical and mediastinal masses, and lymphadenopathy who developed respiratory failure and shock caused by tracheal compression and superior vena cava reflux disorder. The initial diagnosis was maxillary sinus, cervical, and mediastinal abscesses. Initial treatments included maxillary sinus abscess resection, neck abscess incision drainage, and antibiotics. Anaplastic large cell lymphoma (ALCL) was diagnosed ultimately according to pathological and immunohistochemical examination of cervical lesion biopsy tissue. We analyze the reasons for misdiagnosis by comparing clinical and pathological features of ALCL to other systemic illnesses that cause lymphadenopathy. PMID:26770602

  13. 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

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

    PubMed Central

    Gao, Kehai; Li, Hongtao; Huang, Caihong; Li, Huazhuang; Fang, Jun; Tian, Chen

    2016-01-01

    Introduction Anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma that has strong expression of CD30. ALCL can sometimes involve the bone marrow, and in advanced stages, it can produce destructive extranodal lesions. But anaplastic large cell lymphoma kinase (ALK)+ ALCL with soft tissue involvement is very rare. Case report A 35-year-old woman presented with waist pain for over 1 month. The biopsy of soft tissue lesions showed that these cells were positive for ALK-1, CD30, TIA-1, GranzymeB, CD4, CD8, and Ki67 (90%+) and negative for CD3, CD5, CD20, CD10, cytokeratin (CK), TdT, HMB-45, epithelial membrane antigen (EMA), and pan-CK, which identified ALCL. After six cycles of Hyper-CVAD/MA regimen, she achieved partial remission. Three months later, she died due to disease progression. Conclusion This case illustrates the unusual presentation of ALCL in soft tissue with a bad response to chemotherapy. Because of the tendency for rapid progression, ALCL in young adults with extra-nodal lesions are often treated with high-grade chemotherapy, such as Hyper-CVAD/MA. PMID:27445489

  15. 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

  16. Chemotherapy-resistant breast implant-associated anaplastic large cell lymphoma

    PubMed Central

    Parthasarathy, Muralidharan; Orrell, Julian; Mortimer, Caroline; Ball, Liz

    2013-01-01

    A 43-year-old woman presented with a few weeks’ history of discomfort and swelling in her left breast. She had undergone bilateral breast augmentation 8 years previously. There were no risk factors for breast cancer. Clinical examination, mammography and breast ultrasound revealed a large left breast mass adjacent to the breast implant with enlarged axillary lymph nodes. Owing to diagnostic uncertainty, core biopsies were sent to a specialist unit which confirmed breast implant-associated anaplastic large cell lymphoma with involved lymph nodes. Staging investigations confirmed no distant disease. The lymphoma multidisciplinary team recommended cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy, followed by implant removal and local radiotherapy. However, the patient's disease progressed on first-line, and then second-line chemotherapy. She therefore had a mastectomy and axillary node clearance followed by radiotherapy, with a planned delayed left breast reconstruction and removal of the right breast implant. PMID:24285813

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    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. PMID:24431950

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

    PubMed

    Mendiratta, Vibhu; Gandhi, Nikita; Rana, Shiwangi; Shukla, Shailaja

    2016-01-01

    Non-Hodgkin lymphoma is a common childhood T-cell and B-cell neoplasm that originates primarily from lymphoid tissue. Cutaneous involvement can be in the form of a primary extranodal lymphoma, or secondary to metastasis from a non-cutaneous location. The latter is uncommon, and isolated cutaneous involvement is rarely reported. We report a case of isolated secondary cutaneous involvement from nodal anaplastic large cell lymphoma (CD30 + and ALK +) in a 7-year-old boy who was on chemotherapy. This case is reported for its unusual clinical presentation as an acute febrile, generalized papulonodular eruption that mimicked deep fungal infection, with the absence of other foci of systemic metastasis. PMID:26728811

  20. 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

  1. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress

    PubMed Central

    Malcolm, Tim I. M.; Villarese, Patrick; Fairbairn, Camilla J.; Lamant, Laurence; Trinquand, Amélie; Hook, C. Elizabeth; Burke, G. A. Amos; Brugières, Laurence; Hughes, Katherine; Payet, Dominique; Merkel, Olaf; Schiefer, Ana-Iris; Ashankyty, Ibraheem; Mian, Shahid; Wasik, Mariusz; Turner, Martin; Kenner, Lukas; Asnafi, Vahid; Macintyre, Elizabeth; Turner, Suzanne D.

    2016-01-01

    Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) β-rearrangement, which is bypassed in CD4/NPM–ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRα but no comparable clonal TCRβ rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy. PMID:26753883

  2. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress.

    PubMed

    Malcolm, Tim I M; Villarese, Patrick; Fairbairn, Camilla J; Lamant, Laurence; Trinquand, Amélie; Hook, C Elizabeth; Burke, G A Amos; Brugières, Laurence; Hughes, Katherine; Payet, Dominique; Merkel, Olaf; Schiefer, Ana-Iris; Ashankyty, Ibraheem; Mian, Shahid; Wasik, Mariusz; Turner, Martin; Kenner, Lukas; Asnafi, Vahid; Macintyre, Elizabeth; Turner, Suzanne D

    2016-01-01

    Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) β-rearrangement, which is bypassed in CD4/NPM-ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRα but no comparable clonal TCRβ rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy. PMID:26753883

  3. 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.

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

    PubMed

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

    2016-06-28

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

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

    PubMed Central

    2014-01-01

    Background Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. Case presentation We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcutaneous metastases in the scalp area after a ventriculo-peritoneal shunting procedure. The disease rapidly progressed and the child died despite chemotherapy and primary tumour surgical debulking. We molecularly classified the tumour as a group 3 MBL; in addition, we derived stem-like cells (SLC) from a metastatic lesion. Primary tumour, metastases and SLC were further analysed, particularly focusing on features linked to the cutaneous dissemination. Indeed, molecules involved in angiogenesis, cell invasion and epidermal growth factor signalling resulted highly expressed. Conclusions The present report describes a very rare case of subcutaneous metastatic MBL. The tumour, metastases and SLC have been clinically, pathologically and molecularly characterized. Our case is an example of multidisciplinary approach aiming to characterize MBL aggressive behaviour. PMID:24739212

  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. PMID:27018666

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

    PubMed Central

    Baka, Margarita; Pourtsidis, Apostolos; Tsolia, Maria; Bouhoutsou, Despina; Varvoutsi, Maria; Strantzia, Katerina; Kosmidis, Helen

    2013-01-01

    A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL), whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR) in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months), pyrazinamide (the first 2 months), and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time. PMID:23841007

  8. Successful treatment in a child with anaplastic large cell lymphoma and coexistence of pulmonary tuberculosis.

    PubMed

    Baka, Margarita; Doganis, Dimitrios; Pourtsidis, Apostolos; Tsolia, Maria; Bouhoutsou, Despina; Varvoutsi, Maria; Strantzia, Katerina; Kosmidis, Helen

    2013-01-01

    A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL), whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR) in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months), pyrazinamide (the first 2 months), and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time. PMID:23841007

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

    PubMed Central

    Peluso, Michael J.; Chia, David; Sheen, Whitney; Hutchinson, Christoph; Barakat, Lydia

    2012-01-01

    Hemophagocytic syndrome (HPS) arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL). This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified. PMID:22761627

  10. Patient-reported outcomes of brentuximab vedotin in Hodgkin lymphoma and anaplastic large-cell lymphoma

    PubMed Central

    Chen, Robert; Allibone, Suzanne; Bartlett, Nancy L; Brice, Pauline; Chen, Andy; Pose, Katrina; Rich, Lynn; Bonthapally, Vijay; Garfin, Phillip M; Fanale, Michelle

    2016-01-01

    Background Patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or R/R systemic anaplastic large-cell lymphoma (sALCL) treated with brentuximab vedotin (BV) experienced high remission rates in two Phase II trials. With increased response rates and survival times, patient-reported outcomes (PROs) and health-related quality of life (HRQoL) are becoming increasingly important and can help inform treatment decisions to enhance care of cancer patients. Objective The objective was to qualitatively assess HRQoL in long-term survivors treated with BV. Methods An eight-question survey assessing PRO-related aspects was developed and fielded to a subset of patients with HL or sALCL who remained in long-term follow-up after completing BV treatment in the two pivotal studies. Results The survey was completed by 25 of 38 patients (12 with HL, 13 with sALCL). The majority of patients reported that their energy level, outlook on life, difficulties with daily activities, ability to participate in physical activities, and overall HRQoL improved compared to those before BV treatment. Limitations Small sample size and lack of a baseline questionnaire or validated assessment instrument limit broad applicability of these findings to large populations of patients with HL or sALCL. Conclusion This is the first report of BV PRO data in R/R HL and sALCL. Given the patients’ poor prognostic outcomes before stem cell transplant, these encouraging results warrant formal evaluation of PRO end points in BV trials. PMID:27103829

  11. 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.

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

    PubMed Central

    Predmore, Zachary S.; Mattke, Soeren; van Busum, Kristin; Gidengil, Courtney A.

    2015-01-01

    Background: Despite increased cases published on breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), important clinical issues remain unanswered. We conducted a second structured expert consultation process to rate statements related to the diagnosis, management, and surveillance of this disease, based on their interpretation of published evidence. Methods: A multidisciplinary panel of 12 experts was selected based on nominations from national specialty societies, academic department heads, and recognized researchers in the United States. Results: Panelists agreed that (1) this disease should be called “BIA-ALCL”; (2) late seromas occurring >1 year after breast implantation should be evaluated via ultrasound, and if a seroma is present, the fluid should be aspirated and sent for culture, cytology, flow cytometry, and cell block to an experienced hematopathologist; (3) surgical removal of the affected implant and capsule (as completely as possible) should occur, which is sufficient to eradicate capsule-confined BIA-ALCL; (4) surveillance should consist of clinical follow-up at least every 6 months for at least 5 years and breast ultrasound yearly for at least 2 years; and (5) BIA-ALCL is generally a biologically indolent disease with a good prognosis, unless it extends beyond the capsule and/or presents as a mass. They firmly disagreed with statements that chemotherapy and radiation therapy should be given to all patients with BIA-ALCL. Conclusions: Our assessment yielded consistent results on a number of key, incompletely addressed issues regarding BIA-ALCL, but additional research is needed to support these statement ratings and enhance our understanding of the biology, treatment, and outcomes associated with this disease. PMID:25674377

  13. 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. PMID:11100061

  14. Successful Chemo-Radiotherapy for Primary Anaplastic Large Cell Lymphoma of the Lung: A Case Report and Literature Review

    PubMed Central

    Zhao, Qian; Liu, Yongmei; Chen, Huijiao; Zhang, Yan; Du, Zedong; Wang, Jin; Wang, Yongsheng

    2016-01-01

    Patient: Male, 39 Final Diagnosis: Primary anaplastic large cell lymphoma of the lung Symptoms: Hemoptysis • palpitation • shortness of breath Medication: Cyclophosphamide • Doxorubicin • Vincristine • Prednisone Clinical Procedure: Chemoradiotherapy Specialty: Oncology Objective: Rare disease Background: Primary anaplastic large cell lymphoma (ALCL) of the lung is an extremely rare disease. This disease is a great challenge for pneumologists due to its nonspecific clinical presentations and radiological findings. Appropriate invasive biopsy and immunohistochemistry are important for diagnosis. There is currently no standard treatment. Case Report: We report a very rare case of primary pulmonary ALCL in a 39-year-old man. The clinical features, imaging, pathological findings, treatment outcomes, and prognosis, are described. Successful treatment outcomes were achieved after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by involved field radiotherapy of 54Gy/27f. The patient was disease-free after follow-up for 65 months. Conclusions: Our study found that chemotherapy (such as CHOP) is recognized as the first-line regimen for primary ALCL of the lung. For patients with dyspnea caused by a mass blocking the main bronchus, chemoradiotherapy may be a reasonable therapeutic option. The prognosis is better for patients with positive ALK staining. CD56(+), age older than 60 years, Ann Arbor stage III or IV, survivin expression, PS>2, and high serum LDH level and IPI scores are the poor prognostic factors of ALCL. PMID:26852792

  15. 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

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

    PubMed

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

    2015-06-01

    Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies. PMID:25533804

  17. Biomarkers Provide Clues to Early Events in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

    PubMed

    Kadin, Marshall E; Deva, Anand; Xu, Haiying; Morgan, John; Khare, Pranay; MacLeod, Roderick A F; Van Natta, Bruce W; Adams, William P; Brody, Garry S; Epstein, Alan L

    2016-07-01

    Almost 200 women worldwide have been diagnosed with breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The unique location and specific lymphoma type strongly suggest an etio-pathologic link between breast implants and BIA-ALCL. It is postulated that chronic inflammation via bacterial infection may be an etiological factor. BIA-ALCL resembles primary cutaneous ALCL (pcALCL) in morphology, activated T-cell phenotype, and indolent clinical course. Gene expression array analysis, flow cytometry, and immunohistochemistry were used to study pcALCL and BIA-ALCL cell lines. Clinical samples were also studied to characterize transcription factor and cytokine profiles of tumor cells and surrounding lymphocytes. BIA-ALCL and pcALCL were found to have common expression of transcription factors SOCS3, JunB, SATB1, and a cytokine profile suggestive of a Th1 phenotype. Similar patterns were observed in a CD30+ cutaneous lymphoproliferative disorder (LPD). The patterns of cytokine and transcription factor expression suggest that BIA-ALCL is likely to arise from chronic bacterial antigen stimulation of T-cells. Further analysis of cytokine and transcription factor profiles may allow early detection and treatment of BIA-ALCL leading to better prognosis and survival. LEVEL OF EVIDENCE 5: Risk. PMID:26979456

  18. Anaplastic astrocytoma.

    PubMed

    Grimm, Sean A; Chamberlain, Marc C

    2016-07-01

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

  19. 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

  20. 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

  1. High levels of p53 protein expression do not correlate with p53 gene mutations in anaplastic large cell lymphoma.

    PubMed Central

    Cesarman, E.; Inghirami, G.; Chadburn, A.; Knowles, D. M.

    1993-01-01

    Strong immunohistochemical reactivity for p53 tumor suppressor gene product has been reported in a variety of different human malignancies including CD30- (Ki-1) positive anaplastic large cell lymphoma (ALCL). Although high levels of p53 protein have been interpreted as abnormal, rapidly proliferating benign and neoplastic lymphoid cells may have increased p53 expression in the absence of structural alterations. On the other hand, mutations in the p53 gene can lead to a lack of p53 protein production. Structural alterations of the p53 gene have not been documented in cases of ALCL and the mechanism for an abnormal pattern of p53 expression in these lymphomas has not been elucidated. Therefore, to determine whether an altered pattern of p53 expression correlates with mutations in the p53 locus in ALCL, we analyzed the expression of p53 protein immunohistochemically, compared it with the proliferation index using monoclonal antibody Ki-67, and assessed the presence of mutations in exons 5 though 9 of the p53 gene using a single-strand conformation polymorphism assay in a panel of 17 ALCLs. Furthermore, we studied the presence of allelic deletions of chromosome 17p by restriction fragment length polymorphism analysis. We found significant levels of p53 protein expression in 12 of the 15 cases studied, but identified mutations in only one of 17 cases. An allelic deletion in chromosome 17p was identified only in the one case containing a mutated p53 gene. Whereas the case containing structural alterations in the p53 gene did have strong p53 immunoreactivity, 11 cases that lacked p53 mutations in the regions examined also had significant levels of p53. Thus, our studies indicate that strong immunohistochemical reactivity for p53 is not a reliable indicator of the presence of structural alterations of p53 gene exons 5 through 9 in ALCL. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8103295

  2. Anaplastic Transformation of Papillary Thyroid Cancer in the Retroperitoneum

    PubMed Central

    Solomon, James P.; Wen, Fang; Jih, Lily J.

    2015-01-01

    Anaplastic thyroid carcinoma is an aggressive variant of thyroid cancer that in most cases arises from anaplastic transformation of terminally differentiated thyroid carcinomas. This process usually occurs in the thyroid or cervical lymph nodes. Anaplastic transformation in distant metastatic sites is exceedingly rare, only previously documented in a few case reports. We report a rare case of anaplastic transformation of papillary thyroid carcinoma within a large retroperitoneal metastasis in a 64-year-old male 30 years after the initial diagnosis. PMID:26351607

  3. Anaplastic Large Cell Lymphoma

    MedlinePlus

    ... called primary cutaneous ALCL and follows a less aggressive course. In almost all cases of primary cutaneous ... kinase (ALK). While both lymphomas are treated as aggressive lymphomas, the prognosis for ALCL depends on whether ...

  4. KSHV/HHV-8 associated lymph node based lymphomas in HIV seronegative subjects. Report of two cases with anaplastic large cell morphology and plasmablastic immunophenotype

    PubMed Central

    Carbone, A; Gloghini, A; Vaccher, E; Marchetti, G; Gaidano, G; Tirelli, U

    2005-01-01

    Background: Kaposi sarcoma associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) associated lymphomas, which often develop in human immunodeficiency virus (HIV) infected patients with advanced AIDS, present predominantly as primary effusion lymphoma (PEL) or, less frequently, as “solid” extracavitary based lymphomas, associated with serous effusions. These last lymphomas, also called “solid PEL”, have been reported before the development of an effusion lymphoma and after resolution of PEL. Interestingly, KSHV/HHV-8 associated lymphomas that present as solid or extracavitary based lesions in HIV seropositive patients without serous effusions have been reported recently. Methods/Results: This paper provides evidence for the existence of a previously undescribed KSHV/HHV-8 associated lymphoma in HIV seronegative patients without serous effusions. These lymphomas exhibit a predilection for the lymph nodes and display anaplastic large cell morphology. These tumours were completely devoid of common cell type specific antigens, including epithelial and melanocytic cell markers. B and T cell associated antigens and other commonly used lymphoid markers were absent or weakly demonstrable in a fraction of the tumour cells. Conversely, immunohistochemical studies showed strong immunostaining with plasma cell reactive antibodies. Conclusions: Analysis of viral infection and immunohistological studies are of primary importance to define this lymph node based KSHV/HHV-8 associated lymphoma with anaplastic large cell morphology and plasmablastic immunophenotype occurring in HIV seronegative patients without serous effusions. PMID:16189148

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

    PubMed

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

    2007-06-01

    The fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), results from the chromosome translocation t(2;5)(p23;q25) and is present in 50-70 percent of anaplastic large-cell lymphomas (ALCLs). NPM-ALK is a constitutively activated kinase that transforms cells through stimulating several mitogenic signaling pathways. To examine if the NPM-ALK is a potential therapeutic target in ALCL, we used siRNA to specifically downregulate the expression of the NPM-ALK in ALCL cell lines. In this report, we demonstrated viability loss in t(2;5)-positive ALCL cell lines, SUDHL-1 and Karpas 299 cells, but not in lymphoma cell lines without the chromosome translocation, Jurkat and Granta 519 cells. Further study demonstrated that the downregulation of NPM-ALK resulted in decreased cell proliferation and increased cell apoptosis. When used in combination with chemotherapeutic agents, such as doxorubicin, the inhibition of the NPM-ALK augments the chemosensitivity of the tumor cells. These results revealed the importance of continuous expression of NPM-ALK in maintaining the growth of ALCL cells. Our data also suggested that the repression of the fusion gene might be a potential novel therapeutic strategy for NPM-ALK positive ALCLs. PMID:17612934

  6. Locally Advanced Breast Implant-Associated Anaplastic Large-Cell Lymphoma: A Case Report of Successful Treatment with Radiation and Chemotherapy

    PubMed Central

    Estes, Christopher F.; Zhang, Da; Reyes, Ruben; Korentager, Richard; McGinness, Marilee; Lominska, Christopher

    2015-01-01

    The development of breast implant-associated anaplastic large-cell lymphoma (ALCL) is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can be more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surgery, chemotherapy, and external beam radiotherapy. This is a case report of breast implant ALCL with pathologically proven lymph node involvement, the fifth such patient reported. Our patient experienced a favorable outcome with radiation therapy and chemotherapy. PMID:25741471

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

    PubMed

    Estes, Christopher F; Zhang, Da; Reyes, Ruben; Korentager, Richard; McGinness, Marilee; Lominska, Christopher

    2015-01-01

    The development of breast implant-associated anaplastic large-cell lymphoma (ALCL) is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can be more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surgery, chemotherapy, and external beam radiotherapy. This is a case report of breast implant ALCL with pathologically proven lymph node involvement, the fifth such patient reported. Our patient experienced a favorable outcome with radiation therapy and chemotherapy. PMID:25741471

  8. The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53.

    PubMed

    Drakos, E; Atsaves, V; Schlette, E; Li, J; Papanastasi, I; Rassidakis, G Z; Medeiros, L J

    2009-12-01

    p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK+ ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-alpha, or when pifithrin-mu was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK+ ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip(S/L), and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK+ ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK+ ALCL patients. PMID:19741726

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

    PubMed

    Suzuki, Osamu; Abe, Masafumi

    2014-05-01

    Galectin-1 is known to be one of the extracellular matrix proteins. To elucidate the biological roles of galectin-1 in cell adhesion and invasion of human anaplastic large cell lymphoma, we performed cell adhesion and invasion assays using the anaplastic large cell lymphoma cell line H-ALCL, which was previously established in our laboratory. From the cell surface lectin array, treatment with neuraminidase from Arthrobacter ureafaciens which cleaves all linkage types of cell surface sialic acid enhanced Arachis hypogaea (PNA), Helix pomatia (HPA) and Phaseolus vulgaris-L (L-PHA) lectin binding reactivity to cell surface of lymphoma cells suggesting that neuraminidase removes cell surface sialic acid. In cell adhesion and invasion assays treatment with neuraminidase markedly enhanced cell adhesion to galectin-1 and decreased cell invasive capacity through galectin-1. α2,6-linked sialic acid may be involved in masking the effect of the interaction between galectin-1 and cell surface glycans. H-ALCL cells expressed the β-galactoside-α2,6-sialyltransferase ST6Gal1. On resialylation assay by recombinant ST6Gal1 with CMP-Neu5Ac, α2,6-resialylation of L-PHA reactive oligosaccharide by ST6Gal1 resulted in inhibition of H-ALCL cell adhesion to galectin-1 compared to the desialylated H-ALCL cells. On knockdown experiments, knockdown of ST6Gal1 dramatically enhanced cell adhesion to galectin-1. N-glycosylation inhibitor swainsonine treatment resulted in enhancement of cell adhesion to galectin-1. In glycomic analysis using the lectin blocking assay treatment with PNA, Artocarpus integrifolia (Jacalin), Glycine max (SBA), Helix pomatia (HPA), Vicia villosa (VVA), Ulex europaeus (UEA-1), Triticum vulgaris (WGA), Canavalia ensiformis (ConA), Phaseolus vulgaris-L (L-PHA), Phaseolus vulgaris-E4 (E-PHA), Datura stramonium (DSA) lectins resulted in modulation of lymphoma cell to galectin-1 suggesting that several types of glycans may regulate cell adhesion to galectin-1 by

  10. An unusual case of anaplastic lymphoma kinase-positive large B-cell lymphoma in an elderly patient: A case report and discussion

    PubMed Central

    XIONG, HANZHEN; LIU, SHAO-YAN; YANG, YUE-XIN; TAN, XUE-XIAN; LUO, QIU-PING; PENG, JUAN; XIONG, ZHONG-TANG; CHEN, HUI; CHEN, JUAN; LI, ZHI; JIANG, QING-PING

    2016-01-01

    We present an unusual case of anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma, with rapid clinical progression, which occurred in a 90-year-old male patient. The patient presented with numerous enlarged lymph nodes in the neck and mediastinum. Histopathological analysis of a single lymph node detected diffuse large immunoblastic- or plasmablastic-like tumor cells, which were strongly immunoreactive for ALK in a granular cytoplasmic distribution, but negative for the expression of CD20 and CD79a. In addition, polymerase chain reaction assays were unable to detect clonal rearrangements of the T cell receptor-γ and immunoglobulin heavy chain genes in the tumor lesion, and in situ hybridization tested negative for infection with Epstein-Barr virus. The patient underwent a single cycle of chemotherapy using the cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (E-CHOP) regimen; however, the patient developed pleural effusions with respiratory distress, associated with clinical deterioration. The patient succumbed to the disease within 4 months of initial presentation. To the best of our knowledge, this is the eldest patient with this type of lymphoma to be reported in the literature. PMID:27168806

  11. Hodgkin's disease and CD30-positive anaplastic large cell lymphomas--a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study.

    PubMed Central

    Leoncini, L.; Del Vecchio, M. T.; Kraft, R.; Megha, T.; Barbini, P.; Cevenini, G.; Poggi, S.; Pileri, S.; Tosi, P.; Cottier, H.

    1990-01-01

    The authors have examined cellular areas of lymphoma tissue in 28 cases of Hodgkin's disease (HD) or anaplastic large cell lymphoma (ALCL, 'Ki-1 cell lymphoma') to evaluate the boundaries between the two entities. Methods applied included conventional histology; test point analysis; semiautomated morphometry of nuclear profile features of Reed-Sternberg and other atypical large cells (RSALCs); and immunohistochemistry of these elements on all paraffin sections and, in 15 cases, on frozen sections. Mean nuclear profile morphotypes of RSALCs per case varied independently of immunophenotype and histologic diagnosis. Conversely, immunohistochemistry demonstrated significant, although not consistent, preferential positivities of these CD30+ elements for CD15 in HD, and for epithelial membrane antigen (EMA) and CD43 in ALCLs. In the latter, RSALCs also exhibited a tendency for CD45 and CD45RO positivity and for the expression of T-cell-associated antigens. However, there were considerable overlaps. This continuous spectrum of RSALC nuclear profile morphotypes and immunophenotypes, ranging from HD over questionable cases, intermediate between HD and ALCL, to ALCLs, was paralleled by differences in the reactive component of lymphomas. Lymphocytes and granulocytes were significantly deficient in ALCLs. Images Figure 1 PMID:2173409

  12. Identification of C/EBPβ Target Genes in ALK+ Anaplastic Large Cell Lymphoma (ALCL) by Gene Expression Profiling and Chromatin Immunoprecipitation

    PubMed Central

    Bonzheim, Irina; Irmler, Martin; Klier-Richter, Margit; Steinhilber, Julia; Anastasov, Nataša; Schäfer, Sabine; Adam, Patrick; Beckers, Johannes; Raffeld, Mark; Fend, Falko; Quintanilla-Martinez, Leticia

    2013-01-01

    C/EBPβ (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPβ responsible for ALK-mediated oncogenesis. C/EBPβ was knocked down in ALK+ ALCL cell lines with a C/EBPβ-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPβ. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPβ was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPβ-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPβ in ALK-mediated oncogenesis. PMID:23741337

  13. Anaplastic large cell lymphoma in childhood: analysis of 72 patients treated on The United Kingdom Children's Cancer Study Group chemotherapy regimens.

    PubMed

    Williams, Denise M; Hobson, Rachel; Imeson, John; Gerrard, Mary; McCarthy, Keith; Pinkerton, C Ross

    2002-06-01

    From June 1990 to June 1998, 72 patients with anaplastic large cell lymphoma (ALCL) were treated with short intensive multi-agent regimens [non-Hodgkin's lymphoma (NHL) 9000 and 9602]. Diagnosis was based on morphological and immunophenotypic criteria. Treatment for stage I disease consisted of eight courses (2 x vincristine, doxorubicin, prednisolone; 2 x methotrexate; 2 x cytarabine, thioguanine; and 2 x methotrexate etoposide). For stage II, III and non-central nervous system (CNS) stage IV, two COPADM (cyclophosphamide, doxorubicin, prednisolone, methotrexate, vincristine), two CYM (cytarabine methotrexate) and a COPADM was given. For CNS-positive disease, treatment was intensified and contained methotrexate 8 g/m(2) and cytarabine 3 g/m(2). Fifty-nine patients (82%) achieved a remission. Thirteen of these relapsed, with a median time to relapse from the start of treatment of 5 months (range 3-14). Relapse included a new site in 9/13 patients. The probabilities of overall and event free survival at 5 years were 65% (53-76%) and 59% (47-70%), respectively, with a median follow up of 4.3 years. Mediastinal and visceral involvement at presentation were found to be predictive of an increased risk of failure. PMID:12060115

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

    PubMed

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

    2013-01-01

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

  15. Unusual Presentation of Anaplastic Large Cell Lymphoma with Clinical Course Mimicking Fever of Unknown Origin and Sepsis: Autopsy Study of Five Cases

    PubMed Central

    Mosunjac, Marina B.; Sundstrom, J. Bruce; Mosunjac, Mario I.

    2008-01-01

    Aim To describe a subset of cases with the unusual clinical and histomorphological presentation of anaplastic large cell lymphoma (ALCL) mimicking fever of unknown origin (FUO) and sepsis. Methods A pathology database was searched using full term Systematized Nomenclature of Medicine codes for ALCL to identify 23ALCL cases from the period 1999-2006. Of those, five cases that did not have a correct premortem diagnosis were further analyzed to elucidate the reasons for delayed and incorrect pre-mortem diagnosis. The analyzed data included clinical presentation, duration of symptoms, duration of hospital stay, premortem presumed cause of death, white blood cell count, platelet count, anion gap and blood pH, liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase), lactate, coagulation tests (prothrombin time, partial thromboplastin time, fibrinogen, D-dimers), microbiology cultures, and radiology and surgical pathology reports. Autopsy reports were reviewed for description of major gross findings, initial clinical diagnosis, and cause of death. Results Five fatal and pre-mortem unrecognized ALCL cases were characterized by rapid decline, with histologic findings showing predominantly extranodal involvement, intravascular lymphomatosis, and hemophagocytosis. The cases were also characterized by unusual clinical manifestations including a FUO, sepsis, and disseminated intravascular coagulation-like picture, lactic acidosis, hepatosplenomegaly, and absence of significant peripheral adenopathy. Conclusions There is a distinct group of ALCLs with unique and specific clinical, gross autopsy, and histopathologic findings. Recognition of this clinical variant may facilitate early detection and potentially timely diagnosis and therapy. PMID:18925700

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

    PubMed Central

    Manshouri, Roxsan; Shi, Ping; Amin, Hesham M.

    2014-01-01

    NPM-ALK+ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK+ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK+ solid tumors. However, NPM-ALK+ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK+ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK+ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK+ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK+ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials. PMID:25026277

  17. Primary Cutaneous Anaplastic Large-Cell Lymphoma With 6p25.3 Rearrangement in a Cardiac Transplant Recipient: A Case Report and Review of the Literature.

    PubMed

    Olson, Luke C; Cheng, Esther; Mathew, Susan; Torres-Quinones, Marta; Magro, Cynthia

    2016-06-01

    Posttransplant lymphoproliferative disorders define an important form of lymphoproliferative disease causally linked with a state of iatrogenic immune dysregulation inherent to the posttransplant setting. Most posttransplant lymphoproliferative disorders are in the context of Epstein-Barr virus-associated B-cell lymphoproliferative disease, most notably diffuse large-cell B-cell lymphoma. A less common variant falls under the rubric of posttransplant T-cell lymphoproliferative disease, which is largely unrelated to Epstein-Barr virus infection. Anaplastic large-cell lymphoma (ALCL) is the most recognized form of posttransplant T-cell lymphoproliferative disease. Although the 6p25.3 translocation is seen in a variety of B-cell lymphoproliferative disorders, this particular translocation in the spectrum of T-cell lymphoproliferative disease is a fairly specific finding pointing toward a diagnosis of primary cutaneous ALCL and a rare subset of lymphomatoid papulosis. This translocation in the peripheral T-cell lymphoma setting serves as a favorable prognostic predictor. We report a case of an 81-year-old heart transplant recipient who developed an expansile neck mass 17 years after his heart transplant. A diagnosis of cutaneous ALCL was subsequently made with cytogenetic analysis yielding the 6p25.3 translocation. The characteristic biphasic morphology of a small-cell epidermotropic neoplastic cell populace in concert with a dermal based large-cell infiltrate characteristic for those cases of ALCL harboring this translocation was seen. After excision of the nodule, his azathioprine was withheld. He is currently alive and well without evidence of disease. PMID:26863058

  18. 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

  19. CEOP/IVE/GDP Compared With CEOP as the First-line Therapy for Newly Diagnosed Adult Patients With PTCL

    ClinicalTrials.gov

    2016-04-18

    Peripheral T-Cell Lymphoma; Angioimmunoblastic T Cell Lymphoma; ALK-negative Anaplastic Large Cell Lymphoma; Enteropathy Associated T Cell Lymphoma; Subcutaneous Panniculitis Like T Cell Lymphoma; Acute Adult T-Cell Leukemia/Lymphoma

  20. Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation.

    PubMed

    Kiss, Izabella; Unger, Christine; Huu, Chi Nguyen; Atanasov, Atanas Georgiev; Kramer, Nina; Chatruphonprasert, Waranya; Brenner, Stefan; McKinnon, Ruxandra; Peschel, Andrea; Vasas, Andrea; Lajter, Ildiko; Kain, Renate; Saiko, Philipp; Szekeres, Thomas; Kenner, Lukas; Hassler, Melanie R; Diaz, Rene; Frisch, Richard; Dirsch, Verena M; Jäger, Walter; de Martin, Rainer; Bochkov, Valery N; Passreiter, Claus M; Peter-Vörösmarty, Barbara; Mader, Robert M; Grusch, Michael; Dolznig, Helmut; Kopp, Brigitte; Zupko, Istvan; Hohmann, Judit; Krupitza, Georg

    2015-01-28

    An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this

  1. The nature of Hodgkin and Reed-Sternberg cells, their association with EBV, and their relationship to anaplastic large-cell lymphoma.

    PubMed

    Stein, H; Herbst, H; Anagnostopoulos, I; Niedobitek, G; Dallenbach, F; Kratzsch, H C

    1991-02-01

    This review focuses on the cellular origin of Hodgkin and Reed-Sternberg (HRS) cells, their association with the Epstein-Barr virus (EBV), and their relation to Ki-1+ anaplastic large-cell (ALC) lymphoma. The tingibility of HRS cells in paraffin sections for polyclonal immunoglobulin represents a staining artifact and thus can no longer serve as an argument for the histiocytic nature of HRS cells. Immunolabeling studies do not support the putative relationship of HRS cells to cell types such as macrophages or interdigitating reticulum cells, but instead suggest: a) that lymphocyte-predominant (LP) Hodgkin's disease (HD) represents a B-cell neoplasm which is distinct from non-LP HD, and b) that non-LP HD constitutes a syndrome rather than a disease entity, with the existence of T-cell types and B-cell types. HRS cells (and the tumor cells in ALC lymphomas) frequently display an immature genotype in association with late activation markers, leading to the assumption that the tumor cells in many cases of HD (and some cases of ALC lymphoma) may be derived from immature lymphoid cells that are infected by a virus that superimposes characteristics of mature activated lymphocytes on these cells. Southern blotting, in situ hybridization, and polymerase chain reaction (PCR) experiments revealed an association of EBV with HRS cells in a significant proportion of HD cases, suggesting that EBV may be responsible for the dissociation between genotype and phenotype in HRS cells, because EBV is a strong inducer of the activation antigens CD30 and CDw70.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1646624

  2. Chronic reparative changes in medium-sized vessels in a case of primary cutaneous anaplastic large-cell lymphoma with angioinvasive features and cytotoxic phenotype: new histopathological findings in line with indolent clinical behavior.

    PubMed

    Macarenco, Ricardo S; de Oliveira, Deilson Elgui

    2015-05-01

    Angioinvasion/angiodestruction has been reported in a small subset of primary cutaneous anaplastic large-cell lymphomas (PCALCL). Recently, PCALCL with angioinvasive features and cytotoxic phenotype has been characterized as a variant associated with good clinical outcomes despite worrisome histopathologic features. We report a case of PCALCL with angioinvasive features and cytotoxic phenotype associated with reparative changes on the wall of medium-sized vessels involved by the neoplasm, including intimal fibroblastic proliferation and luminal obliteration. This vascular pattern, although previously unreported in PCALCL, is in accordance with the indolent behavior observed in this entity and provides a further link with lymphomatoid papulosis type E. PMID:25365499

  3. Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.

    PubMed

    Michellys, Pierre-Yves; Chen, Bei; Jiang, Tao; Jin, Yunho; Lu, Wenshuo; Marsilje, Thomas H; Pei, Wei; Uno, Tetsuo; Zhu, Xuefeng; Wu, Baogen; Nguyen, Truc Ngoc; Bursulaya, Badry; Lee, Christian; Li, Nanxin; Kim, Sungjoon; Tuntland, Tove; Liu, Bo; Sun, Frank; Steffy, Auzon; Hood, Tami

    2016-02-01

    Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described. PMID:26750252

  4. Remission of ALK-negative primary pulmonary inflammatory myofibroblastic tumor on treatment with clarithromycin: A case report and review of the literature

    PubMed Central

    WATANABE, HIDEHIRO; URUMA, TOMONORI; TAZAKI, GEN; TAJIRI, TAKUMA; KIKUCHI, RYOTA; ITOH, MASAYUKI; AOSHIBA, KAZUTETSU; NAKAMURA, HIROYUKI

    2016-01-01

    Inflammatory myofibroblastic tumors (IMTs) belong to an intermediate group of soft-tissue tumors, they are relatively rare but exhibit a wide range of pathologies, from benign to malignant. At present, no standard treatment has been established, however, it is known to be important to determine the grade of malignancy of the tumor, prior to treatment. The present study reports a 73-year-old female patient with no clinical manifestations, who, when examined radiographically at a health check exhibited bilateral thoracic infiltrative shadows and nodular shadows by chest CT. A metastatic tumor or an organizing pneumonia were suspected. Blood examination showed no abnormal findings, and a pathological diagnosis of IMT was given from the histological findings of the tissue extracted by video-assisted thoracic surgery. Histological analysis established the lack of expression of anaplastic lymphoma kinase (ALK1) and immunoglobulin subtype G4 (IgG4). Alteration of the radiological shadows was observed over several weeks, and after concluding that chronic inflammation was worsening the patient's condition, clarithromycin was administered as a long-term macrolide therapy. The IMT decreased in size, and eight months later it had almost resolved. The patient was last reported to be maintaining a stable condition with no relapse. Some IMT cases have malignant pathology, and should be carefully followed-up. However, in the present case, where the IMT is both ALK1-negative and IgG4-negative, its biological immune responsiveness appears to differ from positive cases, and an inflammatory response was predominant. Clarithromycin, has immunomodulatory and anti-inflammatory effects and appeared to be effective in treating the IMT of the patient in the present study. PMID:26998073

  5. Follicular lymphoma transforming into anaplastic diffuse large B-cell lymphoma of oral cavity: A case report with review of literature

    PubMed Central

    Mittal, Megha; Puri, Abhiney; Nangia, Rajat; Sachdeva, Alisha

    2015-01-01

    Follicular lymphoma (FL) is a common form of non-Hodgkin's lymphoma (NHL) with the ability to transform into a more aggressive disease, frequently to B cell-lymphoblastic lymphoma. Diffuse large B-cell lymphoma (DLBCL) is a subtype of NHL, which is characterized by diffuse proliferation of large neoplastic B-lymphocytes. It accounts for 30% of all NHL and its occurrence in the mandible is very rare. It is often seen in young adults, but in the present case, a 50-year-old male patient presented with painless swelling in left lower jaw since 25 days following extraction of left lower molar teeth. There was a history of fever and submandibular lymph nodes were enlarged. On incisional biopsy, features of NHL-like lesion were observed and confirmed by immunohistochemistry using CD20, bcl-2, CD10, CD3, CD5, Ki67 markers to be FL (3A) lymphoma transforming into DLBCL. This is a very uncommon presentation. PMID:26980969

  6. Anaplastic myeloma in systemic lupus erythematosus.

    PubMed Central

    Butler, R C; Thomas, S M; Thompson, J M; Keat, A C

    1984-01-01

    We describe a patient with systemic lupus erythematosus who developed an unusual form of anaplastic myeloma. Possible relationships between the two disease, and the role played by immunosuppressive therapy, are discussed. Images PMID:6476924

  7. 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. PMID:25936680

  8. Anaplastic Thyroid Carcinoma, Version 2.2015

    PubMed Central

    Haddad, Robert I.; Lydiatt, William M.; Ball, Douglas W.; Busaidy, Naifa Lamki; Byrd, David; Callender, Glenda; Dickson, Paxton; Duh, Quan-Yang; Ehya, Hormoz; Haymart, Megan; Hoh, Carl; Hunt, Jason P.; Iagaru, Andrei; Kandeel, Fouad; Kopp, Peter; Lamonica, Dominick M.; McCaffrey, Judith C.; Moley, Jeffrey F.; Parks, Lee; Raeburn, Christopher D.; Ridge, John A.; Ringel, Matthew D.; Scheri, Randall P.; Shah, Jatin P.; Smallridge, Robert C.; Sturgeon, Cord; Wang, Thomas N.; Wirth, Lori J.; Hoffmann, Karin G.; Hughes, Miranda

    2016-01-01

    This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer. PMID:26358798

  9. 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

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

    ClinicalTrials.gov

    2015-10-02

    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

  11. Congenital Anaplastic Rhabdomyosarcoma Presenting As Abdominal Wall Mass

    PubMed Central

    Mondal, Krishnendu; Mandal, Rupali

    2016-01-01

    Rhabdomyosarcoma encompasses a group of malignant myogenic neoplasms expressing a multitude of clinical and pathological diversities. It is the commonest soft tissue sarcoma of childhood but neonates are rarely affected. Embryonal subtype is the most frequent. Head-neck and genitourinary tracts are predominant sites, while trunk is considered among the unusual sites of rhabdomyosarcoma. Herein we report a case of anaplastic rhabdomyosarcoma in a newborn girl presenting, at the Pediatric Surgery Outpatient Department of North Bengal Medical College and Hospital, India in 2013 with a large tumor mass in the left flank region, arising from abdominal wall muscles. PMID:26870149

  12. 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. PMID:25455735

  13. 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. PMID:26601808

  14. Acquired stuttering due to recurrent anaplastic astrocytoma

    PubMed Central

    Peters, Katherine B; Turner, Scott

    2013-01-01

    Acquired (neurogenic) stuttering is a rare phenomenon seen after cerebral infarction or brain injury. Aetiology of this symptom is unclear, but recent evidence supports that it is a disturbance in the left hemispheric neural network involving the interplay between the cortex and basal ganglia. We present the case of a patient who develops acquired stuttering after a recurrence of a right temporoparietal anaplastic astrocytoma (WHO grade III). We also review other cases of acquired stuttering and known anatomical correlates. PMID:24252834

  15. Management of Atypical and Anaplastic Meningiomas.

    PubMed

    Buttrick, Simon; Shah, Ashish H; Komotar, Ricardo J; Ivan, Michael E

    2016-04-01

    Meningiomas are the most prevalent primary tumor of central nervous system origin and, although most neoplasms are benign, a small proportion exemplifies an aggressive profile characterized by high recurrence rates, pleomorphic histology, and overall resistance to standard treatment. Standard initial therapy for malignant meningiomas includes maximal safe surgical resection followed by focal radiation in certain cases. The role for chemotherapy during recurrence of these aggressive meningiomas is less clear. Prognosis is poor and recurrence of malignant meningiomas is high. This article provides an overview of atypical and anaplastic malignant meningiomas, their treatment, and ongoing research for more effective treatments. PMID:27012388

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

    PubMed

    Xu, Bin; Ghossein, Ronald

    2016-09-01

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

  17. h-prune affects anaplastic thyroid cancer invasion and metastasis.

    PubMed

    Nambu, Junko; Kobayashi, Tsuyoshi; Hashimoto, Masakazu; Tashiro, Hirotaka; Sugino, Keizo; Shimamoto, Fumio; Kikuchi, Akira; Ohdan, Hideki

    2016-06-01

    Anaplastic thyroid cancer is one of the most aggressive human malignancies and is resistant to multimodal treatments. The expression of h-prune, the human homologue of Drosophila prune, has been reported to be correlated with progression and aggressiveness in various cancers including breast, colorectal and pancreatic cancers. We examined the role of h-prune in anaplastic thyroid cancer cell migration, invasion and metastasis. Immunohistochemical analysis of h-prune was performed with 15 surgically resected specimens of anaplastic thyroid cancers. To investigate cell motility, Boyden chamber, wound healing and matrigel invasion assays were performed using cells from anaplastic thyroid cancer cell lines. A murine orthotopic thyroid cancer model was used to investigate metastatic ability. In the immunohistochemical analysis, only weak focal or no staining of h-prune was observed in non-tumor tissue. In contrast, diffuse staining of h-prune was observed in anaplastic thyroid cancer and lymph node metastasis samples. Both inhibition of h-prune phosphodiesterase activity with dipyridamole and small interfering RNA for h-prune suppressed 8505C and KTC-3 cell motility. In addition, treatment with dipyridamole and decreased expression of h-prune suppressed tumor invasion and pulmonary metastasis in a NOD/Shi-scid, IL-2Rγnull (NOG) mouse orthotopic thyroid cancer model. In conclusion, h-prune is frequently expressed in anaplastic thyroid cancer cells and lymph nodes metastasis, and promotes migration and invasion of anaplastic thyroid cancer cells and metastasis in an anaplastic thyroid cancer model. Thus, h-prune shows promise as a targeting candidate against anaplastic thyroid cancer. PMID:27109060

  18. TCF12 is mutated in anaplastic oligodendroglioma.

    PubMed

    Labreche, Karim; Simeonova, Iva; Kamoun, Aurélie; Gleize, Vincent; Chubb, Daniel; Letouzé, Eric; Riazalhosseini, Yasser; Dobbins, Sara E; Elarouci, Nabila; Ducray, Francois; de Reyniès, Aurélien; Zelenika, Diana; Wardell, Christopher P; Frampton, Mathew; Saulnier, Olivier; Pastinen, Tomi; Hallout, Sabrina; Figarella-Branger, Dominique; Dehais, Caroline; Idbaih, Ahmed; Mokhtari, Karima; Delattre, Jean-Yves; Huillard, Emmanuelle; Mark Lathrop, G; Sanson, Marc; Houlston, Richard S

    2015-01-01

    Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO. PMID:26068201

  19. TCF12 is mutated in anaplastic oligodendroglioma

    PubMed Central

    Labreche, Karim; Simeonova, Iva; Kamoun, Aurélie; Gleize, Vincent; Chubb, Daniel; Letouzé, Eric; Riazalhosseini, Yasser; Dobbins, Sara E.; Elarouci, Nabila; Ducray, Francois; de Reyniès, Aurélien; Zelenika, Diana; Wardell, Christopher P.; Frampton, Mathew; Saulnier, Olivier; Pastinen, Tomi; Hallout, Sabrina; Figarella-Branger, Dominique; Dehais, Caroline; Idbaih, Ahmed; Mokhtari, Karima; Delattre, Jean-Yves; Huillard, Emmanuelle; Mark Lathrop, G.; Sanson, Marc; Houlston, Richard S.; Adam, Clovis; Andraud, Marie; Aubriot-Lorton, Marie-Hélène; Bauchet, Luc; Beauchesne, Patrick; Blechet, Claire; Campone, Mario; Carpentier, Antoine; Carpentier, Catherine; Carpiuc, Ioana; Chenard, Marie-Pierre; Chiforeanu, Danchristian; Chinot, Olivier; Cohen-Moyal, Elisabeth; Colin, Philippe; Dam-Hieu, Phong; Desenclos, Christine; Desse, Nicolas; Dhermain, Frederic; Diebold, Marie-Danièle; Eimer, Sandrine; Faillot, Thierry; Fesneau, Mélanie; Fontaine, Denys; Gaillard, Stéphane; Gauchotte, Guillaume; Gaultier, Claude; Ghiringhelli, Francois; Godard, Joel; Marcel Gueye, Edouard; Sebastien Guillamo, Jean; Hamdi-Elouadhani, Selma; Honnorat, Jerome; Louis Kemeny, Jean; Khallil, Toufik; Jouvet, Anne; Labrousse, Francois; Langlois, Olivier; Laquerriere, Annie; Lechapt-Zalcman, Emmanuelle; Le Guérinel, Caroline; Levillain, Pierre-Marie; Loiseau, Hugues; Loussouarn, Delphine; Maurage, Claude-Alain; Menei, Philippe; Janette Motsuo Fotso, Marie; Noel, Georges; Parker, Fabrice; Peoc'h, Michel; Polivka, Marc; Quintin-Roué, Isabelle; Ramirez, Carole; Ricard, Damien; Richard, Pomone; Rigau, Valérie; Rousseau, Audrey; Runavot, Gwenaelle; Sevestre, Henri; Christine Tortel, Marie; Uro-Coste, Emmanuelle; Burel-Vandenbos, Fanny; Vauleon, Elodie; Viennet, Gabriel; Villa, Chiara; Wager, Michel

    2015-01-01

    Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO. PMID:26068201

  20. 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

  1. Therapeutic Targeting of Anaplastic Lymphoma Kinase in Lung Cancer: A Paradigm for Precision Cancer Medicine

    PubMed Central

    Katayama, Ryohei; Lovly, Christine M.; Shaw, Alice T.

    2015-01-01

    The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)-ALK in anaplastic large-cell lymphoma (ALCL). Genomic alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKIs), including crizotinib, ceritinib and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALK-rearranged NSCLC. PMID:25979929

  2. Anaplastic thyroid cancer: multimodal treatment results

    PubMed Central

    Aslan, Zaki Antonio Taissoun; Granados-García, Martín; Luna-Ortiz, Kuauhyama; Guerrero-Huerta, Francisco Javier; Gómez-Pedraza, Antonio; Ñamendys-Silva, Silvio A; Meneses-García, Abelardo; Ordoñez-Mosquera, Juliana María

    2014-01-01

    Background Anaplastic thyroid cancer is a rare and lethal disease. It accounts for 1–2% of thyroid malignancies, but specific mortality is higher than 90%. It is an aggressive locoregional disease with a high metastatic capacity. There is no agreement with regards to the best treatment. We analysed the results of treatment in a mestizo population treated in the National Cancer Institute (Mexico). Methods We reviewed 1,581 files of thyroid carcinomas; of these, 29 (1.83%) had anaplastic thyroid carcinoma. Demographic variables, clinical manifestations, tumour characteristics, and treatments were analysed. Results The median age was 64.5 ± 13.2 years. Females were more affected (female/male ratio: 2.6:1); 21 cases occurred in women (72.4%), and eight in males (27.6%). The most common manifestations were neck enlargement (93.10%) and hoarseness (71.31%). The median tumour size was 8 cm (range: 4–20 cm). The percentage of cases which presented in clinical stage IVA was 10.3%, with 62.1% presenting in clinical stage IVb and 27.6% presenting in clinical stage VIc. Complete resection (R0) (p = 0.05), radiation doses of higher than 33.1 Gy (p = 0.04), and multimodal therapy were associated with better survival. Surgery plus radiotherapy with or without systemic treatment (p = 0.006). The median overall survival was 119 days (IC 95%, 36.3–201.6). Six-month, one-year and two-year survival was 37.9%, 21% and 13%, respectively. Conclusion Complete surgical resection is associated with better survival but is very difficult to achieve due to aggressive biological behaviour. Multimodal therapy is associated with better survival and a better quality of life. There is a need for more effective systemic treatments as extensive surgical resections have little overall benefit in highly invasive and metastatic disease. PMID:25114721

  3. The molecular pattern of histopathological progression to anaplastic meningioma - A case report.

    PubMed

    Och, Waldemar; Kulbacki, Kamil; Szostak, Błażej; Sikorska, Beata; Zakrzewska, Magdalena; Szmuda, Tomasz; Liberski, Paweł P; Budzisz, Tomasz

    2016-01-01

    Meningiomas (MGs) are the most frequent primary tumours of the central nervous system (CNS) and exhibit a large spectrum of histological types and clinical phenotypes. The WHO classification of CNS tumours established strict diagnostic criteria of the benign (Grade 1), atypical (Grade 2) and anaplastic (Grade 3) subtypes. Combined with the resection rate, WHO grading has the most crucial role as the prognostic factor. Additionally, such biomarkers as Ki-67/MIB-1, progesterone receptors and phosphor-histone H3 were correlated with MG progression. Recently, it was suggested that the aggressive behaviour of some MGs is attributed to molecular alterations, regardless of their histopathology. The analysis of loss of heterozygosity (LOH) at chromosomes 1, 9, 10, 14 and 22 was performed. The presented case of WHO Grade 2 MG initially exhibited LOH at chromosomes 10, 14 and 22. In the first recurrence, the tumour genetic profiling revealed additional LOH at chromosome 1p and atypical histopathology. During the second recurrence, an aggressive phenotype was observed and tumour progressed to an anaplastic form. Considering the appearance of the tumour relapses, the set of molecular changes overtook the histopathological progression. The genetic and histopathological imbalance in the tumour progression in secondary anaplastic MGs has not been previously described. The evolution of genetic and histopathological changes was presented in the same patient. In the future, the individualised therapy of potentially more aggressive forms of MGs could be based on certain chromosome aberrations. PMID:27375146

  4. Supratentorial extraventricular anaplastic ependymoma in a child

    PubMed Central

    Khilji, Muhammad Faisal; Hamid, Rana Shoaib; Qureshi, Asim

    2014-01-01

    A young child presented to the emergency department of a tertiary care hospital with on and off headache, focal seizures involving the left side of the body, weakness of left upper and lower limbs and vomiting for 2 weeks. Examination showed an alert child with grade 4/5 powers in left upper and lower limbs. Blood investigations were normal. An urgent CT of the brain showed intra-axial mass in the right frontal cerebral cortex, superolateral to the right lateral ventricle. MRI of the brain showed supratentorial extraventricular mass of 5.20×3.70×3.80 cm, in the right frontal cortex, emitting heterogeneous signals on T1, T2 and fluid-attenuated inversion recovery sequences and impression of astrocytoma, ependymoma or choroid plexus papilloma was made. Complete surgical resection of mass was performed. Histopathology of the mass proved it as WHO grade III anaplastic ependymoma. The child made an uneventful postoperative recovery and radiotherapy was followed. PMID:24623545

  5. A Novel Orthotopic Mouse Model of Human Anaplastic Thyroid Carcinoma

    PubMed Central

    Nucera, Carmelo; Nehs, Matthew A.; Mekel, Michal; Zhang, Xuefeng; Hodin, Richard; Lawler, Jack; Nose, Vânia

    2009-01-01

    Background Orthotopic mouse models of human cancer represent an important in vivo tool for drug testing and validation. Most of the human thyroid carcinoma cell lines used in orthotopic or subcutaneous models are likely of melanoma and colon cancer. Here, we report and characterize a novel orthotopic model of human thyroid carcinoma using a unique thyroid cancer cell line. Methods We used the cell line 8505c, originated from a thyroid tumor histologically characterized by anaplastic carcinoma cell features. We injected 8505c cells engineered using a green fluorescent protein–positive lentiviral vector orthotopically into the thyroid of severe combined immunodeficient mice. Results Orthotopic implantation with the 8505c cells produced thyroid tumors after 5 weeks, showing large neck masses, with histopathologic features of a high-grade neoplasm (anaplasia, necrosis, high mitotic and proliferative indexes, p53 positivity, extrathyroidal invasion, lymph node and distant metastases) and immunoprofile of follicular thyroid cell origin with positivity for thyroid transcription factor-1 and PAX8, and for cytokeratins. Conclusions Here we describe a novel orthotopic thyroid carcinoma model using 8505c cells. This model can prove to be a reliable and useful tool to investigate in vivo biological mechanisms determining thyroid cancer aggressiveness, and to test novel therapeutics for the treatment of refractory or advanced thyroid cancers. PMID:19772429

  6. Low-grade and anaplastic oligodendroglioma.

    PubMed

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

    2016-01-01

    Anaplastic oligodendrogliomas have long attracted interest because of their sensitivity to chemotherapy, in particular in the subset of 1p/19q co-deleted tumors. Recent molecular studies have shown that all 1p/19q co-deleted tumors have IDH mutations and most of them also have TERT mutations. Because of the presence of similar typical genetic alterations in astrocytoma and glioblastoma, the current trend is to diagnose these tumors on the basis of their molecular profile. Further long-term follow-up analysis of both EORTC and RTOG randomized studies on (neo)adjuvant procarbazine, lomustine, vincristine (PCV) chemotherapy have shown that adjuvant chemotherapy indeed improves outcome, and this is now standard of care. It is also equally clear that benefit to PCV chemotherapy is not limited to the 1p/19q co-deleted cases; potential other predictive factors are IDH mutations and MGMT promoter methylation. Moreover, a recent RTOG study on low-grade glioma also noted an improved outcome after adjuvant PCV chemotherapy, thus making (PCV) chemotherapy now standard of care for all 1p/19q co-deleted tumors regardless of grade. It remains unclear whether temozolomide provides the same survival benefit, as no data from well-designed clinical trials on adjuvant temozolomide in this tumor type are available. Another question that remains is whether one can safely leave out radiotherapy as part of initial treatment to avoid cognitive side-effects of radiotherapy. The current data suggest that delaying radiotherapy and treatment with chemotherapy only may be detrimental for overall survival. PMID:26948366

  7. Differential expression of aurora-A kinase in T-cell lymphomas

    PubMed Central

    Kanagal-Shamanna, Rashmi; Lehman, Norman L; O’Donnell, James P; Lim, Megan S; Schultz, Daniel S; Chitale, Dhananjay A; Bueso-Ramos, Carlos E; Medeiros, L Jeffrey; Inamdar, Kedar V

    2016-01-01

    Aurora-A is a mitotic kinase implicated in oncogenesis and is known to be overexpressed in B-cell lymphomas and plasma cell myeloma. The expression of Aurora-A kinase (henceforth referred to as Aurora-A) in T-cell lymphomas is not well characterized. In this study, we assessed Aurora-A expression by immunohistochemical analysis in 100 lymphomas encompassing a variety of T-cell lymphomas as categorized in the World Health Organization classification. Aurora-A expression was highest in anaplastic large-cell lymphomas and variably expressed in other types of T-cell lymphomas. In addition, the pattern of Aurora-A expression was predominantly cytoplasmic in ALK-positive anaplastic large-cell lymphoma and was nuclear in ALK-negative anaplastic large-cell lymphoma and other T-cell lymphomas, suggesting altered biochemical mechanisms of Aurora-A nuclear transport in ALK-positive anaplastic large-cell lymphoma. Reverse transcriptase-PCR analysis showed that Aurora-A is more highly expressed in ALK-positive anaplastic large-cell lymphoma than in ALK-negative anaplastic large-cell lymphoma, and is relatively lower in peripheral T-cell lymphomas. Using western blot analysis and the DEL cell line (derived from ALK-positive anaplastic large-cell lymphoma), we showed that Aurora-A expression is decreased after treatment with either MYC or MEK inhibitors, consistent with the MYC and MAP kinase signaling pathways being involved in driving Aurora-A expression; the greatest decrease was observed after MYC inhibition. These findings provide insights into the possible importance of Aurora-A overexpression in anaplastic large-cell lymphoma pathogenesis, and also suggest that Aurora-A inhibition could be a potential therapeutic approach for patients with anaplastic large-cell lymphoma. PMID:23411487

  8. Microfocus of Anaplastic Carcinoma Arising in Mural Nodule of Ovarian Mucinous Borderline Tumor With Very Rapid and Fatal Outcome.

    PubMed

    Mhawech-Fauceglia, Paulette; Ramzan, Amin; Walia, Saloni; Pham, Huyen Q; Yessaian, Annie

    2016-07-01

    A 36-yr-old woman presented with abdominal discomfort. A computed tomography scan revealed a large left cystic and solid pelvic mass without evidence of metastatic disease. Total hysterectomy with bilateral salpingo-oophorectomy and tumor staging was performed. Grossly, the ovarian mass measured 20×18 cm and the cut surface was multiloculated with 1 single mural nodule measuring 2×1.5 cm. The histologic diagnosis of ovarian mucinous borderline tumor with a microfocus of anaplastic carcinoma arising in sarcoma-like mural nodule, FIGO Stage IA was rendered. After 3 mo, the patient returned with symptomatic anemia. A computed tomography scan showed enlarged retroperitoneal and pelvic lymph nodes. Image-guided biopsy of the pelvic lymph node showed a metastatic anaplastic carcinoma from her primary ovarian carcinoma. Chemotherapy was initiated, but the patient developed fulminant disseminated intravascular coagulation within <1 wk of her presentation which was fatal. PMID:26598983

  9. 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.

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

    PubMed

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

    2008-11-01

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

  11. Malignant Struma Ovarii With a Predominant Component of Anaplastic Carcinoma.

    PubMed

    Fukunaga, Masaharu; Ishibashi, Tomomi; Koyama, Taig; Onoue, Kaoru; Kitai, Satomi; Tanaka, Kuniji; Isonishi, Seiji

    2016-07-01

    Struma ovarii exhibiting malignant histology are uncommon, and aggressive clinical courses with initial extraovarian spread are even more rare. This report describes a case of malignant struma ovarii with a predominant anaplastic carcinoma component. A 65-yr-old, gravida 2, para 2, female presented with lower abdominal discomfort and pain. She had a 12×10×7.5 cm tumor in the right ovary. Intraoperative diagnosis was high-grade spindle cell tumor. Right salpingo-oophorectomy and hysterectomy were performed. Macroscopically, the tumor invading the right tube was a yellow-white solid mass with focal microcysts containing greenish liquid and focal calcification. The tumor was histologically characterized by a spindle cell and pleomorphic sarcomatous component, and a minor component of benign-looking thyroid tissue with ossification. Immunohistochemically, the sarcomatous component was focally positive for CAM 5.2, EMA, thyroid transcription factor-1, and thyroglobulin, indicating anaplastic carcinoma. The patient was treated with chemotherapy and is alive, yet with tumor, 25 mo after surgery. This is the first case of malignant struma ovarii with a predominant component of anaplastic carcinoma. This type of malignant struma ovarii may lead to diagnostic problems, and sampling and differential diagnosis among sarcomatous ovarian tumors are important for making the correct diagnoses. PMID:26630220

  12. Histopathological analysis of anaplastic thyroid carcinoma cases with long-term survival: A report from the Anaplastic Thyroid Carcinoma Research Consortium of Japan.

    PubMed

    Hirokawa, Mitsuyoshi; Sugitani, Iwao; Kakudo, Kennichi; Sakamoto, Atsuhiko; Higashiyama, Takuya; Sugino, Kiminori; Toda, Kazuhisa; Ogasawara, Satoshi; Yoshimoto, Seiichi; Hasegawa, Yasuhisa; Imai, Tsuneo; Onoda, Naoyoshi; Orita, Yorihisa; Kammori, Makoto; Fujimori, Keisei; Yamada, Hiroyuki

    2016-05-31

    The aim of this study was to clarify the histopathological features of anaplastic thyroid carcinoma in patients who achieved long-term survival. We reviewed 88 anaplastic thyroid carcinoma cases in which the patient survived less than 3 months (short-term survival), and 68 anaplastic thyroid carcinoma cases in which the patient survived more than one year (long-term survival) from the database of the Anaplastic Thyroid Carcinoma Research Consortium of Japan. We examined these cases both histologically and immunohistochemically. Six (6.8%) short-term survival cases and 27 (39.7%) long-term survival cases were considered not to be anaplastic thyroid carcinoma after central review. Of these, 12 were revised to papillary carcinoma with squamous cell carcinoma. In cases without chemotherapy, long-term survival was significantly more common if there was a pre-existing tumor, epithelial growth, or lymphocytic infiltration, and short-term survival was more common if neutrophilic infiltration was present. In cases with chemotherapy, long-term survival was significantly more common if epithelial growth or a squamous cell carcinoma component was present, whereas short-term survival was more common in cases with rhabdoid cells. Immunohistochemical results were not related to survival. Some long-term survival cases showed histological findings other than those typically associated with anaplastic thyroid carcinoma. The presence of a pre-existing tumor, epithelial growth, a squamous cell carcinoma component, no neutrophilic infiltration and lymphocytic infiltration may therefore be favorable prognostic factors in anaplastic thyroid carcinoma. PMID:26842589

  13. Metronomic Chemotherapy in Anaplastic Thyroid Carcinoma: A Potentially Feasible Alternative to Therapeutic Nihilism

    PubMed Central

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

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC. PMID:26009682

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

    PubMed

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

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC. PMID:26009682

  15. 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.

  16. Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

    PubMed Central

    Wagle, Nikhil; Grabiner, Brian C.; Van Allen, Eliezer M.; Amin-Mansour, Ali; Taylor-Weiner, Amaro; Rosenberg, Mara; Gray, Nathanael; Barletta, Justine A.; Guo, Yanan; Swanson, Scott J.; Ruan, Daniel T.; Hanna, Glenn J.; Haddad, Robert I.; Getz, Gad; Kwiatkowski, David J.; Carter, Scott L.; Sabatini, David M.; Jänne, Pasi A.; Garraway, Levi A.; Lorch, Jochen H.

    2015-01-01

    SUMMARY Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors. PMID:25295501

  17. 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. PMID:25000710

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

    PubMed Central

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

    2013-01-01

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

  19. Approach to the Patient with Anaplastic Thyroid Carcinoma

    PubMed Central

    2012-01-01

    Anaplastic thyroid carcinoma is the least common but most lethal of thyroid cancers. All patients are classified as stage IV, with the primary lesion restricted to the thyroid gland in stage IVA; locoregional lymph nodes may exist in IVA/IVB; and IVC disease is defined by distant metastases. Prognosis is highly dependent on disease extent at presentation, and staging and establishing a plan of care must be accomplished quickly. Although almost all studies are biased due to their retrospective nature, the most important factors associated with longer survival are completeness of surgical resection (achievable in only a minority of patients) and high-dose (>40 Gy) external beam radiotherapy (preferably intensity modulated radiation therapy). Recent reports suggest that a multimodal approach (surgery, radiation, and chemotherapy) is beneficial. Given the high lethality even with apparent local disease, combination systemic therapy (cytotoxics and/or targeted agents) may improve outcomes in stage IVA/IVB patients. Newer, more effective drug combinations are urgently needed for IVC patients who want aggressive therapy. A candid discussion of the prognosis and management options, including palliative care/hospice, should be held with the patient and caregiver as soon as possible after diagnosis to clarify the patient's preference and expectations. Prospective multicenter clinical trials, incorporating molecular analyses of tumors, are required if we are to improve survival in anaplastic thyroid carcinoma. PMID:22869844

  20. Use of vemurafenib in anaplastic thyroid carcinoma: a case report

    PubMed Central

    Marten, Kristen A; Gudena, Vinay K

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) is a rare, poorly differentiated type of thyroid cancer occurring in less than 5% of all thyroid cancers. Patients typically have a poor prognosis with very few options for treatment.2 With current therapy of surgery, chemotherapy, and radiation, median survival is only 6 months from the time of diagnosis. Several mutations in cell cycle regulation have been discovered in ATC that contribute to its undifferentiated state, one of which is the BRAF kinase mutation. This mutation results in activation of the MAPK pathway and uncontrolled cell proliferation. In this case report, a 51 y old male presented with a 2-week history of hoarseness and was diagnosed with ATC. Genetic analysis revealed a mutation in BRAF kinase; the patient subsequently began therapy with vemurafenib, a BRAF kinase inhibitor indicated for melanoma. After an initial response, the patient quickly declined and consequently died from his disease. Anaplastic thyroid carcinoma is a deadly cancer without an effective treatment. Inhibiting mutated enzymes that drive the development of this cancer is a potential drug target that may improve outcomes in patients with ATC. PMID:26176686

  1. Response of differentiated but not anaplastic teratoma to interferon.

    PubMed Central

    Rustin, G. J.; Kaye, S. B.; Williams, C. J.; Newlands, E. S.; Bagshawe, K. D.; Toy, J. L.

    1984-01-01

    A Phase 2 trial was conducted using intramuscular lymphoblastoid interferon (IFN, Wellcome Research Laboratories), 4 MU per day, in 10 patients with chemotherapy-resistant teratomas. There was stabilisation of disease in 2 patients both of whom were in retrospect considered to have had differentiated teratoma at the time of IFN administration. There was progression of presumed active anaplastic germ cell tumour in 8 patients. One of these patients, a 15-year-old boy with biopsy proven differentiated teratoma has received 2 courses of lymphoblastoid IFN and 1 course of recombinant leukocyte A IFN (Roche Products Ltd.) lasting 5 1/2, 8 and 8+ months respectively. He has had a mixed response in his differentiated tumour which on each occasion has been maintained for the duration that he received IFN. Rising HCG levels during his second course of interferon required additional cytotoxic chemotherapy. Lymphoblastoid IFN does not appear to be active against anaplastic germ cell tumours but both lymphoblastoid and recombinant leukocyte A IFN may be useful in the treatment of unresectable differentiated teratoma. Images Figure 2 Figure 3 PMID:6498061

  2. Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

    SciTech Connect

    Perez-Pinera, Pablo; Chang, Y.; Astudillo, A.; Mortimer, J.; Deuel, T.F. . E-mail: tfdeuel@scripps.edu

    2007-06-29

    Pleiotrophin (PTN, Ptn) is an 18 kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn, it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP){beta}/{zeta}, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTP{beta}/{zeta} signaling pathway in PTN-stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTP{beta}/{zeta} signaling pathway; we now demonstrate that ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the 'dotted' pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTP{beta}/{zeta} signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.

  3. 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

  4. 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. PMID:26305586

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

    PubMed

    Junor, E J; Paul, J; Reed, N S

    1992-04-01

    Ninety-one patients with histologically proven anaplastic carcinoma of the thyroid were referred to the Beatson Oncology Centre between 1961 and 1986. The female:male ratio was 2.4:1 and the median age at presentation was 70 (range 38-92) years. All patients had a thyroid mass at presentation and the most common symptoms were dyspnoea, dysphagia and dysphonia. Five patients had a total thyroidectomy and 28 partial thyroidectomy. Ninety five per cent of patients received external beam radiotherapy. Results show dyspnoea to be the only symptom strongly influencing survival. Total or partial thyroidectomy is associated with increased survival. This association is most marked for patients presenting without dyspnoea. Eighty per cent of patients responded to radiotherapy. PMID:1582515

  6. Anaplastic gliomas: end-of-life care recommendations.

    PubMed

    Dirven, Linda; Sizoo, Eefje M; Taphoorn, Martin J B

    2015-01-01

    Despite multimodal antitumor treatment, all patients with an anaplastic glioma will be confronted with incurability in due course and enter the end-of-life (EOL) phase; the period when the patients' condition declines and tumor-directed treatment is no longer effective. Although palliative care is important in all stages of the disease, it is of utmost importance in the EOL phase. The main goal of palliative care is to improve or maintain the quality of life of the patients and their relatives through the prevention and relief of suffering. This review focuses on different aspects of the EOL phase (symptoms and signs, EOL decision-making, advance care planning, organization of care and caregiver burden) and will provide recommendations to optimize palliative care. PMID:26509292

  7. Initial treatment patterns over time for anaplastic oligodendroglial tumors

    PubMed Central

    Panageas, Katherine S.; 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 Urgoiti, 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.; Lassman, Andrew B.

    2012-01-01

    Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981–2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980–1984 vs 5% in 2005–2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980–1984 vs 38% in 2005–2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005–2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005–2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy. PMID:22661585

  8. 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. PMID:26615136

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

    NASA Astrophysics Data System (ADS)

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

    2006-05-01

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

  10. Relation of CD30 expression to survival and morphology in large cell B cell lymphomas.

    PubMed Central

    Noorduyn, L A; de Bruin, P C; van Heerde, P; van de Sandt, M M; Ossenkoppele, G J; Meijer, C J

    1994-01-01

    AIMS--To investigate whether CD30 expression is correlated with anaplastic morphology, and whether this correlated with a better survival in large cell B cell lymphomas, as has been described for T cell lymphomas. METHODS--CD30 expression was investigated using frozen sections in a series of 146 large cell B cell lymphomas. Clinical data and follow up information were collected from 25 lymphomas with strong CD30 expression, 30 lymphomas with partial CD30 expression, and a control group of 25 lymphomas which did not express CD30. RESULTS--Morphological distinction between anaplastic and non-anaplastic tumours was difficult. Of the cases with an anaplastic morphology, 50% were CD30 positive, as were 24% of the polymorphic centroblastic B cell lymphomas. Only 65% of the morphologically non-anaplastic tumours were completely CD30 negative. There was no difference in survival among patients with lymphomas expressing CD30 and those that did not. Patients with morphologically anaplastic B cell lymphomas did not differ in their survivals from those with other high grade B cell lymphomas. Clinical stage at presentation was the only variable that was significantly associated with survival. CONCLUSIONS--CD30 expression occurs frequently in large cell B cell lymphomas and is poorly related to anaplastic morphology. Morphological distinction between anaplastic and non-anaplastic tumours is difficult. In contrast to T cell lymphomas, CD30 positive B cell lymphomas do not show a relatively favourable clinical course. The results presented here raise serious doubts as to whether large cell B cell lymphoma, based on the expression of CD30 or anaplastic morphology, can really be termed a separate entity. Images PMID:8132806

  11. Anaplastic Lymphoma Kinase (ALK) Signaling in Lung Cancer.

    PubMed

    Ou, Sai-Hong Ignatius; Shirai, Keisuke

    2016-01-01

    Chromosomal rearrangement in the anaplastic lymphoma kinase (ALK) gene was identified as an oncogenic driver in non-small cell lung cancer (NSCLC) in 2007. A multi-targeted ALK/ROS1/MET inhibitor, crizotinib, targeting this activated tyrosine kinase has led to significant clinical benefit including tumor shrinkage and prolonged survival without disease progression and has been approved by US FDA since 2011 for the treatment of advanced ALK-rearranged NSCLC (Ou et al. Oncologist 17:1351-1375, 2012). Knowledge gained from treating ALK-rearranged NSCLC patients including the presenting clinicopathologic characteristics, methods of detecting ALK-rearranged NSCLC, pattern of relapse and acquired resistance mechanisms while on crizotinib, and the clinical activities of more potent ALK inhibitors has led us to a detailed and ever expanding knowledge of the ALK signaling pathway in lung cancer but also raising many more questions that remained to be answered in the future. This book chapter will provide a concise summary of the importance of ALK signaling pathway in lung cancer. Understanding the ALK signaling pathway in lung cancer will likely provide the roadmap to the management of major epithelial malignancies driven by receptor tyrosine kinase rearrangement. PMID:26667344

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

    PubMed Central

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

    2016-01-01

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

  13. O-GlcNAcylation enhances anaplastic thyroid carcinoma malignancy

    PubMed Central

    CHENG, YU; LI, HONGLUN; LI, JIANLIN; LI, JISHENG; GAO, YAN; LIU, BAODONG

    2016-01-01

    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. PMID:27347182

  14. 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

  15. 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. PMID:26934320

  16. 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

  17. Mutation-Independent Activation of the Anaplastic Lymphoma Kinase in Neuroblastoma.

    PubMed

    Regairaz, Marie; Munier, Fabienne; Sartelet, Hervé; Castaing, Marine; Marty, Virginie; Renauleaud, Céline; Doux, Camille; Delbé, Jean; Courty, José; Fabre, Monique; Ohta, Shigeru; Viehl, Philippe; Michiels, Stefan; Valteau-Couanet, Dominique; Vassal, Gilles

    2016-02-01

    Activating mutations of anaplastic lymphoma kinase (ALK) have been identified as important players in neuroblastoma development. Our goal was to evaluate the significance of overall ALK activation in neuroblastoma. Expression of phosphorylated ALK, ALK, and its putative ligands, pleiotrophin and midkine, was screened in 289 neuroblastomas and 56 paired normal tissues. ALK was expressed in 99% of tumors and phosphorylated in 48% of cases. Pleiotrophin and midkine were expressed in 58% and 79% of tumors, respectively. ALK activation was significantly higher in tumors than in paired normal tissues, together with ALK and midkine expression. ALK activation was largely independent of mutations and correlated with midkine expression in tumors. ALK activation in tumors was associated with favorable features, including a younger age at diagnosis, hyperdiploidy, and detection by mass screening. Antitumor activity of the ALK inhibitor TAE684 was evaluated in wild-type or mutated ALK neuroblastoma cell lines and xenografts. TAE684 was cytotoxic in vitro in all cell lines, especially those harboring an ALK mutation. TAE684 efficiently inhibited ALK phosphorylation in vivo in both F1174I and R1275Q xenografts but demonstrated antitumor activity only against the R1275Q xenograft. In conclusion, ALK activation occurs frequently during neuroblastoma oncogenesis, mainly through mutation-independent mechanisms. However, ALK activation is not associated with a poor outcome and is not always a driver of cell proliferation and/or survival in neuroblastoma. PMID:26687816

  18. mRNA Expression in Papillary and Anaplastic Thyroid Carcinoma: Molecular Anatomy of a Killing Switch

    PubMed Central

    Hébrant, Aline; Dom, Geneviève; Dewaele, Michael; Andry, Guy; Trésallet, Christophe; Leteurtre, Emmanuelle; Dumont, Jacques E.; Maenhaut, Carine

    2012-01-01

    Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid neoplasia and represents the end stage of thyroid tumor progression. No effective treatment exists so far. ATC frequently derive from papillary thyroid carcinomas (PTC), which have a good prognosis. In this study, we analyzed the mRNA expression profiles of 59 thyroid tumors (11 ATC and 48 PTC) by microarrays. ATC and PTC showed largely overlapping mRNA expression profiles with most genes regulated in all ATC being also regulated in several PTC. 43% of the probes regulated in all the PTC are similarly regulated in all ATC. Many genes modulations observed in PTC are amplified in ATC. This illustrates the fact that ATC mostly derived from PTC. A molecular signature of aggressiveness composed of 9 genes clearly separates the two tumors. Moreover, this study demonstrates gene regulations corresponding to the ATC or PTC phenotypes like inflammatory reaction, epithelial to mesenchymal transition (EMT) and invasion, high proliferation rate, dedifferentiation, calcification and fibrosis processes, high glucose metabolism and glycolysis, lactate generation and chemoresistance. The main qualitative differences between the two tumor types bear on the much stronger EMT, dedifferentiation and glycolytic phenotypes showed by the ATC. PMID:23115614

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

    PubMed

    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

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

    PubMed

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

    2013-01-01

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

  1. 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

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

    PubMed

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

    2016-09-01

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

  3. A visual latent semantic approach for automatic analysis and interpretation of anaplastic medulloblastoma virtual slides.

    PubMed

    Cruz-Roa, Angel; González, Fabio; Galaro, Joseph; Judkins, Alexander R; Ellison, David; Baccon, Jennifer; Madabhushi, Anant; Romero, Eduardo

    2012-01-01

    A method for automatic analysis and interpretation of histopathology images is presented. The method uses a representation of the image data set based on bag of features histograms built from visual dictionary of Haar-based patches and a novel visual latent semantic strategy for characterizing the visual content of a set of images. One important contribution of the method is the provision of an interpretability layer, which is able to explain a particular classification by visually mapping the most important visual patterns associated with such classification. The method was evaluated on a challenging problem involving automated discrimination of medulloblastoma tumors based on image derived attributes from whole slide images as anaplastic or non-anaplastic. The data set comprised 10 labeled histopathological patient studies, 5 for anaplastic and 5 for non-anaplastic, where 750 square images cropped randomly from cancerous region from whole slide per study. The experimental results show that the new method is competitive in terms of classification accuracy achieving 0.87 in average. PMID:23285547

  4. An integrated texton and bag of words classifier for identifying anaplastic medulloblastomas.

    PubMed

    Galaro, Joseph; Judkins, Alexander R; Ellison, David; Baccon, Jennifer; Madabhushi, Anant

    2011-01-01

    In this paper we present a combined Bag of Words and texton based classifier for differentiating anaplastic and non-anaplastic medulloblastoma on digitized histopathology. The hypothesis behind this work is that histological image signatures may reflect different levels of aggressiveness of the disease and that texture based approaches can help discriminate between more aggressive and less aggressive phenotypes of medulloblastoma. The bag of words approach attempts to model the occurrence of differently expressed image features. In this work we choose to model the image features via textons which can quantitatively capture and model texture appearance in the images. The texton-based features, obtained via two methods, the Haar Wavelet responses and MR8 filter bank, provide spatial orientation and rotation invariant attributes. Applying these features to the bag of words framework yields textural representations that can be used in conjunction with a classifier (κ-nearest neighbor) or a content based image retrieval system. Over multiple runs of randomized cross validation, a κ-NN classifier in conjunction with Haar wavelets and the texton, bag of words approach yielded a mean classification accuracy of 80, an area under the precision recall curve of 87 and an area under the ROC curve of 83 in distinguishing between anaplastic and non-anaplastic medulloblastomas on a cohort of 36 patient studies. PMID:22255080

  5. 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

  6. Cutaneous metastasis from anaplastic thyroid carcinoma exhibiting exclusively a spindle cell morphology. A case report and review of literature.

    PubMed

    Danialan, Richard; Tetzlaff, Michael T; Torres-Cabala, Carlos A; Mays, Stephen R; Prieto, Victor G; Bell, Diana; Curry, Jonathan L

    2016-03-01

    Anaplastic thyroid carcinoma is a highly aggressive cancer accounting for 1-2% of thyroid malignancies. Cutaneous metastases from anaplastic thyroid carcinoma are exceedingly rare. We report a 65-year-old woman with anaplastic thyroid carcinoma (BRAF V600E mutation) who had lymph node metastases (pT4 N1b) treated by total thyroidectomy, postoperative radiotherapy, adjuvant chemotherapy (paclitaxel and pazopanib) and targeted therapy (vemurafenib). Nine months after initial diagnosis, radiographic studies revealed multiple pulmonary metastases. A dermatologic examination showed a solitary 1.2-cm chest nodule. Skin biopsy from this nodule revealed infiltrative dermal spindle cells arranged in poorly formed fascicles. Immunohistochemical studies demonstrated the tumor cells to be PAX-8 (+), pancytokeratin (+, focally), TTF-1 (-) and SOX-10 (-). Comparison with the patient's primary anaplastic thyroid carcinoma revealed focal areas of poorly differentiated spindle cells morphologically similar to the malignant spindle cells in the skin biopsy. Together, these findings confirmed the diagnosis of anaplastic thyroid carcinoma metastatic to skin. Cutaneous metastasis of anaplastic thyroid carcinoma composed exclusively of spindle cells broadens the histologic differential diagnosis of cutaneous spindle cell malignancies and presents further diagnostic challenges. PAX-8 may be useful in discerning the spindle cell component of anaplastic thyroid carcinoma from other spindle cell malignancies in the skin. PMID:26347145

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

    PubMed

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

    2015-03-01

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

  8. Anti-ALK Antibodies in Patients with ALK-Positive Malignancies Not Expressing NPM-ALK

    PubMed Central

    Damm-Welk, Christine; Siddiqi, Faraz; Fischer, Matthias; Hero, Barbara; Narayanan, Vignesh; Camidge, David Ross; Harris, Michael; Burke, Amos; Lehrnbecher, Thomas; Pulford, Karen; Oschlies, Ilske; Siebert, Reiner; Turner, Suzanne; Woessmann, Wilhelm

    2016-01-01

    Patients with Nucleophosmin (NPM)- Anaplastic Lymphoma Kinase (ALK) fusion positive Anaplastic Large Cell Lymphoma produce autoantibodies against ALK indicative of an immune response against epitopes of the chimeric fusion protein. We asked whether ALK-expression in other malignancies induces specific antibodies. Antibodies against ALK were detected in sera of one of 50 analysed ALK-expressing neuroblastoma patients, 13 of 21 ALK positive non-small cell lung carcinoma (NSCLC) patients, 13 of 22 ALK translocation-positive, but NPM-ALK-negative lymphoma patients and one of one ALK-positive rhabdomyosarcoma patient, but not in 20 healthy adults. These data suggest that boosting a pre-existent anti-ALK immune response may be more feasible for patients with ALK-positive NSCLC, lymphomas and rhabdomyosarcomas than for tumours expressing wild-type ALK. PMID:27471553

  9. 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. PMID:27498938

  10. A Rare Case of Pleomorphic Carcinoma of the Lung Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement.

    PubMed

    Shiroyama, Takayuki; Tanaka, Ayako; Tamiya, Motohiro; Hamaguchi, Masanari; Osa, Akio; Takeoka, Sawa; Tani, Eriko; Azuma, Yuichiro; Morishita, Naoko; Suzuki, Hidekazu; Okamoto, Norio; Kimura, Kenji; Kadota, Yoshihisa; Kawahara, Kunimitsu; Hirashima, Tomonori; Kawase, Ichiro

    2015-01-01

    Molecular testing for anomalies, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase (ALK) rearrangement, is part of the current standard of care for non-small cell lung cancer, particularly adenocarcinoma. ALK rearrangement occurs most frequently in adenocarcinoma cells and rarely in non-adenocarcinoma cells. We herein report a rare case of pleomorphic lung carcinoma with ALK rearrangement in both its adenocarcinoma and spindle cell components. This case suggests the possibility of ALK rearrangement in pleomorphic carcinoma. PMID:26521903

  11. Development of anaplastic Wilms tumor and subsequent relapse in a child with diaphanospondylodysostosis.

    PubMed

    Tasian, Sarah K; Kim, Grace E; Miniati, Douglas N; DuBois, Steven G

    2012-10-01

    Diaphanospondylodysostosis (DSD) is a rare skeletal dysplasia syndrome resulting from disordered mesenchymal differentiation. Children with DSD generally die in utero or during the first month of life from severe thoracic insufficiency syndrome. An association of DSD with nephroblastomatosis has been observed, but the natural history of such nephroblastomatosis remains poorly characterized due to the rarity of the underlying condition. We describe a patient with DSD who developed bilateral hyperplastic nephroblastomatosis that ultimately evolved into therapy-resistant anaplastic Wilms tumor (nephroblastoma). PMID:22469945

  12. Development of Anaplastic Wilms Tumor and Subsequent Relapse in a Child with Diaphanospondylodysostosis

    PubMed Central

    Tasian, Sarah K.; Kim, Grace E.; Miniati, Douglas N.; DuBois, Steven G.

    2012-01-01

    Diaphanospondylodysostosis (DSD) is a rare skeletal dysplasia syndrome resulting from disordered mesenchymal differentiation. Children with DSD generally die in utero or during the first month of life from severe thoracic insufficiency syndrome. An association of DSD with nephroblastomatosis has been observed, but the natural history of such nephroblastomatosis remains poorly characterized due to the rarity of the underlying condition. We describe a patient with DSD who developed bilateral hyperplastic nephroblastomatosis that ultimately evolved into therapy-resistant anaplastic Wilms tumor (nephroblastoma). PMID:22469945

  13. 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

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

    PubMed

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

    2015-04-13

    A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo. PMID:25873174

  15. 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. PMID:26859575

  16. 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

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

    PubMed Central

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

    2016-01-01

    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. PMID:26859575

  18. Juvenile Granulosa Cell Tumour: Anaplastic Variant with Omental Deposits

    PubMed Central

    Rao, Anuradha C.K.; Monappa, Vidya

    2016-01-01

    Juvenile Granulosa Cell Tumour (JGCT) of ovary represents a small fraction of all primary ovarian malignancies. It is a subtype of granulosa cell tumour that is almost always found during the first three decades of life. Histologically, it differs from the typical adult type of granulosa cell tumour. It accounts for 5-15% of all granulosa cell tumours, majority being unilateral. Herein, we describe an unusual histopathological variant of JGCT with numerous large cystic spaces, anaplasia and focal syncytiotrophoblast like giant cells. PMID:27042471

  19. Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors

    PubMed Central

    Panageas, Katherine S.; Reiner, Anne S.; 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 Urgoiti, 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.; Lassman, Andrew B.

    2014-01-01

    Background Anaplastic oligodendroglial tumors are rare, and median survival varies widely. Analysis of 1p19q deletion is performed commonly and is an important prognostic factor. However, age and other clinical variables also carry prognostic value, and it is unclear how to incorporate them into clinical decision making or to combine them for prognostication. Methods We compiled a retrospective database of 1013 patients with newly diagnosed anaplastic oligodendrogliomas or oligoastrocytomas and performed a recursive partitioning analysis to generate independent prognostic classes among 587 patients with informative 1p19q status. Variables included for survival classification were age (continuous), history of prior low-grade glioma, 1p19q deletion status, histology (presence or absence of an astrocytic component), tumor lobe, tumor hemisphere, gender, extent of resection, postresection treatment, and performance status at diagnosis. Results Recursive partitioning analysis identified 5 prognostic groups based on hazard similarity: class I (age <60 y, 1p19q codeleted), class II (age <43 y, not codeleted), class III (age 43–59 y, not codeleted, frontal lobe tumor or age ≥60 y, codeleted), class IV (age 43–59 y, not codeleted, not frontal lobe tumor or age 60–69 y, not codeleted), and class V (age ≥70 y, not codeleted). Survival differences were highly significant (P < .0001), with medians ranging from 9.3 years (95% CI: 8.4–16.0) for class I to 0.6 years (95% CI: 0.5–0.9) for class V. Conclusions These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome. PMID:24997140

  20. 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

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

    PubMed

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

    2016-07-01

    Papillary and rhabdoid meningiomas are pathologically World Health Organization (WHO) grade III. Any correlation between clinical prognosis and pathologic component is not clear. We analyzed the prognoses of patients with meningiomas with a rhabdoid or papillary component compared to those of patients with anaplastic meningiomas. From 1994 to June 2013, 14 anaplastic meningiomas, 6 meningiomas with a rhabdoid component, and 5 meningiomas with papillary component were pathologically diagnosed. We analyzed magnetic resonance imaging (MRI) findings, extent of removal, adjuvant treatment, progression-free survival (PFS), overall survival (OS), and pathologic features of 14 anaplastic meningiomas (group A), 5 meningiomas with a predominant (≥50%) papillary or rhabdoid component (group B1), and 6 meningiomas without a predominant (<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

  2. Anaplastic meningioma: octreotide therapy for a case of recurrent and progressive intracranial disease.

    PubMed

    Rammo, Richard; Rock, Adam; Transou, Andrea; Raghunathan, Aditya; Rock, Jack

    2016-02-01

    Meningiomas are common intracranial tumors categorized as Grades I-III per the current WHO guidelines. A small percentage of meningiomas are Grades II and III, which are likely to recur after initial treatment. Grade III meningiomas are considered to be malignant and warrant aggressive management. If surgery and radiation fail to produce lasting remission, effective treatment options for patients with progressive anaplastic meningiomas are elusive. The authors present the case of a patient with a meningioma that gradually progressed from Grade I to Grade III over 12 years despite repeated surgery and radiation therapy. The patient has been in remission for over 3 years following octreotide therapy. PMID:26274993

  3. Complete remission of anaplastic thyroid carcinoma after concomitant treatment with docetaxel and radiotherapy.

    PubMed

    Abe, Ichiro; Karasaki, Satoko; Matsuda, Yayoi; Sakamoto, Shohei; Nakashima, Torahiko; Yamamoto, Hidetaka; Kawate, Hisaya; Ohnaka, Keizo; Nakashima, Hisashi; Kobayashi, Kunihisa; Oda, Yoshinao; Nomura, Masatoshi; Takayanagi, Ryoichi

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) although rare is the most lethal form of thyroid cancer. The mortality rate for ATC is very high, with a median survival time of only 5 months; the survival rate at 1 year after diagnosis is <20%. Management of ATC is extremely difficult and rife with uncertainties. Herein, we describe a 75-year-old woman who presented with ATC and was successfully treated using concomitant treatment with docetaxel and high-dose radiotherapy. This case appears to be the first to have been reported in the literature involving complete remission of ATC confirmed by autopsy, suggesting the therapeutic potential of this combination. PMID:25789182

  4. Complete Remission of Anaplastic Thyroid Carcinoma after Concomitant Treatment with Docetaxel and Radiotherapy

    PubMed Central

    Abe, Ichiro; Karasaki, Satoko; Matsuda, Yayoi; Sakamoto, Shohei; Nakashima, Torahiko; Yamamoto, Hidetaka; Kawate, Hisaya; Ohnaka, Keizo; Nakashima, Hisashi; Kobayashi, Kunihisa; Oda, Yoshinao; Nomura, Masatoshi; Takayanagi, Ryoichi

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) although rare is the most lethal form of thyroid cancer. The mortality rate for ATC is very high, with a median survival time of only 5 months; the survival rate at 1 year after diagnosis is <20%. Management of ATC is extremely difficult and rife with uncertainties. Herein, we describe a 75-year-old woman who presented with ATC and was successfully treated using concomitant treatment with docetaxel and high-dose radiotherapy. This case appears to be the first to have been reported in the literature involving complete remission of ATC confirmed by autopsy, suggesting the therapeutic potential of this combination. PMID:25789182

  5. UbcH10 overexpression may represent a marker of anaplastic thyroid carcinomas

    PubMed Central

    Pallante, P; Berlingieri, M T; Troncone, G; Kruhoffer, M; Orntoft, T F; Viglietto, G; Caleo, A; Migliaccio, I; Decaussin-Petrucci, M; Santoro, M; Palombini, L; Fusco, A

    2005-01-01

    The hybridisation of an Affymetrix HG_U95Av2 oligonucleotide array with RNAs extracted from six human thyroid carcinoma cell lines and a normal human thyroid primary cell culture led us to the identification of the UbcH10 gene that was upregulated by 150-fold in all of the carcinoma cell lines in comparison to the primary culture cells of human normal thyroid origin. Immunohistochemical studies performed on paraffin-embedded tissue sections showed abundant UbcH10 levels in thyroid anaplastic carcinoma samples, whereas no detectable UbcH10 expression was observed in normal thyroid tissues, in adenomas and goiters. Papillary and follicular carcinomas were only weakly positive. These results were further confirmed by RT–PCR and Western blot analyses. The block of UbcH10 protein synthesis induced by RNA interference significantly reduced the growth rate of thyroid carcinoma cell lines. Taken together, these results would indicate that UbcH10 overexpression is involved in thyroid cell proliferation, and may represent a marker of thyroid anaplastic carcinomas. PMID:16106252

  6. Anaplastic Carcinoma Arising in a Mucinous Cystic Neoplasm Masquerading as Pancreatic Pseudocyst.

    PubMed

    Aldaoud, Najla; Joudeh, Amani; Al-Momen, Sami; Alnahawi, Mamdouh; Al-Abbadi, Mousa A

    2016-06-01

    Mucinous cystic neoplasms (MCN) of the pancreas can vary from benign to premalignant and malignant. Preoperative diagnosis is essential to offer the patient appropriate treatment. Occasionally these cases may harbor anaplastic carcinoma while clinically masquerade as a pseudocyst. Here in, we report an unusual case of a 37-year old female presented with recurrent abdominal pain that was suspected clinically and by imaging studies to have a pseudocyst. EUS-FNA with internal drainage of the cyst was performed. Cytological evaluation of the cyst fluid showed numerous inflammatory cells composed mainly of many neutrophils admixed with macrophages reminiscent of the usual pseudocyst content but there were scattered rare dyscohesive malignant cells which were highly pleomorphic with multinucleation. Immunostains on the cell block showed immunoreactivity of these cells including the multinucleated cells for Cam 5.2 and AE1/AE3 and focally for Ber-Ep4, Moc -31, and CA19-9. The subsequent resection confirmed the presence of anaplastic (undifferentiated) carcinoma (AC) arising in a MCN of the pancreas. Diagn. Cytopathol. 2016;44:538-542. © 2016 Wiley Periodicals, Inc. PMID:27028547

  7. Brain Tumor in an In Vitro Fertilization–Facilitated Pregnancy: Fourth Ventricle Anaplastic Ependymoma in the Second Trimester

    PubMed Central

    Ryskeldiyev, Nurzhan; Olenbay, Gabit; Auezova, Raushan; Killeen, Tim; Aldiyarova, Nurgul; Akhmetzhanova, Zauresh; Cesnulis, Evaldas; Akshulakov, Serik

    2016-01-01

    We present a case of fourth ventricle anaplastic ependymoma in a pregnancy which was the first result of three rounds of in vitro fertilization (IVF) and embryo transfer. Whether hormonal treatment can directly or indirectly precipitate brain tumors to develop or become symptomatic is unclear. PMID:27330925

  8. Brain Tumor in an In Vitro Fertilization-Facilitated Pregnancy: Fourth Ventricle Anaplastic Ependymoma in the Second Trimester.

    PubMed

    Ryskeldiyev, Nurzhan; Olenbay, Gabit; Auezova, Raushan; Killeen, Tim; Aldiyarova, Nurgul; Akhmetzhanova, Zauresh; Cesnulis, Evaldas; Akshulakov, Serik

    2016-06-01

    We present a case of fourth ventricle anaplastic ependymoma in a pregnancy which was the first result of three rounds of in vitro fertilization (IVF) and embryo transfer. Whether hormonal treatment can directly or indirectly precipitate brain tumors to develop or become symptomatic is unclear. PMID:27330925

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

    PubMed

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

    2016-07-12

    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

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

    PubMed

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

    2009-12-01

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

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

    PubMed Central

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

    2009-01-01

    Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFRamp), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1ploss19qloss) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFRamp were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with

  12. Anaplastic lymphoma kinase translocation is correlated with anaplastic lymphoma kinase expression and mutually exclusive with epidermal growth factor receptor mutation in Taiwanese non-small cell lung cancer.

    PubMed

    Hsu, Sheng-Chi; Hung, Tsai-Hsien; Wang, Chih-Wei; Ng, Kwai-Fong; Chen, Tse-Ching

    2015-05-01

    The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is an important biomarker for target therapy. The aim of this study is to better understand the clinical and molecular features of the EML4-ALK fusion gene in lung cancer patients in Taiwan and therefore to generate an efficient algorithm for the detection of ALK translocation. In the first cohort, ALK translocation was identified in 1 adenocarcinoma from 100 lung cancer patients by using break apart fluorescent in situ hybridization (FISH). Next, we detected 6 ALK translocations in another 40 EGFR wild type adenocarcinomas but not in 40 cases with EGFR mutation. Histological analysis revealed that solid growth with signet-ring cells or cribriform glands with extracellular mucin were noted in all the 7 ALK translocated cases. One ALK positive cancer with mucinous cribriform pattern had no ALK expression. ALK expression was correlated with ALK translocation (p < 0.001), but not with ALK gene copy number gain (CNG) (P = 0.838). ALK translocation was also mutually exclusive with EGFR mutation in Taiwanese non-small cell lung cancer (P = 0.033). These results indicate that screening tests for EGFR mutation status and/or ALK expression could help efficiently select ALK translocated patients for target therapy. PMID:25708242

  13. 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.

  14. An extraneural primary anaplastic ependymoma at the subcutaneous inguinal region: Report of a rare case.

    PubMed

    Sayar, Hamide; Ersen, Ayca; Kurtul, Neslihan; Yazar, Mehmet Fatih; Balakan, Ozan

    2015-01-01

    Ependymomas commonly arise in the central nervous system. Extraneural presentation is quite rare. Herein, we describe a primary extraneural ependymoma in a young female. The mass was located in the right inguinal area. The cut surface of the 7.5 mm × 6.5 mm × 4.5 mm sized tumor was brownish-yellow in color. Histologically, it was hypercellular exhibiting pseudorosette or rosette formations and some papillary structures. Mitosis was counted as high as 10 per 10 high power fields. Neither necrosis nor vascular endothelial proliferation within the tumor was observed. Tumor cells showed strong glial fibrillary acidic protein immunoreactivity. On epithelial membrane antigen, intracytoplasmic dot-like immunostaining was observed. This is the first report presenting a primary extraneural anaplastic ependymoma arising in the inguinal subcutaneous region. PMID:26549094

  15. Evolution of Renal Cysts to Anaplastic Sarcoma of Kidney in a Child With DICER1 Syndrome.

    PubMed

    Wu, Mona Kay; Goudie, Catherine; Druker, Harriet; Thorner, Paul; Traubici, Jeffrey; Grant, Ronald; Albrecht, Steffen; Weber, Evan; Charles, Adrian; Priest, Jack R; Fabian, Marc Robert; Foulkes, William D

    2016-07-01

    Anaplastic sarcoma of kidney (ASK) is a rare neoplasm recently associated with DICER1 mutations. We report a child with germline DICER1 mutation who developed ASK in preexisting septated renal cysts, which were likely cystic nephroma. From age 2.5 to 6 years, sonographic imaging illustrated changes in the size and number of renal cysts, followed at age 8.8 years by a mass, pathologically an ASK. Lung cysts resected in infancy were diagnosed retrospectively as pleuropulmonary blastoma. Both tumors had acquired somatic DICER1 mutations. Ultrasonographic evolution of renal cysts to ASK has not previously been documented. Children with both pulmonary and renal cysts are candidates for DICER1 mutation testing. PMID:26928971

  16. Imaging findings of anaplastic astrocytoma in a child with maple syrup urine disease: a case report.

    PubMed

    Aw-Zoretic, Jessie; Wadhwani, Nitin R; Lulla, Rishi R; Rishi, Lulla R; Ryan, Maura E

    2015-09-01

    Maple syrup urine disease (MSUD) is an inborn error of branched-chain amino acid metabolism, which usually presents in childhood with encephalopathy due to cerebral edema and dysmyelination. Even with treatment, metabolic stressors may precipitate later episodes of acute decompensation. Changes related to cerebral and white matter edema have been described by magnetic resonance imaging (MRI), and imaging can aid in both initial diagnosis and evaluation of decompensation. To date, there are no published known reports of cancer in patients with MSUD. Here, we present the first case report of an anaplastic astrocytoma in a teenager with MSUD, with a discussion of imaging findings and the use of magnetic resonance spectroscopy (MRS) to help distinguish between tumor and metabolic changes. PMID:26084772

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

    PubMed Central

    Bai, Lei; Sehgal, Amita

    2015-01-01

    Though evidence is mounting that a major function of sleep is to maintain brain plasticity and consolidate memory, little is known about the molecular pathways by which learning and sleep processes intercept. Anaplastic lymphoma kinase (Alk), the gene encoding a tyrosine receptor kinase whose inadvertent activation is the cause of many cancers, is implicated in synapse formation and cognitive functions. In particular, Alk genetically interacts with Neurofibromatosis 1 (Nf1) to regulate growth and associative learning in flies. We show that Alk mutants have increased sleep. Using a targeted RNAi screen we localized the negative effects of Alk on sleep to the mushroom body, a structure important for both sleep and memory. We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk. Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes. PMID:26536237

  18. Acute Hydrocephalus due to Secondary Leptomeningeal Dissemination of an Anaplastic Oligodendroglioma

    PubMed Central

    Stark, Andreas M.; Hugo, Heinz-Herrmann; Mehdorn, H. Maximilian; Knerlich-Lukoschus, Friederike

    2009-01-01

    Secondary leptomeningeal dissemination of oligodendroglioma is very rare. We report the case of a 38-year-old Caucasian male who presented with acute hydrocephalus. 8 months before, the patient had undergone craniotomy for right frontal anaplastic oligodendroglioma, WHO grade III. By that time, there was no evidence of tumor dissemination. MRI now ruled out local tumor progression but revealed meningeal contrast enhancement along the medulla, the myelon, and the cauda equina. Repeated lumbar puncture revealed increased cerebro-spinal fluid (CSF) pressure and protein content. Malignant cells were not detectable. Surgical treatment consisted in (1) placement of an ommaya reservoir for daily CSF puncture, (2) Spinal dural biopsy confirming leptomeningeal oligodendroglioma metastasis, and (3) ventriculo-peritoneal shunt placement after CSF protein has decreased to 1500–2000 mg/l. PMID:20052406

  19. Diagnostic Assays for Identification of Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

    PubMed Central

    Weickhardt, Andrew J.; Aisner, Dara L.; Franklin, Wilbur A.; Varella-Garcia, Marileila; Doebele, Robert C.; Camidge, D. Ross

    2014-01-01

    In series dominated by adenocarcinoma histology, approximately 5% of non–small cell lung cancers (NSCLCs) harbor an anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib, a tyrosine kinase inhibitor with significant activity against ALK, has demonstrated high response rates and prolonged progression-free survival in ALK-positive patients enrolled in phase 1/2 clinical trials. In 2011, crizotinib received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of proven ALK-positive NSCLC using an FDA-approved diagnostic test. Currently, only break-apart fluorescence in situ hybridization testing is FDA approved as a companion diagnostic for crizotinib; however, many other assays are available or in development. In the current review, the authors summarize the diagnostic tests available, or likely to become available, that could be used to identify patients with ALK-positive NSCLC, highlighting the pros and cons of each. PMID:23280244

  20. Anaplastic lymphoma kinase-positive squamous cell carcinoma of the lung: A case report

    PubMed Central

    YAMAMOTO, YOKO; KODAMA, KEN; MANIWA, TOMOHIRO; TAKEDA, MASASHI; KISHIMA, HIROKI

    2016-01-01

    It is widely known that echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement mostly occurs in the adenocarcinoma subtype of non-small-cell lung cancer (NSCLC). Patients with squamous cell carcinoma harboring the ALK rearrangement are extremely rare. This is a case report of a squamous cell carcinoma patient with EML4-ALK rearrangement. An elderly man with a heavy smoking history presented with a mass lesion in the right main bronchus. Bronchoscopic biopsy of the tumor confirmed a diagnosis of squamous cell carcinoma, and it was proven to harbor ALK rearrangement, based on fluorescence in situ hybridization, but not epidermal growth factor receptor mutations. The patient underwent radiation therapy, with a markedly favorable response. ALK-targeted treatment may be a viable option if disease progression occurs in such a case in the future. PMID:27330767

  1. Chemoradiation for anaplastic oligodendrogliomas: clinical outcomes and prognostic value of molecular markers.

    PubMed

    Minniti, Giuseppe; Arcella, Antonella; Scaringi, Claudia; Lanzetta, Gaetano; Di Stefano, Domenica; Scarpino, Stefania; Pace, Andrea; Giangaspero, Felice; Osti, Mattia Falchetto; Enrici, Riccardo Maurizi

    2014-01-01

    Combination of procarbazine, lomustine and vincristine (PCV) with radiation therapy (RT) has been associated with longer survival in patients with anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), especially in those with chromosome 1p/19q codeletion. We report a multicenter retrospective study of 84 consecutive adult patients with AO and AOA treated with RT plus concomitant and adjuvant temozolomide (TMZ) between February 2004 and January 2011. Correlations between chromosome 1p/19q codeletion, isocitrate dehydrogenase1 (IDH1) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. For all 84 patients the median overall survival (OS) and progression-free survival rates were 55.6 and 45.2 months, respectively. Grade 3 or 4 hematological toxicity occurred in 17 % of patients. Chromosome 1p/19q codeletion was detected in 57 %, IDH1 mutation in 63 %, and MGMT promoter methylation in 74 % of evaluable patients. In multivariate analysis the presence of chromosome 1p/19q codeletion was associated with significant survival benefit (median OS 34 months in noncodeleted tumors and not reached in codeleted tumors; HR 0.16, 95 % CI 0.03-0.45; P = 0.005). IDH1 mutation was also of prognostic significance for longer survival (P = 0.001; HR 0.20, 95 % 0.06-0.41), whereas MGMT promoter methylation was only of borderline significance. The study indicates that RT with concomitant and adjuvant TMZ is a relatively safe treatment associated with longer survival in patients with 1p/19q codeleted and IDH1 mutated tumors. Results from ongoing randomized studies will be essential to clarify if RT plus TMZ may provide survival as good as or better than RT combined with PCV for patients with AO and AOA. PMID:24162810

  2. 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.

  3. A pilot study of combined suicide/cytokine gene therapy in two patients with end-stage anaplastic thyroid carcinoma.

    PubMed

    Barzon, Luisa; Pacenti, Monia; Taccaliti, Augusto; Franchin, Elisa; Bruglia, Matteo; Boscaro, Marco; Palù, Giorgio

    2005-05-01

    This study represents the first report of gene therapy for anaplastic thyroid carcinoma, one of the most aggressive solid tumors in humans. Two patients with end-stage anaplastic thyroid carcinoma were treated by direct intratumor injection of retroviral vector producer cells followed by ganciclovir. The retroviral vector carried the human IL-2 gene and the suicide gene thymidine kinase of herpes simplex virus type 1. Treatment was safe and associated with only mild adverse events. Transduction of tumor cells and production of T helper type 1 cytokines was demonstrated in tumor biopsies. Gene therapy led also to a marked increase in T helper type 1 cytokine expression in peripheral blood mononuclear cells. Radiological evaluation of injected tumor masses demonstrated local tumor necrosis. PMID:15713704

  4. Pleomorphic xanthoastrocytoma with anaplastic features: A rare case report and review of literature with reference to current management

    PubMed Central

    Patibandla, M. R.; Nayak, Madhukar; Purohit, A. K.; Thotakura, Amit Kumar; Uppin, Megha; Challa, Sundaram

    2016-01-01

    Pleomorphic xanthoastrocytoma (PXA) is an uncommon tumor constitutes less than 1% of all astrocytic glial neoplasms was first reported in 1979. PXA commonly occurs in young patients and manifests itself first as seizures followed by focal neurological deficits. The role of radiotherapy or chemotherapy has not yet been established because of the relative infrequency of this disease. PXA is classified as grade II tumor in the WHO classification of tumors of the CNS. In literature 9 to 20 % PXA may undergo malignant change at recurrence or may display at the time of initial presentation. Malignant transformation is mainly associated with high mitotic activity and necrosis. The criteria for PXA with anaplastic features was five or more mitotic activity per 10 high power fields, necrosis, microvascular proliferation, marked cellular anaplasia, and high Ki-67 labeling indices. PXA with anaplastic features management is highly controversial as very sparse literature is available. We are reporting a case of PXA with anaplastic features with atypical radiology and tried to review the up to date literature regarding this rare tumor. PMID:27366280

  5. Pleomorphic xanthoastrocytoma with anaplastic features: A rare case report and review of literature with reference to current management.

    PubMed

    Patibandla, M R; Nayak, Madhukar; Purohit, A K; Thotakura, Amit Kumar; Uppin, Megha; Challa, Sundaram

    2016-01-01

    Pleomorphic xanthoastrocytoma (PXA) is an uncommon tumor constitutes less than 1% of all astrocytic glial neoplasms was first reported in 1979. PXA commonly occurs in young patients and manifests itself first as seizures followed by focal neurological deficits. The role of radiotherapy or chemotherapy has not yet been established because of the relative infrequency of this disease. PXA is classified as grade II tumor in the WHO classification of tumors of the CNS. In literature 9 to 20 % PXA may undergo malignant change at recurrence or may display at the time of initial presentation. Malignant transformation is mainly associated with high mitotic activity and necrosis. The criteria for PXA with anaplastic features was five or more mitotic activity per 10 high power fields, necrosis, microvascular proliferation, marked cellular anaplasia, and high Ki-67 labeling indices. PXA with anaplastic features management is highly controversial as very sparse literature is available. We are reporting a case of PXA with anaplastic features with atypical radiology and tried to review the up to date literature regarding this rare tumor. PMID:27366280

  6. Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG 9402

    PubMed Central

    Cairncross, Gregory; Wang, Meihua; Shaw, Edward; Jenkins, Robert; Brachman, David; Buckner, Jan; Fink, Karen; Souhami, Luis; Laperriere, Normand; Curran, Walter; Mehta, Minesh

    2013-01-01

    Purpose Anaplastic oligodendrogliomas, pure (AO) and mixed (anaplastic oligoastrocytoma [AOA]), are chemosensitive, especially if codeleted for 1p/19q, but whether patients live longer after chemoradiotherapy is unknown. Patients and Methods Eligible patients with AO/AOA were randomly assigned to procarbazine, lomustine, and vincristine (PCV) plus radiotherapy (RT) versus RT alone. The primary end point was overall survival (OS). Results Two hundred ninety-one eligible patients were randomly assigned: 148 to PCV plus RT and 143 to RT. For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT v 4.7 years for RT; hazard ratio [HR] = 0.79; 95% CI, 0.60 to 1.04; P = .1). Patients with codeleted tumors lived longer than those with noncodeleted tumors (PCV plus RT: 14.7 v 2.6 years, HR = 0.36, 95% CI, 0.23 to 0.57, P < .001; RT: 7.3 v 2.7 years, HR = 0.40, 95% CI, 0.27 to 0.60, P < .001), and the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT (14.7 v 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = .03). For those with noncodeleted tumors, there was no difference in median survival by treatment arm (2.6 v 2.7 years; HR = 0.85; 95% CI, 0.58 to 1.23; P = .39). In Cox models that included codeletion status, the adjusted OS for all patients was prolonged by PCV plus RT (HR = 0.67; 95% CI, 0.50 to 0.91; P = .01). Conclusion For the subset of patients with 1p/19q codeleted AO/AOA, PCV plus RT may be an especially effective treatment, although this observation was derived from an unplanned analysis. PMID:23071247

  7. 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. PMID:26884249

  8. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients.

    PubMed

    Gambacorti Passerini, Carlo; Farina, Francesca; Stasia, Alessandra; Redaelli, Sara; Ceccon, Monica; Mologni, Luca; Messa, Cristina; Guerra, Luca; Giudici, Giovanni; Sala, Elena; Mussolin, Lara; Deeren, Dries; King, Michael H; Steurer, Michael; Ordemann, Rainer; Cohen, Amos M; Grube, Matthias; Bernard, Lea; Chiriano, Gianpaolo; Antolini, Laura; Piazza, Rocco

    2014-02-01

    Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile. PMID:24491302

  9. 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.

  10. 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

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

    PubMed

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

    2013-05-01

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

  12. Identification of Oncogenic Point Mutations and Hyperphosphorylation of Anaplastic Lymphoma Kinase in Lung Cancer12

    PubMed Central

    Wang, Yi-Wei; Tu, Pang-Hsien; Lin, Kuen-Tyng; Lin, Shu-Chen; Ko, Jenq-Yuh; Jou, Yuh-Shan

    2011-01-01

    The oncogenic property of anaplastic lymphoma kinase (ALK) plays an essential role in the pathogenesis of various cancers and serves as an important therapeutic target. In this study, we identified frequent intragenic loss of heterozygosity and six novel driver mutations within ALK in lung adenocarcinomas. Overexpression of H694R or E1384K mutant ALK leads to hyperphosphorylation of ALK, and activation of its downstream mediators STAT3, AKT, and ERK resulted in enhanced cell proliferation, colony formation, cell migration, and tumor growth in xenograft models. Furthermore, the activated phospho-Y1604 ALK was increasingly detected in 13 human lung cancer cell lines and 263 lung cancer specimens regardless of tumor stages and types. Treatment of two different ALK inhibitors, WHI-P154 and NVP-TAE684, resulted in the down-regulation of aberrant ALK signaling, shrinkage of tumor, and suppression of metastasis and significantly improved survival of ALK mutant-bearing mice. Together, we identified that novel ALK point mutations possessed tumorigenic effects mainly through hyperphosphorylation of Y1604 and activation of downstream oncogenic signaling. The upregulated phospho-Y1604 ALK could serve as a diagnostic biomarker for lung cancer. Furthermore, targeting oncogenic mutant ALKs with inhibitors could be a promising strategy to improve the therapeutic efficacy of fatal lung cancers. PMID:21847362

  13. Significance and evaluation of anaplastic lymphoma kinase by immunohistochemistry in non-small cell lung cancer.

    PubMed

    Ding, Shuting; Liu, Nan; Zhao, Huanyu; Jiang, Guiyang; Zhang, Xiupeng; Wang, Enhua

    2016-08-01

    We used immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) to evaluate anaplastic lymphoma kinase (ALK) protein expression and gene rearrangements, respectively, in 283 cases of wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer biopsy specimens. Immunohistochemistry was positive for ALK in 52 cases (18.4 %), and there was no significant difference in staining between various monoclonal antibodies (Roche ALK test kit, D5F3, p-ALK, and EML4-ALK). On RT-PCR, 36 cases (12.7 %) were positive for ALK. Immunohistochemistry and RT-PCR were both positive in 35 cases and both negative in 230 cases, and both have a high consistency (265/283, 93.6 %). Including 17 cases, immunohistochemistry was positive but RT-PCR was negative, and in one case, immunohistochemistry was negative but RT-PCR was positive. On fluorescence in situ hybridization (FISH) testing of these 18 cases, only three cases were positive (one RT-PCR was positive; two immunohistochemistry were positive). There is a high prevalence of ALK positivity in wild-type EGFR non-small cell lung cancer. Immunohistochemistry for the detection of ALK gene rearrangements was highly consistent with RT-PCR, and thus, it is a good screening tool but produces false positive results that necessitate further screening by RT-PCR or FISH. PMID:26886284

  14. 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

  15. Identification of anaplastic lymphoma kinase as a potential therapeutic target in Basal Cell Carcinoma

    PubMed Central

    Wang, Claire Q.F.; Suárez-Fariñas, Mayte; Gonzalez, Juana; Shah, Kejal R.; Chen, Jie; Coats, Israel; Felsen, Diane; Carucci, John A.; Krueger, James G.

    2013-01-01

    The pathogenesis of BCC is associated with sonic hedgehog (SHH) signaling. Vismodegib, a smoothened inhibitor that targets this pathway, is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. We studied gene expression profiling of BCC tumour tissues coupled with laser capture microdissection to identify tumour specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. We found a >250 fold increase (FDR<10−4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger expression of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 (members of SHH-pathway) mRNA by approximately 60% and 20%, respectively (p<0.01). Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promote keratinocyte proliferation. Hence, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients. PMID:24163262

  16. Chemosensitivity of Anaplastic Thyroid Cancer Based on a Histoculture Drug Response Assay

    PubMed Central

    Uruno, Takashi; Masaki, Chie; Akaishi, Junko; Matsuzu, Kenichi; Suzuki, Akifumi; Ohkuwa, Keiko; Shibuya, Hiroshi; Kitagawa, Wataru; Nagahama, Mitsuji; Sugino, Kiminori; Ito, Koichi

    2015-01-01

    The chemosensitivity of anaplastic thyroid cancer (ATC) to some cytotoxic agents was investigated by the histoculture drug response assay (HDRA). Thirty specimens from 22 patients with ATC were obtained from surgically resected subjects. The drugs tested were paclitaxel (PTX), docetaxel (DOC), adriamycin (ADM), nedaplatin (254-S), cisplatin (CDDP), carboplatin (CBDCA), etoposide (VP-16), 5-fluorouracil (5-FU), mitomycin C (MMC), and cyclophosphamide (CPA). PTX was the most effective agent, and 25 of 29 cases (86.2%) had high inhibition rates (IRs; over 70%), while DOC, another taxane, had lower IRs (median, 32.6%). 254-S had the second highest IR (median 68.1%), higher than other platins, CDDP (median 47.3%) and CBDCA (median 27.4%). The IR of 50% dose PTX (20 μg/mL, median 30.6%) was markedly decreased, while that of 50% dose 254-S (10 μg/mL, median 63.3%) still retained its inhibition effect compared to 100% dose. Most recurrent samples had higher IRs than primary lesions, but the IRs of different drugs differed between primary and recurrent lesions, even with samples from the same patients. PTX has a higher IR to ATC tissues in the HDRA, which suggests that it may be a key drug for the treatment of patients with ATC. PMID:25866510

  17. Chemosensitivity of anaplastic thyroid cancer based on a histoculture drug response assay.

    PubMed

    Uruno, Takashi; Masaki, Chie; Akaishi, Junko; Matsuzu, Kenichi; Suzuki, Akifumi; Ohkuwa, Keiko; Shibuya, Hiroshi; Kitagawa, Wataru; Nagahama, Mitsuji; Sugino, Kiminori; Ito, Koichi

    2015-01-01

    The chemosensitivity of anaplastic thyroid cancer (ATC) to some cytotoxic agents was investigated by the histoculture drug response assay (HDRA). Thirty specimens from 22 patients with ATC were obtained from surgically resected subjects. The drugs tested were paclitaxel (PTX), docetaxel (DOC), adriamycin (ADM), nedaplatin (254-S), cisplatin (CDDP), carboplatin (CBDCA), etoposide (VP-16), 5-fluorouracil (5-FU), mitomycin C (MMC), and cyclophosphamide (CPA). PTX was the most effective agent, and 25 of 29 cases (86.2%) had high inhibition rates (IRs; over 70%), while DOC, another taxane, had lower IRs (median, 32.6%). 254-S had the second highest IR (median 68.1%), higher than other platins, CDDP (median 47.3%) and CBDCA (median 27.4%). The IR of 50% dose PTX (20 μg/mL, median 30.6%) was markedly decreased, while that of 50% dose 254-S (10 μg/mL, median 63.3%) still retained its inhibition effect compared to 100% dose. Most recurrent samples had higher IRs than primary lesions, but the IRs of different drugs differed between primary and recurrent lesions, even with samples from the same patients. PTX has a higher IR to ATC tissues in the HDRA, which suggests that it may be a key drug for the treatment of patients with ATC. PMID:25866510

  18. Late Intervention with anti-BRAFV600E Therapy Induces Tumor Regression in an Orthotopic Mouse Model of Human Anaplastic Thyroid Cancer

    PubMed Central

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

    2012-01-01

    Human anaplastic thyroid cancer (ATC) is a lethal disease with an advanced clinical presentation and median survival of 3 months. The BRAFV600E oncoprotein is a potent transforming factor that causes human thyroid cancer cell progression in vitro and in vivo; therefore, we sought to target this oncoprotein in a late intervention model of ATC in vivo. We used the human ATC cell line 8505c, which harbors the BRAFV600E and TP53R248G mutations. Immunocompromised mice were randomized to receive the selective anti-BRAFV600E inhibitor, PLX4720, or vehicle by oral gavage 28 d after tumor implantation, 1 wk before all animals typically die due to widespread metastatic lung disease and neck compressive symptoms in this model. Mice were euthanized weekly to evaluate tumor volume and metastases. Control mice showed progressive tumor growth and lung metastases by 35 d after tumor implantation. At that time, all control mice had large tumors, were cachectic, and were euthanized due to their tumor-related weight loss. PLX4720-treated mice, however, showed a significant decrease in tumor volume and lung metastases in addition to a reversal of tumor-related weight loss. Mouse survival was extended to 49 d in PLX4720-treated animals. PLX4720 treatment inhibited cell cycle progression from 28 d to 49 d in vivo. PLX4720 induces striking tumor regression and reversal of cachexia in an in vivo model of advanced thyroid cancer that harbors the BRAFV600E mutation. PMID:22202162

  19. Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas-Same Entity or First Cousins?

    PubMed

    Alexandrescu, Sanda; Korshunov, Andrey; Lai, Siang Hui; Dabiri, Salma; Patil, Sushama; Li, Rong; Shih, Chie-Schin; Bonnin, Jose M; Baker, Jonathan A; Du, Emma; Scharnhorst, David W; Samuel, David; Ellison, David W; Perry, Arie

    2016-03-01

    Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved. PMID:26238627

  20. Epigenetic deregulation of the anaplastic lymphoma kinase gene modulates mesenchymal characteristics of oral squamous cell carcinomas

    PubMed Central

    Huang, Tim Hui-Ming

    2013-01-01

    DNA hypermethylation of promoter CpG islands is associated with epigenetic silencing of tumor suppressor genes in oral squamous cell carcinomas (OSCCs). We used a methyl-CpG-binding domain protein capture method coupled with next-generation sequencing (MBDCap-seq) to survey global DNA methylation patterns in OSCCs with and without nodal metastasis and normal mucosa (total n = 58). Of 1462 differentially methylated CpG islands identified in OSCCs relative to normal controls, MBDCap-seq profiling uncovered 359 loci linked to lymph node metastasis. Interactive network analysis revealed a subset of these loci (n = 23), including the anaplastic lymphoma kinase (ALK) gene, are potential regulators and effectors of invasiveness and metastatic progression. Promoter methylation of ALK was preferentially observed in OSCCs without node metastasis, whereas relatively lower methylation levels were present in metastatic tumors, implicating an active state of ALK transcription in the latter group. The OSCC cell line, SCC4, displayed reduced ALK expression that corresponded to extensive promoter CpG island methylation. SCC4 treatment with demethylating agents induced ALK expression and increased invasion and migration characteristics. Inhibition of ALK activity in OSCC cells with high ALK expression (CAL27, HSC3 and SCC25), decreased cell growth and resulted in changes in invasive potential and mesenchymal marker expression that were cell-line dependent. Although ALK is susceptible to epigenetic silencing during oral tumorigenesis, overwriting this default state may be necessary for modulating invasive processes involved in nodal metastases. Given the complex response of OSCC cells to ALK inhibition, future studies are required to assess the feasibility of targeting ALK to treat invasive OSCCs. PMID:23568951

  1. An integrative analysis of treatment, outcomes and prognostic factors for primary spinal anaplastic ependymomas.

    PubMed

    Chen, Peiqin; Sui, Mingxing; Ye, Jingliang; Wan, Zhiping; Chen, Feng; Luo, Chun

    2015-06-01

    The aim of this study was to elucidate the role of treatment modalities in primary spinal anaplastic ependymomas (PSAE) and identify promising prognostic factors. PSAE are rare tumors of the central nervous system with poorly understood clinical characteristics and treatment outcomes. We reviewed the literature in PubMed, Web of Science and Scopus databases to identify patients with PSAE. Multivariate Cox proportional hazards analysis and univariate Kaplan-Meier analysis were performed on the PSAE patients and overall survival (OS) and progression-free survival (PFS) were assessed to evaluate the clinical outcomes. Of the 40 patients with PSAE, the tumors were mostly intramedullary (n=19; 47.5%) and frequently involved the thoracic cord (n=25; 62.5%). Eighteen patients suffered recurrence during the follow-up with a median PFS of 24 months. The 1, 2, and 5year OS rates of the PSAE patients were 91.5%, 82.1%, and 63.1%, respectively. Gross total resection (GTR) was independently associated with prolonged PFS (hazard ratio [HR] 0.11; p=0.004) and OS (HR 0.11; p=0.003) in the multivariate analysis. Adjuvant radiotherapy also conferred improved PFS (HR 0.15; p=0.008) and OS (HR 0.16; p=0.022). Age, sex, tumor location and chemotherapy did not influence the outcomes in this group. The results of our study suggest that GTR and adjuvant radiotherapy are strong prognostic indicators in patients with PSAE and the role of chemotherapy is yet to be defined. PMID:25769252

  2. 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. PMID:25913249

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

    PubMed Central

    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.

    2011-01-01

    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. PMID:21636710

  4. SNP Array Analysis Reveals Novel Genomic Abnormalities Including Copy Neutral Loss of Heterozygosity in Anaplastic Oligodendrogliomas

    PubMed Central

    Idbaih, Ahmed; Ducray, François; Dehais, Caroline; Courdy, Célia; Carpentier, Catherine; de Bernard, Simon; Uro-Coste, Emmanuelle; Mokhtari, Karima; Jouvet, Anne; Honnorat, Jérôme; Chinot, Olivier; Ramirez, Carole; Beauchesne, Patrick; Benouaich-Amiel, Alexandra; Godard, Joël; Eimer, Sandrine; Parker, Fabrice; Lechapt-Zalcman, Emmanuelle; Colin, Philippe; Loussouarn, Delphine; Faillot, Thierry; Dam-Hieu, Phong; Elouadhani-Hamdi, Selma; Bauchet, Luc; Langlois, Olivier; Le Guerinel, Caroline; Fontaine, Denys; Vauleon, Elodie; Menei, Philippe; Fotso, Marie Janette Motsuo; Desenclos, Christine; Verelle, Pierre; Ghiringhelli, François; Noel, Georges; Labrousse, François; Carpentier, Antoine; Dhermain, Frédéric; Delattre, Jean-Yves; Figarella-Branger, Dominique

    2012-01-01

    Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations). To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named “Prise en charge des OLigodendrogliomes Anaplasiques (POLA),” has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively. At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD. Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD. PMID:23071531

  5. 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

  6. Aberrant Expression of Anaplastic Lymphoma Kinase in Ovarian Carcinoma Independent of Gene Rearrangement.

    PubMed

    Tang, Shaoxian; Yang, Fei; Du, Xiang; Lu, Yongming; Zhang, Ling; Zhou, Xiaoyan

    2016-07-01

    Ovarian carcinoma is the leading cause of death from gynecologic malignancies. The oncogenic role of anaplastic lymphoma kinase (ALK) is well characterized in many hematopoietic and solid tumors. ALK expression in ovarian carcinoma has been reported but the exact status of ALK protein and its association with clinicopathologic features requires further investigation. ALK expression was determined by immunohistochemistry in 110 primary ovarian carcinomas, including 85 cases of serous carcinoma and 25 cases of mucinous carcinoma. Fluorescence in situ hybridization (FISH) and real-time reverse transcription polymerase chain reaction (RT-PCR) were used for evaluating ALK translocation in ALK-positive ovarian carcinomas. Among 110 ovarian carcinomas, 23 (20.9%) cases were ALK positive by immunohistochemistry. All ALK-positive cases were ovarian high-grade serous carcinoma. ALK expression was detected in 23/85 (27.1%) ovarian serous carcinoma and 0/25 (0%) in ovarian mucinous carcinoma. None of the 23 ALK IHC-positive cases harbored ALK gene translocations by FISH or RT-PCR. ALK protein expression was associated with patient age, tumor stage, and histologic type. Specifically, the probability of ALK protein expression was significantly higher in high-grade serous carcinomas in older patients (above 50 y) with advanced disease (FIGO stage III and IV) compared with the low-grade serous and mucinous carcinomas in younger patients with relatively early disease. In conclusion, aberrant ALK expression is observed in ovarian serous carcinoma but not in mucinous carcinoma, is independent of gene translocation, and might be associated with progression and prognosis. PMID:27271776

  7. 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

  8. Jelly Belly Trans-Synaptic Signaling to Anaplastic Lymphoma Kinase Regulates Neurotransmission Strength and Synapse Architecture

    PubMed Central

    Rohrbough, Jeffrey; Kent, Karla S.; Broadie, Kendal; Weiss, Joseph B.

    2012-01-01

    In Drosophila the secreted signaling molecule Jelly Belly (Jeb) activates Anaplastic Lymphoma Kinase (Alk), a receptor tyrosine kinase, in multiple developmental and adult contexts. We have shown previously that Jeb and Alk are highly enriched at Drosophila synapses within the CNS neuropil and neuromuscular junction (NMJ) and postulated a conserved intercellular signaling function. At the embryonic and larval NMJ Jeb is localized in the motor neuron presynaptic terminal whereas Alk is concentrated in the muscle postsynaptic domain surrounding boutons, consistent with anterograde trans-synaptic signaling. Here, we show by functional inhibition of Jeb-Alk signaling that neurotransmission is regulated by Jeb secretion. Jeb is a novel negative regulator of neuromuscular transmission. Reduction or inhibtion of Alk function results in enhanced synaptic transmission. Activation of Alk conversely inhibits synaptic transmission. Restoration of wildtype postsynaptic Alk expression in Alk partial loss-of-function mutants rescues NMJ transmission phenotypes and confirms that postsynaptic Alk regulates NMJ transmission. The effects of impaired Alk signaling on neurotransmission are observed in the absence of associated changes in NMJ structure. Complete removal of Jeb in motor neurons, however, disrupts both presynaptic bouton architecture and postsynaptic differentiation. Non-physiologic activation of Alk signaling also negatively regulates NMJ growth. Activation of Jeb-Alk signaling triggers the Ras-MAP kinase cascade in both pre- and postsynaptic compartments. These novel roles for Jeb-Alk signaling in the modulation of synaptic function and structure have potential implications for recently reported Alk functions in human addiction, retention of spatial memory, cognitive dysfunction in neurofibromatosis and the pathogenesis of amyotrophic lateral sclerosis. PMID:22949158

  9. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing

    PubMed Central

    Kunstman, John W.; Juhlin, C. Christofer; Goh, Gerald; Brown, Taylor C.; Stenman, Adam; Healy, James M.; Rubinstein, Jill C.; Choi, Murim; Kiss, Nimrod; Nelson-Williams, Carol; Mane, Shrikant; Rimm, David L.; Prasad, Manju L.; Höög, Anders; Zedenius, Jan; Larsson, Catharina; Korah, Reju; Lifton, Richard P.; Carling, Tobias

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention. PMID:25576899

  10. Is ALK-gene rearrangement overlooked in primary gastrointestinal T-cell lymphomas? About two cases.

    PubMed

    Mneimneh, Wadad S; Vyas, Shikhar Gautam; Cheng, Liang; Cummings, Oscar W; Czader, Magdalena

    2015-12-01

    A 41-year-old male patient with a history of ankylosing spondylitis and Crohn disease, treated with immunomodulators and disease-modifying drugs, was diagnosed with a primary intestinal T-cell lymphoma that followed a 7.5-year-course. This transmural proliferation lacked cytological characteristics of anaplastic large cell lymphoma (ALCL), and was CD8-positive, and CD30- and anaplastic lymphoma kinase (ALK)-negative by immunohistochemistry (IHC). However, ALK-gene rearrangement (ALK-gr) was detected by fluorescence in situ hybridization (FISH) in both initial and persistent disease. The possibility of indolent T-cell lymphoproliferative disease of the gastrointestinal tract with atypical features (transmural involvement) related to ALK-gr was suggested. A previous case of aggressive 'enteropathy-associated ALCL' in the context of celiac disease was recently reported, which also lacked anaplastic morphology, and where CD30 and ALK expression was incidentally demonstrated by IHC, and ALK-gr subsequently confirmed by FISH. These two recent cases represent two distinct rare entities pertaining to the group of primary intestinal T-cell lymphomas, and they both show unexpected ALK-gr. This suggests that ALK-gr has been overlooked in the group of primary intestinal T-cell lymphomas. Performing IHC and FISH tests for ALK-gr in primary gastrointestinal T-cell lymphomas might be of importance, particularly with the advancement of targeted therapy that could impact treatment and prognosis. PMID:26531107

  11. Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK).

    PubMed

    Ott, Gregory R; Cheng, Mangeng; Learn, Keith S; Wagner, Jason; Gingrich, Diane E; Lisko, Joseph G; Curry, Matthew; Mesaros, Eugen F; Ghose, Arup K; Quail, Matthew R; Wan, Weihua; Lu, Lihui; Dobrzanski, Pawel; Albom, Mark S; Angeles, Thelma S; Wells-Knecht, Kevin; Huang, Zeqi; Aimone, Lisa D; Bruckheimer, Elizabeth; Anderson, Nathan; Friedman, Jay; Fernandez, Sandra V; Ator, Mark A; Ruggeri, Bruce A; Dorsey, Bruce D

    2016-08-25

    Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein. PMID:27527804

  12. Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study.

    PubMed

    Williams, Denise; Mori, Tetsuya; Reiter, Alfred; Woessman, Wilhelm; Rosolen, Angelo; Wrobel, Grazyna; Zsiros, Jozsef; Uyttebroeck, Anne; Marky, Ildiko; Le Deley, Marie-Cécile; Brugières, Laurence

    2013-10-01

    In an international study of systemic childhood ALCL, 12/463 patients had CNS involvement, three of which had isolated CNS disease. Comparative analysis of CNS positive and negative patients showed no difference in ALK positivity, immunophenotype, presence of B symptoms or other sites of disease. The lymphohistiocytic variant was over represented in the CNS positive group (36% vs. 5%). With multi-agent chemotherapy, including high dose methotrexate, Ara-C and intrathecal treatment, the event free and overall survival of the CNS positive group at 5 years were 50% (95%CI, 25-75%) and 74% (45-91%), respectively with a median follow up of 4.1 years. PMID:23720354

  13. Breast implant-associated anaplastic large cell lymphoma: a systematic review of the literature and mini-meta analysis.

    PubMed

    Thompson, Philip A; Prince, H Miles

    2013-09-01

    Breast implant-associated ALCL (BIA-ALCL) is a rare, but likely under-reported entity, which most commonly presents with an effusion developing between the breast implant and the host fibrous capsule that surrounds it. It has been described in association with breast implants used for post-cancer reconstructive surgery and when implanted for purely cosmetic reasons. Two different presentations are seen; presentation with an effusion alone +/- co-existing capsular contracture, without an associated mass, and presentation with a mass lesion +/- an effusion. These two presentations are associated with very different outcomes, with women presenting with effusion alone having an excellent long-term survival, even in the absence of specific therapy other than implant removal. In these women, no further therapy other than implant removal is likely necessary. In contrast, women presenting with a mass lesion have a higher rate of relapse and may require more aggressive therapy. PMID:23765424

  14. 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. PMID:26488903

  15. Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors

    PubMed Central

    Dima, Mariavittoria; Kang, Kristy S.; Dasrath, Florence; Liao, Xiao-Hui; Refetoff, Samuel; Montagna, Cristina; Di Cristofano, Antonio

    2011-01-01

    Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr−/− tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients. PMID:22190384

  16. A North American brain tumor consortium phase II study of poly-ICLC for adult patients with recurrent anaplastic gliomas.

    PubMed

    Butowski, Nicholas; Lamborn, Kathleen R; Lee, Bee L; Prados, Michael D; Cloughesy, Timothy; DeAngelis, Lisa M; Abrey, Lauren; Fink, Karen; Lieberman, Frank; Mehta, Minesh; Ian Robins, H; Junck, Larry; Salazar, Andres M; Chang, Susan M

    2009-01-01

    This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Fifty five patients were enrolled in the study. Ten were ineligible after central review of pathology. Eleven percent of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide. PMID:18850068

  17. A North American brain tumor consortium phase II study of Poly-ICLC for adult patients with recurrent anaplastic gliomas

    PubMed Central

    Butowski, Nicholas; Lamborn, Kathleen R.; Lee, Bee L; Prados, Michael D.; Cloughesy, Timothy; DeAngelis, Lisa M.; Abrey, Lauren; Fink, Karen; Lieberman, Frank; Mehta, Minesh; Robins, H. Ian; Junck, Larry; Salazar, Andres M.; Chang, Susan M.

    2011-01-01

    Purpose This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). Methods and Materials This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Results 55 patients were enrolled in the study. 10 were ineligible after central review of pathology. 11% of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Conclusions Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide. PMID:18850068

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

    PubMed

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

    2015-02-01

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

  19. 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. Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer.

    PubMed

    Landi, Lorenza; Cappuzzo, Federico

    2016-02-01

    Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting. PMID:26582431

  1. Successful palliative approach with high-intensity focused ultrasound in a patient with metastatic anaplastic pancreatic carcinoma: a case report

    PubMed Central

    Ungaro, Antonio; Orsi, Franco; Casadio, Chiara; Galdy, Salvatore; Spada, Francesca; Cella, Chiara Alessandra; Tonno, Clementina Di; Bonomo, Guido; Vigna, Paolo Della; Murgioni, Sabina; Frezza, Anna Maria; Fazio, Nicola

    2016-01-01

    We report a case of a 74-year-old man with a metastatic anaplastic pancreatic carcinoma (APC). After an early tumour progression on first-line chemotherapy with cisplatin and gemcitabine, even though it was badly tolerated, he was treated with a combination of systemic modified FOLFIRI and high-intensity focused ultrasound (HIFU) on the pancreatic mass. A tumour showing partial response with a clinical benefit was obtained. HIFU was preferred to radiotherapy because of its shorter course and minimal side effects, in order to improve the patient’s clinical conditions. The patient is currently on chemotherapy, asymptomatic with a good performance status. In referral centres, with specific expertise, HIFU could be safely and successfully combined with systemic chemotherapy for treatment of metastatic pancreatic carcinoma. PMID:27170835

  2. Successful palliative approach with high-intensity focused ultrasound in a patient with metastatic anaplastic pancreatic carcinoma: a case report.

    PubMed

    Ungaro, Antonio; Orsi, Franco; Casadio, Chiara; Galdy, Salvatore; Spada, Francesca; Cella, Chiara Alessandra; Tonno, Clementina Di; Bonomo, Guido; Vigna, Paolo Della; Murgioni, Sabina; Frezza, Anna Maria; Fazio, Nicola

    2016-01-01

    We report a case of a 74-year-old man with a metastatic anaplastic pancreatic carcinoma (APC). After an early tumour progression on first-line chemotherapy with cisplatin and gemcitabine, even though it was badly tolerated, he was treated with a combination of systemic modified FOLFIRI and high-intensity focused ultrasound (HIFU) on the pancreatic mass. A tumour showing partial response with a clinical benefit was obtained. HIFU was preferred to radiotherapy because of its shorter course and minimal side effects, in order to improve the patient's clinical conditions. The patient is currently on chemotherapy, asymptomatic with a good performance status. In referral centres, with specific expertise, HIFU could be safely and successfully combined with systemic chemotherapy for treatment of metastatic pancreatic carcinoma. PMID:27170835

  3. Alectinib-Induced Alopecia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

    PubMed Central

    Koizumi, Tomonobu; Fukushima, Toshirou; Gomi, Daisuke; Kobayashi, Takashi; Sekiguchi, Nodoka; Sakamoto, Akiyuki; Sasaki, Shigeru; Mamiya, Keiko

    2016-01-01

    Alectinib, a novel alternative anaplastic lymphoma kinase (ALK) inhibitor, is highly effective against ALK-positive non-small cell lung cancer (NSCLC) and is well tolerated. Molecular targeted agents generally have little contribution to alopecia. We encountered a case of alopecia that developed gradually over 2 months after initiation of alectinib administration for the treatment of ALK-positive NSCLC. The patient had no history of alopecia in previous treatments of cisplatin + pemetrexed and crizotinib. The present case indicates that alopecia should be taken into consideration as toxicity during alectinib treatment, which could adversely affect the psychological and emotional condition and quality of life even in patients treated with specific molecular targeted agents. PMID:27194980

  4. The hsp70 inhibitor VER155008 induces paraptosis requiring de novo protein synthesis 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

    2014-11-01

    In this study, we evaluated the effect of the hsp70 inhibitor VER155008 on survival of anaplastic thyroid carcinoma (ATC) cells. In ATC cells, VER155008 increased the percentages of dead cells and vacuolated cells. VER155008 did not lead to the cleavage of caspase-3 protein regardless of pretreatment with z-VAD-fmk. VER155008 increased LC3-II protein levels but the protein levels were not changed by autophagy inhibitors. VER155008 caused the dilatation of endoplasmic reticulum (ER), and the increased mRNA levels of Bip and CHOP, suggesting paraptosis. VER155008-induced paraptosis was attenuated by pretreatment with cycloheximide. In conclusion, VER155008 induces paraptosis characterized by cytoplasmic vacuolation, independence of caspase, dilatation of ER and induction of ER stress markers in ATC cells. Moreover, VER155008-induced paraptosis requires de novo protein synthesis in ATC cells. PMID:25450359

  5. Anaplastic plasmacytomas: relationships to normal memory B cells and plasma cell neoplasms of immunodeficient and autoimmune mice.

    PubMed

    Qi, Chen-Feng; Shin, Dong-Mi; Li, Zhaoyang; Wang, Hongsheng; Feng, Jianxum; Hartley, Janet W; Fredrickson, Torgny N; Kovalchuk, Alexander L; Morse, Herbert C

    2010-05-01

    Anaplastic plasmacytomas (APCTs) from NFS.V(+) congenic mice and pristane-induced plasmacytic PCTs from BALB/c mice were previously shown to be histologically and molecularly distinct subsets of plasma cell neoplasms (PCNs). Here we extended these comparisons, contrasting primary APCTs and PCTs by gene expression profiling in relation to the expression profiles of normal naïve, germinal centre, and memory B cells and plasma cells. We also sequenced immunoglobulin genes from APCT and APCT-derived cell lines and defined surface phenotypes and chromosomal features of the cell lines by flow cytometry and by spectral karyotyping and fluorescence in situ hybridization. The results indicate that APCTs share many features with normal memory cells and the plasma cell-related neoplasms (PLs) of FASL-deficient mice, suggesting that APCTs and PLs are related and that both derive from memory B cells. Published in 2010 by John Wiley & Sons, Ltd. PMID:20217872

  6. 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. PMID:27270301

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

    PubMed

    Weber, Britta; Liu, Mitchell; Sobkin, Paul; Morris, Stephan W; Hout, David; van der Westhuizen, Nicholas; Tonseth, R Petter; Saltman, David L

    2016-03-01

    Local ablative therapy with stereotactic ablative radiotherapy may improve survival in oncogene-addicted lung cancer patients with extracranial oligometastatic disease treated with targeted therapies. There is limited data on the use of radiofrequency ablation (RFA) in this same setting. We present a case of an anaplastic lymphoma kinase (ALK)-positive lung cancer patient with hepatic oligometastatic progression who was successfully treated with both stereotactic ablative radiation and RFA while continuing with an ALK inhibitor. PMID:27087977

  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. IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy.

    PubMed

    Minniti, Giuseppe; Scaringi, Claudia; Arcella, Antonella; Lanzetta, Gaetano; Di Stefano, Domenica; Scarpino, Stefania; Bozzao, Alessandro; Pace, Andrea; Villani, Veronica; Salvati, Maurizio; Esposito, Vincenzo; Giangaspero, Felice; Enrici, Riccardo Maurizi

    2014-06-01

    Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46 months (range 12-89 months), median and 5-year overall survival rates were 50.5 months (95 % CI, 37.8-63.2) and 38% (95 % CI, 25.7-50.7%), and median and 5-year progression-free survival rates were 36 months (95% CI, 28.5-44.0) and 22 % (95 % CI, 10-34%), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60% of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (P = 0.001), MGMT methylation (P = 0.01), age < 50 years (P = 0.02), and extent of resection (P = 0.04) were significantly associated with longer survival. Our study confirms the favorable prognostic value of IDH1 mutation and MGMT methylation in patients with AA treated with RT plus concomitant and adjuvant TMZ. The superiority of combined radiochemotherapy over other treatment modalities remains to be demonstrated. PMID:24748470

  10. Dysphasia and phantosmia as first presentation of multifocal cerebral anaplastic astrocytomas: case report and review of the literatures.

    PubMed

    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

    2015-05-01

    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

  11. Pediatric Radical Abdominal Trachelectomy for Anaplastic Embryonal Rhabdomyosarcoma of the Uterine Cervix: An Alternative to Radical Hysterectomy

    PubMed Central

    Kayton, Mark L.; Wexler, Leonard H.; Lewin, Sharyn N.; Park, Kay J.; La Quaglia, Michael P.; Abu-Rustum, Nadeem R.

    2016-01-01

    Rhabdomyosarcoma arising in the female genital tract carries five-year survival in excess of 80%, but lifelong infertility may be a consequence of local control strategies. We present the technique and outcome for a fertility-sparing, radical abdominal trachelectomy in a 12-year-old girl with anaplastic, embryonal rhabdomyosarcoma involving the uterine cervix. The patient had presented to our center following the piecemeal resection of a uterine cervical mass; because of concern about microscopic residual disease, we classified her as group II-A according to the International Rhabdomyosarcoma Study (IRS) system. Staging studies excluded the presence of distant disease. The patient received four cycles of multiagent chemotherapy and then underwent radical abdominal trachelectomy, with removal of the uterine cervix, parametria, vaginal cuff, and regional lymph nodes. Microscopically, the specimen showed treatment effect and no residual tumor. Regional nodes were negative. Radical abdominal trachelectomy, which has not been previously reported for rhabdomyosarcoma, has appeared to secure local disease control in this case, while preserving the patient’s future fertility potential. In properly selected cases of rhabdomyosarcoma of the uterine cervix, where involvement of the uterus proper is not present, radical abdominal trachelectomy may be an attractive fertility-sparing alternative to radical hysterectomy. PMID:19361657

  12. The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on 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

    2015-04-01

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

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

    PubMed Central

    Wang, Kai; Kim, Sun Young; Jang, Jiryeon; Kim, Seung Tae; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Young Suk; Lee, Jiyun; Lee, Woo Yong; Park, Yoon Ah; Huh, Jung Wook; Yun, Seong Hyeon; Do, In-Gu; Kim, Seok Hyung; Balasubramanian, Sohail; Stephens, Philip J.; Ross, Jeffrey S.; Li, Gang Gary; Hornby, Zachary; Ali, Siraj M.; Miller, Vincent A.; Kim, Kyoung-Mee; Ou, Sai-Hong Ignatius

    2015-01-01

    Purpose Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. Experimental designs Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial. Results Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib. Conclusions ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors. PMID:26172300

  14. 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

  15. 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

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

    PubMed Central

    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.

    2014-01-01

    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. PMID:24993250

  17. 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. PMID:7745436

  18. 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.

  19. A headache presenting in the emergency room, a clinical manifestation of an unfortunate diagnosis (grade III left frontal anaplastic ependymoma with 1p deletion)

    PubMed Central

    Flores-Robles, B J; Hurtarte-Sandoval, A R; Harrison, R M; Cuevas, C C

    2013-01-01

    An 18-year-old girl presented with a headache and behavioural changes. She was found to have a frontal mass. Neuroimaging revealed an intra-axial mass, located at the left frontal cortical/subcortical region approximately 6×7, 5×7, 5 cm (TxApxL), having a heterogeneous density with cysts and calcification. She had total gross excision of the neoplasm. Histopathological examination revealed an anaplastic ependymoma. Fluorescence in situ hybridisation, a molecular cytogenetic test, reported deletion of 1p without deletion of 19q. The patient had a good postoperative improvement. PMID:23912654

  20. Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas.

    PubMed

    Boström, J; Meyer-Puttlitz, B; Wolter, M; Blaschke, B; Weber, R G; Lichter, P; Ichimura, K; Collins, V P; Reifenberger, G

    2001-08-01

    We investigated 67 meningothelial tumors (20 benign meningiomas, 34 atypical meningiomas, and 13 anaplastic meningiomas) for losses of genetic information from chromosome arms 1p and 9p, as well as for deletion, mutation, and expression of the tumor suppressor genes CDKN2A (p16(INKa)/MTS1), p14(ARF), CDKN2B (p15(INK4b)/MTS2) (all located at 9p21) and CDKN2C (1p32). Comparative genomic hybridization and microsatellite analysis showed losses on 1p in 11 anaplastic meningiomas (85%), 23 atypical meningiomas (68%), and 5 benign meningiomas (25%). One atypical meningioma with loss of heterozygosity on 1p carried a somatic CDKN2C mutation (c.202C>T: R68X). Losses on 9p were found in five anaplastic meningiomas (38%), six atypical meningiomas (18%), and one benign meningioma (5%). Six anaplastic meningiomas (46%) and one atypical meningioma (3%) showed homozygous deletions of the CDKN2A, p14(ARF), and CDKN2B genes. Two anaplastic meningiomas carried somatic point mutations in CDKN2A (c.262G>T: E88X and c.262G>A: E88K) and p14(ARF) (c.305G>T: G102V and c.305G>A: G102E). One anaplastic meningioma, three atypical meningiomas, and one benign meningioma without a demonstrated homozygous deletion or mutation of CDKN2A, p14(ARF), or CDKN2B lacked detectable transcripts from at least one of these genes. Hypermethylation of CDKN2A, p14(ARF), and CDKN2B could be demonstrated in one of these cases. Taken together, our results indicate that CDKN2C is rarely altered in meningiomas. However, the majority of anaplastic meningiomas either show homozygous deletions of CDKN2A, p14(ARF), and CDKN2B, mutations in CDKN2A and p14(ARF), or lack of expression of one or more of these genes. Thus, inactivation of the G(1)/S-phase cell-cycle checkpoint is an important aberration in anaplastic meningiomas. PMID:11485924

  1. 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. PMID:23345276

  2. PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in vitro and in vivo model of anaplastic thyroid carcinoma.

    PubMed

    Passaro, Carmela; Volpe, Massimiliano; Botta, Ginevra; Scamardella, Eloise; Perruolo, Giuseppe; Gillespie, David; Libertini, Silvana; Portella, Giuseppe

    2015-01-01

    PARP inhibitors are mostly effective as anticancer drugs in association with DNA damaging agents. We have previously shown that the oncolytic adenovirus dl922-947 induces extensive DNA damage, therefore we hypothesized a synergistic antitumoral effect of the PARP inhibitor olaparib in association with dl922-947. Anaplastic thyroid carcinoma was chosen as model since it is a particularly aggressive tumor and, because of its localized growth, it is suitable for intratumoral treatment with oncolytic viruses. Here, we show that dl922-947 infection induces PARP activation, and we confirm in vitro and in vivo that PARP inhibition increases dl922-947 replication and oncolytic activity. In vitro, the combination with olaparib exacerbates the appearance of cell death markers, such as Annexin V positivity, caspase 3 cleavage, cytochrome C release and propidium iodide permeability. In vivo, we also observed a better viral distribution upon PARP inhibition. Changes in CD31 levels suggest a direct effect of olaparib on tumor vascularization and on the viral distribution within the tumor mass. The observation that PARP inhibition enhances the effects of dl922-947 is highly promising not only for the treatment of anaplastic thyroid carcinoma but, in general, for the treatment of other tumors that could benefit from the use of oncolytic viruses. PMID:25139258

  3. A case of long-term 24-month survival in pancreatic anaplastic carcinoma (giant cell type) after S1 postoperative adjuvant chemotherapy

    PubMed Central

    Nitta, Toshikatsu; Fujii, Kensuke; Kataoka, Jun; Tominaga, Tomo; Kawasaki, Hiroshi; Ishibashi, Takashi

    2016-01-01

    We herein describe the case of a 70-year-old female patient diagnosed with pancreatic carcinoma. An abdominal enhanced computed tomography scan revealed a poorly enhanced mass (17 mm × 15 mm in size) in the pancreatic head. Magnetic resonance cholangiopancreatography revealed stenosis of the main pancreatic and common bile ducts caused by a mass-neighboring cyst. Based on these findings, we performed subtotal stomach-preserving pancreaticoduodenectomy. The patient demonstrated a good postoperative course, and was discharged from our hospital in remission 49 days after the surgery. Pathological findings confirmed that it was anaplastic pancreas carcinoma (giant cell type). After the surgery, we performed S-1 adjuvant chemotherapy 100 mg/day for four weeks, repeated similarly every six weeks for a total of four courses. We have followed this case for over 2 years so far with adjuvant chemotherapy, and no recurrence or metastasis has been revealed. Adjuvant chemotherapy with S-1 in patients with resected anaplastic carcinoma of the pancreas is also recommended as a result of Japan Adjuvant Study Group of Pancreatic Cancer 01(JASPAC-01) like the ordinary pancreatic ductal carcinomas. There is a possibility to achieve long-term survival in cases in which multidisciplinary treatment such as a curative resection and adjuvant chemotherapy are performed. PMID:27111877

  4. Multiple Pluripotent Stem Cell Markers in Human Anaplastic Thyroid Cancer: The Putative Upstream Role of SOX2

    PubMed Central

    Carina, Valeria; Zito, Giovanni; Pizzolanti, Giuseppe; Richiusa, Pierina; Criscimanna, Angela; Rodolico, Vito; Tomasello, Laura; Pitrone, Maria; Arancio, Walter

    2013-01-01

    Background Anaplastic thyroid carcinoma (ATC) is a rare and aggressive endocrine tumor with highly undifferentiated morphology. It has been suggested that cancer stem cells (CSCs) might play a central role in ATC. The objectives of this study were (i) to characterize CSCs from ex vivo ATC specimens by investigating the expression of several pluripotent stem cell markers, and (ii) to evaluate in vitro drug resistance modifications after specific CSC transcription factor switch-off. Methods In ex vivo experiments, eight formalin-fixed, paraffin-embedded ATC specimens were analyzed by reverse-transcription and real-time quantitative PCR and immunohistochemistry. In in vitro experiments using ATC SW1736 cells, the expression levels of OCT-4, NANOG, and ABCG2 and the sensitivity to either cisplatin or doxorubicin were evaluated after silencing. Results OCT-4, KLF4, and SOX2 transcription factors and C-KIT and THY-1 stem surface antigens showed variable up-regulation in all ATC cases. The SW1736 cell line was characterized by a high percentage of stem population (10.4±2.1% of cells were aldehyde dehydrogenase positive) and high expression of several CSC markers (SOX2, OCT4, NANOG, C-MYC, and SSEA4). SOX2 silencing down-regulated OCT-4, NANOG, and ABCG2. SOX2 silencing sensitized SW1736 cells, causing a significant cell death increase (1.8-fold) in comparison to control cells with 10 μM cisplatin (93.9±3.4% vs. 52.6±9.4%, p<0.01) and 2.7 fold with 0.5 μM doxorubicin (45.8±9.9% vs. 17.1±3.4% p<0.01). ABCG2 silencing caused increased cell death with both cisplatin (74.9±1.4%) and doxorubicin treatment (74.1±0.1%) vs. no-target–treated cells (respectively, 45.8±1.0% and 48.6±1.0%, p<0.001). Conclusions : The characterization of CSCs in ATC through the analysis of multiple pluripotent stem cell markers might be useful in identifying cells with a stem-like phenotype capable of resisting conventional chemotherapy. In addition, our data demonstrate that SOX2

  5. 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

  6. Anaplastic thyroid cancer

    MedlinePlus

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

  7. O-GlcNAcylation enhances the invasion of thyroid anaplastic cancer cells partially by PI3K/Akt1 pathway

    PubMed Central

    Zhang, Peng; Wang, Chunli; Ma, Tao; You, Shengyi

    2015-01-01

    Background The PI3K family participates in multiple signaling pathways to regulate cellular functions. PI3K/Akt signaling pathway plays an important role in tumorigenesis and development. O-GlcNAcylation, a posttranslational modification, is thought to modulate a wide range of biological processes, such as transcription, cell growth, signal transduction, and cell motility. O-GlcNAcylation is catalyzed by the nucleocytoplasmic enzymes, OGT and OGA, which adds or removes O-GlcNAc moieties, respectively. Abnormal O-GlcNAcylation has been implicated in a variety of human diseases. However, the role of O-GlcNAcylation in tumorigenesis and progression of cancer is still under-investigated. Understanding the O-GlcNAc-associated molecular mechanism might be significant for diagnosis and therapy of cancer. Methods Human thyroid anaplastic cancer 8305C cells were used to evaluate the role of O-GlcNAcylation in tumorigenesis and progression of cancer. The global O-GlcNAc level of intracellular proteins was up-regulated by OGA inhibitor Thiamet-G treatment or OGT over-expression. Cell proliferation was assessed by MTT assay. Invasion in vitro was determined by Transwell assay, and phosphorylation of Akt1 at Ser473 was assessed by Western blot for activity of Akt1. PI3K-specific inhibitor LY294002 and RNA interference of Akt1 were used to investigate the impact of PI3K/Akt signaling on the regulation of O-GlcNAcylation during tumor progression. Results Cell models with remarkably up-regulated O-GlcNAcylation were constructed, and then cell proliferation and invasion were determined. The results indicated that the proliferation was not affected by OGA inhibition or OGT overexpression, while the invasion of 8305C cells with OGA inhibition or OGT overexpression was obviously increased. Akt1 activity was stimulated by elevated O-GlcNAcylation by mediating phosphorylation at Ser473. The enhanced invasion of thyroid cancer cells by Thiamet-G treatment or OGT overexpression was

  8. Targeting TGF-β1 inhibits invasion of anaplastic thyroid carcinoma cell through SMAD2-dependent S100A4-MMP-2/9 signalling

    PubMed Central

    Zhang, Kejun; Liu, Xiaoli; Hao, Fengyun; Dong, Anbing; Chen, Dong

    2016-01-01

    Objective: Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. However, the molecular mechanisms of ATC invasion are poorly understood. The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in promoting tumor metastasis. TGF-β1 was found to be overexpressed in anaplastic thyroid cancer (ATC). We therefore tested our hypothesis that targeted down-regulation of TGF-β1 inhibits invasion of ATC cells. Methods: Effects of TGF-β1 stimulation or TGF-β1 sliencing by small interfering RNA (TGF-β1 siRNA) on invasion in 8505C and SW1736 cells in vitro was detected. Using siRNAs and inhibitors to examine the TGF-β1 signaling pathway. Results: TGF-β1 siRNA inhibits cell migration and invasion in vitro, followed by inactivation of pSMAD2, S100A4 and MMP-2/9. TGF-β stimulation activated pSMAD2-dependent S100A4 and MMP-2/9 expression, and increased cell migration and invasion. The depletion of pSMAD2 or S100A4 or MMP-2/9 expression inhibited TGF-β signaling pathway. Moreover, it significantly weakened the proinvasive effects of TGF-β on ATC cells. Conclusions: Therapies targeting the TGF-β1 inhibits invasion of ATC cells by impeding the SMAD2-dependent S100A4-MMP-2/9 signalling in vitro. PMID:27347327

  9. Detection of rearrangement of anaplastic lymphoma kinase (ALK) and mutation of epidermal growth factor receptor (EGFR) in primary pulmonary lymphoepithelioma-like carcinoma

    PubMed Central

    Wang, Liang; Lin, Yongbin; Cai, Qingqing; Long, Hao; Zhang, Yu; Rong, Tiehua

    2015-01-01

    Background Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a distinct rare subtype of lung cancer. The prevalence of anaplastic lymphoma kinase (ALK) rearrangement and epidermal growth factor receptor (EGFR) mutation in primary pulmonary LELC had not been thoroughly investigated. Methods We investigated a cohort of 42 patients with primary pulmonary LELC and genotyped for ALK rearrangement and EGFR mutation. ALK rearrangement was detected by fluorescence in situ hybridization (FISH). EGFR mutational analysis of exons 18 through 21 was analyzed by TaqMan real-time polymerase chain reaction (PCR). Results Epstein-Barr virus-encoded RNAs (EBERs) showed positive signals in all 42 patients. By immunohistochemistry staining, all patients demonstrated positive expression of CK5/6 and P63, but almost all patients were negative for TTF-1 (34/34, 100%) or CK7 (34/35, 97.1%). None of the 42 patients had ALK rearrangement. Of 42 patients tested, only one patient (2.4%) harbored L858R mutation and gefitinib was applied to this case, however no objective response was observed and the progression free survival (PFS) time was only 1 month. Conclusions Primary pulmonary LELC is a unique histological subtype of lung cancer. ALK rearrangement and EGFR mutation are lack and they may not be the oncogenic driver gene in pulmonary LELC. Future efforts should be made to explore other oncogenic driver gene to guide targeted therapy in this rare disease to determine the optimal treatment. Keywords Pulmonary lymphoepithelioma-like carcinoma (LELC); anaplastic lymphoma kinase (ALK); epidermal growth factor receptor (EGFR); targeted therapy; Epstein-Barr virus (EBV) PMID:26543602

  10. Primary CNS T-cell Lymphomas: A Clinical, Morphologic, Immunophenotypic, and Molecular Analysis.

    PubMed

    Menon, Madhu P; Nicolae, Alina; Meeker, Hillary; Raffeld, Mark; Xi, Liqiang; Jegalian, Armin G; Miller, Douglas C; Pittaluga, Stefania; Jaffe, Elaine S

    2015-12-01

    Primary central nervous system (CNS) lymphomas are relatively rare with the most common subtype being diffuse large B-cell lymphoma. Primary CNS T-cell lymphomas (PCNSTL) account for <5% of CNS lymphomas. We report the clinical, morphologic, immunophenotypic, and molecular characteristics of 18 PCNSTLs. Fifteen cases were classified as peripheral T-cell lymphoma, not otherwise specified, 2 of which were of γδ T-cell derivation and 1 was TCR silent; there was 1 anaplastic large cell lymphoma, ALK-positive and 2 anaplastic large cell lymphoma, ALK-negative. Median age was 58.5 years (range, 21 to 81 y), with an M:F ratio of 11:7. Imaging results showed that 15 patients had supratentorial lesions. Regardless of subtype, necrosis and perivascular cuffing of tumor cells were frequently observed (11/18 cases). CD3 was positive in all cases but 1; 10/17 were CD8-positive, and 5/17 were CD4-positive. Most cases studied had a cytotoxic phenotype with expression of TIA1 (13/15) and granzyme-B (9/13). Polymerase chain reaction analysis of T-cell receptor γ rearrangement confirmed a T-cell clone in 14 cases with adequate DNA quality. Next-generation sequencing showed somatic mutations in 36% of cases studied; 2 had >1 mutation, and none showed overlapping mutations. These included mutations in DNMT3A, KRAS, JAK3, STAT3, STAT5B, GNB1, and TET2 genes, genes implicated previously in other T-cell neoplasms. The outcome was heterogenous; 2 patients are alive without disease, 4 are alive with disease, and 6 died of disease. In conclusion, PCNSTLs are histologically and genomically heterogenous with frequent phenotypic aberrancy and a cytotoxic phenotype in most cases. PMID:26379152

  11. Upregulated Neuro-oncological Ventral Antigen 1 (NOVA1) Expression Is Specific to Mature and Immature T- and NK-Cell Lymphomas

    PubMed Central

    Kim, Eun Kyung; Yoon, Sun Och; Kim, Soo Hee; Yang, Woo Ick; Cho, Yoon Ah; Kim, Soo Jeong

    2016-01-01

    Background: Recent studies have revealed that the splicing factor neuro-oncological ventral antigen 1 (NOVA1) is enriched in fibroblasts and accumulated T cells of tertiary lymphoid structures. In the present study, we investigated NOVA1 expression in various subtypes of mature and immature T- and natural killer (NK)-cell lymphomas as well as in various B-cell lymphoma subtypes. Methods: NOVA1 immunoexpression was evaluated in hyperplastic palatine tonsils (n = 20), T- and NK-cell lymphomas (n = 177), diffuse large B-cell lymphomas (n = 151), and other types of B cell lymphomas (n = 31). Nuclear staining intensity and percentage of positive tumor cells were graded. NOVA1 mRNA expression was analyzed in various lymphoma cell lines. Results: Tumor cells of T- and NK-cell lymphomas showed higher expression levels of NOVA1 than did normal paracortical T cells, and 56.5% of T- and NK-cell lymphoma cases showed diffuse and strong expression. The NOVA1 expression level varied according to the subtype; it was higher in angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL), and T lymphoblastic leukemia/lymphoma (T-LBL), but it was lower in ALK-positive ALCL. In almost all B-cell lymphomas, NOVA1 expression was very low or negative. NOVA1 mRNA was also expressed in Jurkat, a T-LBL cell line. Conclusions: The present findings suggest that NOVA1 upregulation may be involved in certain subtypes of T- and NK-cell lymphomas, but not in B-cell lymphomas. Upregulated NOVA1 expression seems to be a specific biological feature of activated T cells such as T- and NK-cell lymphomas. PMID:26922803

  12. Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study.

    PubMed

    Ahluwalia, Manmeet S; Xie, Hao; Dahiya, Saurabh; Hashemi-Sadraei, Nooshin; Schiff, David; Fisher, Paul G; Chamberlain, Marc C; Pannullo, Susan; Newton, Herbert B; Brewer, Cathy; Wood, Laura; Prayson, Richard; Elson, Paul; Peereboom, David M

    2015-03-01

    Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors. PMID:25534576

  13. Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer

    PubMed Central

    Zhang, Lisa; Zhang, Yaqin; Mehta, Amit; Boufraqech, Myriem; Davis, Sean; Wang, Jing; Tian, Ze; Yu, Zhiya; Boxer, Matthew B.; Kiefer, Jeffrey A.; Copland, John A.; Smallridge, Robert C.; Li, Zhuyin; Shen, Min; Kebebew, Electron

    2015-01-01

    Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC. PMID:25940539

  14. Successful oral desensitization against skin rash induced by alectinib in a patient with anaplastic lymphoma kinase-positive lung adenocarcinoma: A case report.

    PubMed

    Shirasawa, Masayuki; Kubotaa, Masaru; Harada, Shinya; Niwa, Hideyuki; Kusuhara, Seiichiro; Kasajima, Masashi; Hiyoshi, Yasuhiro; Ishihara, Mikiko; Igawa, Satoshi; Masuda, Noriyuki

    2016-09-01

    Alectinib has been approved for the treatment of patients with anaplastic lymphoma kinase (ALK) gene rearrangement-positive advanced non-small cell lung cancer. In terms of adverse effects, the occurrence of a severe skin rash induced by alectinib is reportedly rare, compared with the occurrence of skin rash induced by epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). In the present case report, a 76-year-old woman with ALK-positive lung adenocarcinoma experienced disease progression after undergoing first-line chemotherapy. Subsequently, alectinib was administered as a second-line therapy. However, she discontinued alectinib therapy after 11days because of the occurrence of an alectinib-induced skin rash. Since the skin rash improved within one week, we attempted to perform oral desensitization to alectinib. The patient has not shown any recurrence of the rash or disease progression for 7 months since the successful oral desensitization to alectinib. Here, we describe the first case of successful oral desensitization against a skin rash induced by alectinib in a patient with ALK-positive lung adenocarcinoma. Desensitization to overcome adverse effects and to enable sustained treatment with alectinib should be considered in patients who develop alectinib sensitivities. PMID:27565916

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

    PubMed Central

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

    2014-01-01

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

  16. 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

  17. The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of 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

    2016-02-01

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

  18. 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. © 2015 Wiley Periodicals, Inc. PMID:25773758

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

    PubMed

    Yoshida, Tatsuya; Hida, Toyoaki; Yatabe, Yasushi

    2016-07-01

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

  20. Aberrant expression of anaplastic lymphoma kinase in lung adenocarcinoma: Analysis of circulating free tumor RNA using one-step reverse transcription-polymerase chain reaction.

    PubMed

    Bruno, Rossella; Giordano, Mirella; Giannini, Riccardo; Alì, Greta; Puppo, Gianfranco; Ribechini, Alessandro; Chella, Antonio; Fontanini, Gabriella

    2016-09-01

    Lung adenocarcinoma patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements respond well to approved ALK inhibitors. However, to date, limited evidence is available regarding whether using circulating free tumor mRNA to identify aberrant ALK expression is possible, and its feasibility remains to be clearly addressed. The present study evaluated ALK expression by a one-step reverse transcription‑polymerase chain reaction (PCR) assay on the circulating free tumor mRNA from 12 lung adenocarcinoma patients. Additionally, the present study tested for ALK rearrangements by fluorescence in situ hybridization (FISH) and immunohistochemistry. A molecular genetic characterization was performed on tumor tissues and plasma samples. Aberrant ALK expression was detected in 2/12 patients using mRNA purified from plasma specimens and the results agreed with the FISH and immunohistochemistry findings of solid biopsy samples. The detection of aberrant ALK expression on circulating free tumor RNA may be feasible using a one‑step real‑time PCR assay and may be particularly helpful when a solid biopsy sample is not available. PMID:27430882

  1. Outcomes for patients with anaplastic astrocytoma treated with chemoradiation, radiation therapy alone or radiation therapy followed by chemotherapy: a retrospective review within the era of temozolomide.

    PubMed

    Shonka, Nicole A; Theeler, Brett; Cahill, Daniel; Yung, Alfred; Smith, Lynette; Lei, Xiudong; Gilbert, Mark R

    2013-06-01

    Treatment for anaplastic astrocytoma (AA) is controversial. To assess three primary treatment approaches, patients from a single institution were retrospectively evaluated. To represent modern treatment selection, patients diagnosed with AA from December 2003 to December 2009 were selected. Those with insufficient data, incomplete pathology, and transformation or reclassification to glioblastoma in fewer than 6 months were excluded. A total of 163 patients were included in the final analyses. Median follow-up time was 4.2 years (range 0.5-7.8 years). Median age and Karnofsky performance status at diagnosis were 39.2 years and 90, respectively. 23.6 % of patients underwent biopsy, and 72.2 % underwent resection. Approximately 31 % received concurrent chemoradiation (CRT), 26.1 % had radiation therapy alone (RT), 38.2 % had radiation therapy followed by chemotherapy (RT-C), and 3 % were treated only with chemotherapy. Temozolomide was used almost exclusively during CRT (94.2 %) and adjuvantly. A median of 9.5 cycles of adjuvant chemotherapy was given. The combination of radiation and chemotherapy, either concurrent or sequential trended toward a higher rate of radiation necrosis. Median progression free survival (PFS) favored RT (not reached) over CRT (1.5 years) and RT-C (3.6 years) adjusted for pairwise comparison (p = 0.033, p = 0.050). Median overall survival (OS) was 5.7 years, and did not differ significantly by treatment group. OS for patients with AA did not vary by initial treatment selection. Although the longer PFS in those receiving RT versus CRT may be confounded by pseudoprogression, the equivalent OS among groups supports RT. PMID:23526410

  2. CLM29 and CLM24, pyrazolopyrimidine derivatives, have antitumoral activity in vitro in anaplastic thyroid cancer, with or without BRAF mutation.

    PubMed

    Fallahi, Poupak; Ferrari, Silvia Martina; La Motta, Concettina; Materazzi, Gabriele; Bocci, Guido; Da Settimo, Federico; Miccoli, Paolo; Antonelli, Alessandro

    2016-07-01

    We have studied the antitumor activity of two new "pyrazolo[3,4-d]pyrimidine" compounds (CLM29 and CLM24) that inhibit several targets (including the RET tyrosine kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, with an antiangiogenic effect) in primary anaplastic thyroid cancer (ATC) cell cultures and in the human cell line 8305C (undifferentiated thyroid cancer). The antitumor effect of CLM29 and CLM24 was tested in: nine primary ATC cultures obtained from patients at the time of surgery at the concentrations of 1, 5, 10, 30, 50 µM; in 8305C cells at 1, 5, 10, 30, 50 µM for CLM29, and 0.001, 0.01, 0.1, 1, 10, 100 µM for CLM24. CLM29, and CLM24 significantly inhibited the proliferation of 8305C cells. A significant reduction of proliferation with CLM29 and CLM24 in ATC cells (P < 0.01, for both, ANOVA) was shown. CLM29 and CLM24 increased the percentage of apoptotic ATC cells dose-dependently (P < 0.001, ANOVA). The (V600E) BRAF mutation was observed in three ATCs; the results about the inhibition of proliferation by CLM29 and CLM24, obtained in ATC from tumors with (V600E) BRAF mutation were similar to those from tumors without BRAF mutation. CLM29 inhibited migration and invasion (P < 0.01) of primary ATC cells, while CLM24 had no significant effect. The antitumor activity of two new "pyrazolo[3,4-d]pyrimidine" compounds (CLM24, CLM29) in vitro in ATC, independent from BRAF mutation, has been shown, allowing a future clinical evaluation. PMID:26286966

  3. Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells

    PubMed Central

    Sattu, Kamaraj; Hochgräfe, Falko; Wu, Jianmin; Umapathy, Ganesh; Schönherr, Christina; Ruuth, Kristina; Chand, Damini; Witek, Barbara; Fuchs, James; Li, Pui-Kai; Hugosson, Fredrik; Daly, Roger J; Palmer, Ruth H; Hallberg, Bengt

    2013-01-01

    Activation of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is a key oncogenic mechanism in a growing number of tumor types. In the majority of cases, ALK is activated by fusion with a dimerizing partner protein as a result of chromosomal translocation events, most studied in the case of the nucleophosmin–ALK and echinoderm microtubule-associated protein-like 4–ALK oncoproteins. It is now also appreciated that the full-length ALK receptor can be activated by point mutations and by deletions within the extracellular domain, such as those observed in neuroblastoma. Several studies have employed phosphoproteomics approaches to find substrates of ALK fusion proteins. In this study, we used MS-based phosphotyrosine profiling to characterize phosphotyrosine signaling events associated with the full-length ALK receptor. A number of previously identified and novel targets were identified. One of these, signal transducer and activator of transcription 3 (STAT3), has previously been observed to be activated in response to oncogenic ALK signaling, but the significance of this in signaling from the full-length ALK receptor has not been explored further. We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines. Furthermore, knockdown of STAT3 by RNA interference resulted in a reduction in myelocytomatosis neuroblastom (MYCN) protein levels downstream of ALK signaling. These observations, together with a decreased level of MYCN and inhibition of neuroblastoma cell growth in the presence of STAT3 inhibitors, suggest that activation of STAT3 is important for ALK signaling activity in neuroblastoma. PMID:23889739

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

    PubMed

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

    2016-01-01

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

  5. 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.

  6. 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

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

    2016-01-12

    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

  7. Altered expression of mir-222 and mir-25 influences diverse gene expression changes in transformed normal and anaplastic thyroid cells, and impacts on MEK and TRAIL protein expression

    PubMed Central

    Aherne, Sinéad T.; Smyth, Paul; Freeley, Michael; Smith, Leila; Spillane, Cathy; O'leary, John; Sheils, Orla

    2016-01-01

    Thyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer-related deaths each year. Our group and others have previously demonstrated dysfunctional microRNA (miRNA or miR) expression in the context of thyroid cancer. The objective of the present study was to investigate the impact of synthetic manipulation of expression of miR-25 and miR-222 in benign and malignant thyroid cells. miR-25 and miR-222 expression was upregulated in 8505C (an anaplastic thyroid cell line) and Nthy-ori (a SV40-immortalised thyroid cell line) cells, respectively. A transcriptomics-based approach was utilised to identify targets of the two miRNAs and real-time PCR and western blotting were used to validate a subset of the targets. Almost 100 mRNAs of diverse functions were found to be either directly or indirectly targeted by both miR-222 and miR-25 [fold change ≥2, false discovery rate (FDR) ≤0.05]. Gene ontology analysis showed the miR-25 gene target list to be significantly enriched for genes involved in cell adhesion. Fluidigm real-time PCR technologies were used to validate the downregulation of 23 and 22 genes in response to miR-25 and miR-222 overexpression, respectively. The reduction of the expression of two miR-25 protein targets, TNF-related apoptosis-inducing ligand (TRAIL) and mitogen-activated protein kinase kinase 4 (MEK4), was also validated. Manipulating the expression of both miR-222 and miR-25 influenced diverse gene expression changes in thyroid cells. Increased expression of miR-25 reduced MEK4 and TRAIL protein expression, and cell adhesion and apoptosis are important aspects of miR-25 functioning in thyroid cells. PMID:27353001

  8. 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

  9. MGMT Promoter Methylation Is Prognostic but Not Predictive for Outcome to Adjuvant PCV Chemotherapy in Anaplastic Oligodendroglial Tumors: A Report From EORTC Brain Tumor Group Study 26951

    PubMed Central

    van den Bent, Martin J.; Dubbink, Hendrikus J.; Sanson, Marc; van der Lee-Haarloo, Cathleen R.; Hegi, Monika; Jeuken, Judith W.M.; Ibdaih, Ahmed; Brandes, Alba A.; Taphoorn, Martin J.B.; Frenay, Marc; Lacombe, Denis; Gorlia, Thierry; Dinjens, Winand N.M.; Kros, Johan M.

    2009-01-01

    Purpose O6-methylguanine-methyltransferase (MGMT) promoter methylation has been shown to predict survival of patients with glioblastomas if temozolomide is added to radiotherapy (RT). It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendroglial tumors (AOT). Patients and Methods In the European Organisation for the Research and Treatment of Cancer study 26951, 368 patients with AOT were randomly assigned to either RT alone or to RT followed by adjuvant PCV. From 165 patients of this study, formalin-fixed, paraffin-embedded tumor tissue was available for MGMT promoter methylation analysis. This was investigated with methylation specific multiplex ligation-dependent probe amplification. Results In 152 cases, an MGMT result was obtained, in 121 (80%) cases MGMT promoter methylation was observed. Methylation strongly correlated with combined loss of chromosome 1p and 19q loss (P = .00043). In multivariate analysis, MGMT promoter methylation, 1p/19q codeletion, tumor necrosis, and extent of resection were independent prognostic factors. The prognostic significance of MGMT promoter methylation was equally strong in the RT arm and the RT/PCV arm for both progression-free survival and overall survival. In tumors diagnosed at central pathology review as glioblastoma, no prognostic effect of MGMT promoter methylation was observed. Conclusion In this study, on patients with AOT MGMT promoter methylation was of prognostic significance and did not have predictive significance for outcome to adjuvant PCV chemotherapy. The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with glioblastoma. PMID:19901104

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

    PubMed Central

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

    2014-01-01

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

  11. Anaplastic, plasmablastic, and plasmacytic plasmacytomas of mice: relationships to human plasma cell neoplasms and late-stage differentiation of normal B cells.

    PubMed

    Qi, Chen-Feng; Zhou, Jeff X; Lee, Chang Hoon; Naghashfar, Zohreh; Xiang, Shao; Kovalchuk, Alexander L; Fredrickson, Torgny N; Hartley, Janet W; Roopenian, Derry C; Davidson, Wendy F; Janz, Siegfried; Morse, Herbert C

    2007-03-15

    We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V(+) congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-beta2M(-/-) mice. NFS.V(+) tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V(+) and SJL-beta2M(-/-) mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease. PMID:17363561

  12. 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

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

    PubMed Central

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

    2014-01-01

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

  14. 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

  15. Efficacy of bronchoscopic biopsy for the detection of epidermal growth factor receptor mutations and anaplastic lymphoma kinase gene rearrangement in lung adenocarcinoma

    PubMed Central

    Zhu, Pei; Pan, Qingqing; Wang, Mengzhao; Zhong, Wei; Zhao, Jing

    2015-01-01

    Background To explore the efficacy of bronchoscopic biopsy for the detection of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in lung adenocarcinoma. Methods All patients with bronchoscopic biopsy-proven lung adenocarcinoma at the Peking Union Medical College Hospital from January 2009 to November 2011 were enrolled. Scorpion amplification refractory mutation system (ARMS) was used to detect EGFR gene mutations and fluorescence in situ hybridization (FISH) to detect ALK rearrangement. The correlation of immunohistochemistry (IHC) results with standard methods for EGFR mutation status and ALK rearrangement were checked. Results Bronchoscopic specimens were successfully used to detect EGFR mutation and ALK rearrangement with success rates of 85.2% and 71.3%, respectively, in non-small cell lung cancer patients. EGFR analysis by ARMS yielded a positive result in 35.8% (33/92) and positive ALK rearrangement was detected by FISH in 7.8% (6/77) of cases. It was more likely to be unsuccessful in patients with tumor cells less than 100/high power field and the ratio tumor numbers in 0–10%. In EGFR-IHC, the sensitivity and specificity of E746-A750 deletions were 73.3% (11/15) and 93.3% (70/75), respectively, and those of L858R were 93.3% (14/15) and 93.2% (69/74), respectively. In ALK-IHC, the sensitivity and specificity were 50% (3/6) and 100% (71/71), respectively. Conclusions Small bronchoscopic specimens could achieve higher successful detection rates via EGFR mutation and ALK gene rearrangement. PMID:26557908

  16. Clinical effect of pemetrexed as the first‐line treatment in Chinese patients with advanced anaplastic lymphoma kinase‐positive non‐small cell lung cancer

    PubMed Central

    Ma, Di; Hao, Xuezhi; Wang, Yan; Xing, Puyuan

    2016-01-01

    Background The efficacy of pemetrexed‐based first‐line chemotherapy in anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC) has been demonstrated in several studies; however, there is a lack of data from Chinese populations. Methods The clinicopathological characteristics and treatment outcomes of 52 patients with ALK‐positive advanced NSCLC who received pemetrexed as first‐line chemotherapy at the Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences were retrospectively reviewed. The primary end points were response rate and progression‐free survival (PFS). Results The gender proportion was balanced and the median age was 51 years (range 26–76). Of the 52 patients, 46 (88.5%) had stage IV disease, predominantly adenocarcinoma (98.1%). Sixteen patients were current/former smokers and 36 were never/light smokers. The most common sites of metastasis were the pleura (36.5%), bone (30.8%), lung (26.9%), and brain (17.3%). The median PFS was 9.5 months (95% confidence interval 7.454–11.536). At the time of analysis, partial remission was achieved in 18 (34.6%) patients, stable disease in 26 (50.0%), and progressive disease in eight (15.4%); none of the patients achieved complete remission. The objective response rate was 34.6% and the disease control rate was 84.6%. Common adverse events with pemetrexed were neutropenia (53.8%), nausea and vomiting (51.9%), leukopenia (32.7%), and fatigue (25.0%), mainly at grades 1 or 2. Conclusions Pemetrexed is efficient and tolerated as first‐line treatment for ALK‐positive NSCLC in a cohort of Chinese patients and may prove to be an alternative option for the treatment of ALK‐positive NSCLC. PMID:27385988

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

    ClinicalTrials.gov

    2016-07-14

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

  18. Native and rearranged ALK copy number and rearranged cell count in NSCLC: Implications for ALK inhibitor therapy

    PubMed Central

    Camidge, D. Ross; Skokan, Margaret; Kiatsimkul, Porntip; Helfrich, Barbara; Lu, Xian; Barón, Anna E.; Schulte, Nathan; Maxson, DeLee; Aisner, Dara L.; Franklin, Wilbur A.; Doebele, Robert C.; Varella-Garcia, Marileila

    2013-01-01

    Background Anaplastic Lymphoma Kinase positive (ALK+) non-small cell lung cancer (NSCLC) responds to ALK inhibitors. Clinically, ≥ 15% cells showing rearrangements by break-apart FISH classify tumors as positive. Increases in native and rearranged ALK copy number also occur. Methods 1426 NSCLC clinical specimens (174 ALK+ and 1252 ALK negative), and 24 ALK negative NSCLC cell lines were investigated. ALK copy number and genomic status were assessed by FISH. Results Clinical specimens with 0–9%, 10–15%, 16–30%, 31–50% and >50% of ALK+ cells were found in 79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Increased native ALK copy number (≥3 copies/cell in ≥40% cells) was detected in 19% of ALK+ and 62% of ALK negative tumors. In ALK negative tumors, abundant focal amplification of native ALK was rare (0.8%). Other atypical patterns occurred in ~6% of tumors. Mean native ALK copy number ranged from 2.1–6.9 in cell lines and was not correlated with crizotinib sensitivity (IC50s 0.34–2.8 uM) (r=0.279, p=0.1764). Neither native, nor rearranged ALK copy number, nor percentage cells positive correlated with extra-central nervous system progression free survivalin ALK+ patients on crizotinib. Conclusions 8.5% of cases are below the established positivity threshold by ≤5%. Further investigation of ALK by other diagnostic techniques in such cases may be warranted. Native ALK copy number increases alone are not associated with sensitivity to ALK inhibition in vitro. However, rare complex patterns of increased native ALK in patients should be studied further as atypical rearrangements contained within these may otherwise be missed. PMID:24022839

  19. Preclinical efficacy of the oncolytic measles virus expressing the sodium iodide symporter in iodine non-avid anaplastic thyroid cancer: a novel therapeutic agent allowing noninvasive imaging and radioiodine therapy.

    PubMed

    Reddi, H V; Madde, P; McDonough, S J; Trujillo, M A; Morris, J C; Myers, R M; Peng, K W; Russell, S J; McIver, B; Eberhardt, N L

    2012-09-01

    Anaplastic thyroid cancer is an extremely aggressive disease resistant to radioiodine treatment because of loss of sodium iodide symporter (NIS) expression. To enhance prognosis of this fatal cancer, we validated the preclinical efficacy of measles virus (MV)-NIS, the vaccine strain of the oncolytic MV (MV-Edm), modified to include the NIS gene. Western blotting analysis confirmed that a panel of eight anaplastic thyroid cancer (ATC)-derived cell lines do not express NIS protein, but do express CD46, the MV receptor. In vitro cell death assays and in vivo xenograft studies demonstrate the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines. Radioactive iodine uptake along with single-photon emission computed tomography (SPECT)-computed tomography imaging of KTC-3 xenografts after (99)Tc(m) administration confirmed NIS expression in vitro and in vivo, respectively, after virus treatment. Adjuvant administration of RAI, to MV-NIS-treated KTC-3 tumors showed a trend for increased tumor cell killing. As current treatment for ATC is only palliative, and MV-NIS is currently Food and Drug Administration approved for human clinical trials in myeloma, our data indicate that targeting ATC with MV-NIS could prove to be a novel therapeutic strategy for effective treatment of iodine-resistant ATC and will expedite its testing in clinical trials for this aggressive disease. PMID:22790962

  20. Homozygous deletion of TNFRSF4, TP73, PPAP2B and DPYD at 1p and PDCD5 at 19q identified by multiplex ligation-dependent probe amplification (MLPA) analysis in pediatric anaplastic glioma with questionable oligodendroglial component

    PubMed Central

    2014-01-01

    Background Pediatric oligodendrogliomas are rare and appear to show a different molecular profile from adult tumors. Some gliomas display allelic losses at 1p/19q in pediatric patients, although less frequently than in adult patients, but this is rare in tumors with an oligodendroglial component. The molecular basis of this genomic abnormality is unknown in pediatric gliomas, but it represents a relatively common finding in pediatric oligodendroglioma-like neoplasms with leptomeningeal dissemination. Results Multiplex ligation-dependent probe amplification (MLPA) analysis using SALSA P088-B1 for the analysis of the 1p/19q allelic constitution in a pediatric anaplastic (oligodendro)-glioma showed homozygous co-deletion for markers: TNFRSF4 (located at 1p36.33), TP73 (1p36.32), PPAP2B (1pter-p22.1), DPYD (1p21.3), and PDCD5 (19q13.12), and hemizygous deletion of BAX (19q13.3-q13.4). No sequence changes for R132 and R172 of the IDH1/2 genes were identified. Conclusions The molecular findings in this pediatric anaplastic glioma do not allow for a clearly definitive pathological diagnosis. However, the findings provide data on a number of 1p/19q genomic regions that, because of homozygotic deletion, might be the location of genes that are important for the development and clinical evolution of some malignant gliomas in children. PMID:24387276

  1. CD20-negative diffuse large B-cell lymphomas: biology and emerging therapeutic options.

    PubMed

    Castillo, Jorge J; Chavez, Julio C; Hernandez-Ilizaliturri, Francisco J; Montes-Moreno, Santiago

    2015-06-01

    CD20-negative diffuse large B-cell lymphoma (DLBCL) is a rare and heterogeneous group of lymphoproliferative disorders. Known variants of CD20-negative DLBCL include plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in human herpesvirus 8-associated multicentric Castleman disease and anaplastic lymphoma kinase-positive DLBCL. Given the lack of CD20 expression, atypical cellular morphology and aggressive clinical behavior characterized by chemotherapy resistance and inferior survival rates, CD20-negative DLBCL represents a challenge from the diagnostic and therapeutic perspectives. The goals of the present review are to summarize the current knowledge on the biology of the distinct variants of CD20-negative DLBCL, provide future therapeutic directions based on the limited preclinical and clinical data available, and increase awareness concerning these rare malignancies among pathologists and clinicians. PMID:25641215

  2. Thinking large.

    PubMed

    Devries, Egbert

    2016-05-01

    Egbert Devries was brought up on a farm in the Netherlands and large animal medicine has always been his area of interest. After working in UK practice for 12 years he joined CVS and was soon appointed large animal director with responsibility for building a stronger large animal practice base. PMID:27154956

  3. 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

  4. Peptides derived from the dependence receptor ALK are proapoptotic for ALK-positive tumors

    PubMed Central

    Aubry, A; Galiacy, S; Ceccato, L; Marchand, C; Tricoire, C; Lopez, F; Bremner, R; Racaud-Sultan, C; Monsarrat, B; Malecaze, F; Allouche, M

    2015-01-01

    ALK is a receptor tyrosine kinase with an oncogenic role in various types of human malignancies. Despite constitutive activation of the kinase through gene alterations, such as chromosomal translocation, gene amplification or mutation, treatments with kinase inhibitors invariably lead to the development of resistance. Aiming to develop new tools for ALK targeting, we took advantage of our previous demonstration identifying ALK as a dependence receptor, implying that in the absence of ligand the kinase-inactive ALK triggers or enhances apoptosis. Here, we synthesized peptides mimicking the proapoptotic domain of ALK and investigated their biological effects on tumor cells. We found that an ALK-derived peptide of 36 amino acids (P36) was cytotoxic for ALK-positive anaplastic large-cell lymphoma and neuroblastoma cell lines. In contrast, ALK-negative tumor cells and normal peripheral blood mononuclear cells were insensitive to P36. The cytotoxic effect was due to caspase-dependent apoptosis and required N-myristoylation of the peptide. Two P36-derived shorter peptides as well as a cyclic peptide also induced apoptosis. Surface plasmon resonance and mass spectrometry analysis of P36-interacting proteins from two responsive cell lines, Cost lymphoma and SH-SY5Y neuroblastoma, uncovered partners that could involve p53-dependent signaling and pre-mRNA splicing. Furthermore, siRNA-mediated knockdown of p53 rescued these cells from P36-induced apoptosis. Finally, we observed that a treatment combining P36 with the ALK-specific inhibitor crizotinib resulted in additive cytotoxicity. Therefore, ALK-derived peptides could represent a novel targeted therapy for ALK-positive tumors. PMID:25950466

  5. P17.01CHROMOSOME ARM 9P LOSS OF HETEROZYGOSITY IS A MARKER OF SHORTER SURVIVAL IN 1P/19Q CO-DELETED ANAPLASTIC OLIGODENDROGLIOMA. A POLA NETWORK STUDY

    PubMed Central

    Alentorn, A.; Dehais, C.; Carpentier, C.; Mokhtari, K.; Ducray, F.; Figarella-Branger, D.; Delattre, J.; Idbaih, A.; (POLA)”, POLA Network “Prise en charge des OLigodendrogliomes Anaplasiques

    2014-01-01

    Anaplastic or WHO grade III oligodendrogliomas (AO) are a heterogeneous subgroup of diffuse glial tumors in adults. Three major histomolecular subtypes with clinical relevance have been individualized: (i) 1p/19q co-deleted AO -80% of cases-, (ii) non 1p/19q co-deleted and IDH mutated AO -10% of cases- and (iii) non 1p/19q co-deleted and IDH wild-typeAO -10% of cases-. 1p/19q co-deleted AO, and to a lesser extent IDH mutated AO, have better prognosis and better response to treatment with a median survival of more than 10 years, as shown in two phase III international trials. We have recently shown that loss of heterozygosity (LOH) in chromosome arm 9p, with copy number loss -CL LOH- or without -Copy Neutral LOH- is a frequent event in AO. Interestingly, 9p CN LOH, inducing gene under-expression, has biological significance. In the present study, we address the prognostic value of 9p loss in 1p/19q co-deleted AO. In the present study, 228 AO exhibiting 1p/19q co-deletion were included. All tumors were centrally reviewed in the setting of the French national network for high-grade oligodendroglial tumors (POLA network) that recruits prospectively newly diagnosed anaplastic oligodendroglial tumors. Tumor DNA was analyzed using high-resolution single nucleotide polymorphism array analysis. In the entire series, 70/228 (1/3) harbored 9p loss including CN-LOH, homozygous loss or CL-LOH. 9p loss was associated with a worse prognosis in 1p19q co-deleted AO in univariate analysis (3-years OS of 98% vs. 74%, p < 0.001) whereas PFS at three years was not significantly different (3-years PFS of 88% vs. 66% p = 0.1). After adjustment for age, KPS, and treatment, multivariate analysis demonstrated 9p loss to be an independent prognostic factor for OS, p-value = 0.03, HR = 4.9 [1.2-16], but not for PFS. 1p19q co-deleted AO harboring 9p loss have shorter overall survival compared to their non 9p-lost counterparts in this prospective cohort. Further studies are needed to validate

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

    PubMed Central

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

    2015-01-01

    Stereotactic gamma knife surgery (GKS)-induced brain tumors are extremely rare, and no ependymal tumors induced by GKS have been reported. Therefore, little is known about their clinical, pathologic, and genetic features. In addition, a regimen of adjuvant chemotherapy for anaplastic ependymoma (AE) has not been established. A 77-year-old man presented with a gait disturbance and left-side cerebellar ataxia more than 19 years after GKS performed for a cerebellar arteriovenous malformation. Imaging studies demonstrated an enhancing mass in the irradiated field with signs of intraventricular dissemination. Surgical resection confirmed the diagnosis of AE. Temozolomide (TMZ) was administrated postoperatively because the methylated promoter region of O6-methylguanine-DNA methyltransferase (MGMT) and 1p36 deletion were observed. Surprisingly, images 16 days after TMZ initiation demonstrated a complete resolution of the residual tumor that was maintained after three cycles of TMZ. This first case report of GKS-induced AE emphasizes the importance of genetic evaluation of MGMT and chromosomal deletion of 1p36 that are not commonly performed in primary ependymal tumors. In addition, it is speculated that a GKS-induced tumor may have a different genetic background compared with the primary tumor because the pathogenesis of the tumors differed. PMID:26251808

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

    PubMed

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

    2015-07-01

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

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

    PubMed

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

    2013-05-01

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

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

    PubMed Central

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

    2016-01-01

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

  10. Altered expression of mir-222 and mir-25 influences diverse gene expression changes in transformed normal and anaplastic thyroid cells, and impacts on MEK and TRAIL protein expression.

    PubMed

    Aherne, Sinéad T; Smyth, Paul; Freeley, Michael; Smith, Leila; Spillane, Cathy; O'Leary, John; Sheils, Orla

    2016-08-01

    Thyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer-related deaths each year. Our group and others have previously demonstrated dysfunctional microRNA (miRNA or miR) expression in the context of thyroid cancer. The objective of the present study was to investigate the impact of synthetic manipulation of expression of miR-25 and miR-222 in benign and malignant thyroid cells. miR-25 and miR-222 expression was upregulated in 8505C (an anaplastic thyroid cell line) and Nthy-ori (a SV40-immortalised thyroid cell line) cells, respectively. A transcriptomics-based approach was utilised to identify targets of the two miRNAs and real-time PCR and western blotting were used to validate a subset of the targets. Almost 100 mRNAs of diverse functions were found to be either directly or indirectly targeted by both miR-222 and miR-25 [fold change ≥2, false discovery rate (FDR) ≤0.05]. Gene ontology analysis showed the miR-25 gene target list to be significantly enriched for genes involved in cell adhesion. Fluidigm real-time PCR technologies were used to validate the downregulation of 23 and 22 genes in response to miR-25 and miR-222 overexpression, respectively. The reduction of the expression of two miR-25 protein targets, TNF-related apoptosis‑inducing ligand (TRAIL) and mitogen-activated protein kinase kinase 4 (MEK4), was also validated. Manipulating the expression of both miR-222 and miR-25 influenced diverse gene expression changes in thyroid cells. Increased expression of miR-25 reduced MEK4 and TRAIL protein expression, and cell adhesion and apoptosis are important aspects of miR-25 functioning in thyroid cells. PMID:27353001

  11. Nuclear Localization Signal-Enhanced Polyurethane-Short Branch Polyethylenimine-Mediated Delivery of Let-7a Inhibited Cancer Stem-Like Properties by Targeting the 3'-UTR of HMGA2 in Anaplastic Astrocytoma.

    PubMed

    Yang, Meng-Yin; Chen, Ming-Teh; Huang, Pin-I; Wang, Chien-Ying; Chang, Yun-Chin; Yang, Yi-Ping; Lo, Wen-Liang; Sung, Wen-Hsing; Liao, Yi-Wen; Lee, Yi-Yen; Chang, Yuh-Lih; Tseng, Ling-Ming; Chen, Yi-Wei; Ma, Hsin-I

    2015-01-01

    Anaplastic astrocytoma (AA) is a grade III glioma that often occurs in middle-aged patients and presents a uniformly poor prognosis. A small subpopulation of cancer stem cells (CSCs) possessing a self-renewing capacity is reported to be responsible for tumor recurrence and therapeutic resistance. An accumulating amount of microRNAs (miRNA) were found aberrantly expressed in human cancers and regulate CSCs. Efforts have been made to couple miRNAs with nonviral gene delivery approaches to target specific genes in cancer cells. However, the efficiency of delivery of miRNAs to AA-derived CSCs is still an applicability hurdle. The present study aimed to investigate the effectiveness and applicability of nonviral vector-mediated delivery of Let-7a with regard to eradication of AA and AA-derived CSC cells. Herein, our miRNA/mRNA microarray and RT-PCR analysis showed that the expression of Let-7a, a tumor-suppressive miRNA, is inversely correlated with the levels of HMGA2 and Sox2 in the AA side population (SP(+)) cells. Luciferase reporter assay showed that Let-7a directly targets the 3'-UTRs of HMGA2 in AA-SP(+) cells. Knockdown of HMGA2 significantly suppressed the protein expression of Sox2 in AA-SP(+) cells, whereas overexpression of HMGA2 upregulated Sox2 expression in AA-SP(-). Nuclear localization signal (NLS) peptides can facilitate nuclear targeting of DNA and are used to improve gene delivery. Using polyurethane-short branch polyethylenimine (PU-PEI) as a therapeutic delivery vehicle, we conjugated NLS with Let-7 and successfully delivered it to AA-SP(+) cells, resulting in significantly suppressed expression of HMGA2 and Sox2, tumorigenicity, and CSC-like abilities. This treatment facilitated the differentiation of AA-SP(+) cells into non-SP CSCs. Furthermore, PU-PEI-mediated delivery of NLS-conjugated Let-7a in AA-SP(+) cells suppressed the expression of drug-resistant and antiapoptotic genes, and increased cell sensitivity to radiation. Finally, the in vivo

  12. Large bowel resection - slideshow

    MedlinePlus

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

  13. 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.

  14. Large intestine (colon) (image)

    MedlinePlus

    The large intestine is the portion of the digestive system most responsible for absorption of water from the indigestible ... the ileum (small intestine) passes material into the large intestine at the cecum. Material passes through the ...

  15. 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.

  16. 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.

  17. A large inflammatory myofibroblastic tumor involving both stomach and spleen: A case report and review of the literature

    PubMed Central

    CHEN, WEN-CHAO; JIANG, ZHEN-YU; ZHOU, FAN; WU, ZHENG-RONG; JIANG, GUI-XING; ZHANG, BU-YI; CAO, LI-PING

    2015-01-01

    Inflammatory myofibroblastic tumor (IMT) is a rare, benign neoplasm that most commonly occurs in pediatric patients; it has been described as a pseudosarcomatous proliferation of spindled myofibroblasts mixed with lymphoplasmacytic cells. IMT has been reported in a number of locations throughout the body; however, cases occurring in the gastrointestinal tract are rare and to date, no case involving both the stomach and spleen has been reported. The current study presents a case of an extremely large IMT invading both the stomach and spleen in a 50-year-old female, presenting with a three-month history of left-sided abdominal distension without abdominal pain, fever or vomiting. As the tumor had invaded the stomach and spleen, it was completely excised and concomitantly, the entire stomach and spleen were removed. Histological examination of the biopsy revealed fascicles of spindle cells in a mixed inflammatory background, with inflammatory cells that were immunopositive for vimentin, smooth muscle actin, and negative for anaplastic lymphoma kinase and CD30, confirming the diagnosis of IMT. Four months following local excision of the mass, accompanied by a total gastrectomy and splenectomy, no abdominal distension, abdominal pain, fever or vomiting were observed and no IMT recurrence was identified. PMID:25624905

  18. 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…

  19. 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.

  20. 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...

  1. Large Scale Computing

    NASA Astrophysics Data System (ADS)

    Capiluppi, Paolo

    2005-04-01

    Large Scale Computing is acquiring an important role in the field of data analysis and treatment for many Sciences and also for some Social activities. The present paper discusses the characteristics of Computing when it becomes "Large Scale" and the current state of the art for some particular application needing such a large distributed resources and organization. High Energy Particle Physics (HEP) Experiments are discussed in this respect; in particular the Large Hadron Collider (LHC) Experiments are analyzed. The Computing Models of LHC Experiments represent the current prototype implementation of Large Scale Computing and describe the level of maturity of the possible deployment solutions. Some of the most recent results on the measurements of the performances and functionalities of the LHC Experiments' testing are discussed.

  2. Large bowel resection - discharge

    MedlinePlus

    ... large bowel). You may also have had a colostomy . ... have diarrhea. You may have problems with your colostomy. ... protect it if needed. If you have a colostomy, follow care instructions from your provider. Sitting on ...

  3. 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

  4. 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.

  5. 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 ...

  6. Large pore alumina

    SciTech Connect

    Ternan, M. )

    1994-04-01

    Earlier the authors reported preparation conditions for an alumina material which contained large diameter macropores (0.1-100 [mu]). The preparation variable that caused the formation of the uncommonly large macropores was the large acid/alumina ratios which were very much greater than the ones used in the preparation of conventional porous aluminas. The alumina material had large BET surface areas (200 m[sup 2]/g) and small mercury porosimetry surface areas (1 m[sup 2]/g). This indicated that micropores (d[sub MIP]<2 nm) were present in the alumina, since they were large enough for nitrogen gas molecules to enter, but too small for mercury to enter. As a result they would be too small for significant diffusion rates of residuum molecules. In earlier work, the calcining temperature was fixed at 500[degrees]C. In the current work, variations in both calcining temperature and calcining time were used in an attempt to convert some of the micropores into mesopores. 12 refs., 2 figs., 1 tab.

  7. 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.

  8. Large TV display system

    NASA Technical Reports Server (NTRS)

    Liu, Hua-Kuang (Inventor)

    1986-01-01

    A relatively small and low cost system is provided for projecting a large and bright television image onto a screen. A miniature liquid crystal array is driven by video circuitry to produce a pattern of transparencies in the array corresponding to a television image. Light is directed against the rear surface of the array to illuminate it, while a projection lens lies in front of the array to project the image of the array onto a large screen. Grid lines in the liquid crystal array are eliminated by a spacial filter which comprises a negative of the Fourier transform of the grid.

  9. Large gauged Q balls

    NASA Astrophysics Data System (ADS)

    Anagnostopoulos, K. N.; Axenides, M.; Floratos, E. G.; Tetradis, N.

    2001-12-01

    We study Q balls associated with local U(1) symmetries. Such Q balls are expected to become unstable for large values of their charge because of the repulsion mediated by the gauge force. We consider the possibility that the repulsion is eliminated through the presence in the interior of the Q ball of fermions with charge opposite to that of the scalar condensate. Another possibility is that two scalar condensates of opposite charge form in the interior. We demonstrate that both these scenarios can lead to the existence of classically stable, large, gauged Q balls. We present numerical solutions, as well as an analytical treatment of the ``thin-wall'' limit.

  10. 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…

  11. Large N Cosmology

    NASA Astrophysics Data System (ADS)

    Hawking, S. W.

    2001-09-01

    The large N approximation should hold in cosmology even at the origin of the universe. I use ADS-CFT to calculate the effective action and obtain a cosmological model in which inflation is driven by the trace anomaly. Despite having ghosts, this model can agree with observations.

  12. 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…

  13. 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

  14. 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…

  15. 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…

  16. 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...

  17. 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…

  18. Launching large antennas

    NASA Astrophysics Data System (ADS)

    Brandli, H. W.

    1983-09-01

    Large antennas will provide communication to rural and remote areas in times of need. This is seen as facilitating the work of law enforcement agencies. All mobile radio communications will enjoy advantages in distances covered and information relayed owing to the large number of beams possible from super radio transmitters in space. If the antennas are placed in low-earth orbit, advantages will be realized in the remote sensing of the earth's resources. It is pointed out that with umbrella or bicyclelike antennas turned outward toward space, the universe could be scouted for signals from intelligent life. Various concepts that have been put forward by U.S. companies are described. These include the radial rib, wrap rib, and parabolic erectable truss designs. Others are the mesh hoop column collapsable umbrella made of gold and molybdenum and the maypole design.

  19. Coherent large telescopes

    NASA Astrophysics Data System (ADS)

    Nelson, J. E.

    Present ground-based telescopes are compared with those of the future. The inherent limitations of ground-based telescopes are reviewed, and existing telescopes and their evolution are briefly surveyed in order to see the trends that led to the present period of innovative telescope design. The major telescope types and the critical design factors that must be considered in designing large telescopes for the future are reviewed, emphasizing economicality. As an example, the Ten Meter Telescope project at the University of California is discussed in detail, including the telescope buildings, domes, and apertures, the telescope moving weights, the image quality, and the equipment. Finally, a brief review of current work in progress on large telescopes is given.

  20. Hulls for Large Seaplanes

    NASA Technical Reports Server (NTRS)

    Magaldi, Giulio

    1925-01-01

    In reality, the principle of similitude is not applicable to the hulls, the designing of which increases in difficulty with increasing size of the seaplanes. In order to formulate, at least in a general way, the basic principles of calculation, we must first summarize the essential characteristics of a hull with reference to its gradual enlargement. In this study, we will disregard hulls with wing stubs, as being inapplicable to large seaplanes.

  1. 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.

  2. 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.

  3. Gyrokinetic large eddy simulations

    SciTech Connect

    Morel, P.; Navarro, A. Banon; Albrecht-Marc, M.; Carati, D.; Merz, F.; Goerler, T.; Jenko, F.

    2011-07-15

    The large eddy simulation approach is adapted to the study of plasma microturbulence in a fully three-dimensional gyrokinetic system. Ion temperature gradient driven turbulence is studied with the GENE code for both a standard resolution and a reduced resolution with a model for the sub-grid scale turbulence. A simple dissipative model for representing the effect of the sub-grid scales on the resolved scales is proposed and tested. Once calibrated, the model appears to be able to reproduce most of the features of the free energy spectra for various values of the ion temperature gradient.

  4. Large space structures testing

    NASA Technical Reports Server (NTRS)

    Waites, Henry; Worley, H. Eugene

    1987-01-01

    There is considerable interest in the development of testing concepts and facilities that accurately simulate the pathologies believed to exist in future spacecraft. Both the Government and Industry have participated in the development of facilites over the past several years. The progress and problems associated with the development of the Large Space Structure Test Facility at the Marshall Flight Center are presented. This facility was in existence for a number of years and its utilization has run the gamut from total in-house involvement, third party contractor testing, to the mutual participation of other Government Agencies in joint endeavors.

  5. Large, Bright Wind Ripples

    NASA Technical Reports Server (NTRS)

    2003-01-01

    MGS MOC Release No. MOC2-397, 20 June 2003

    This Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) image shows large, relatively bright ripples of windblown sediment in the Sinus Sabaeus region south of Schiaparelli Basin. The surrounding substrate is thickly mantled by very dark material, possibly windblown silt that settled out of the atmosphere. The picture is located near 7.1oS, 343.7oW. Sunlight illuminates the scene from the left.

  6. Large Windblown Ripples

    NASA Technical Reports Server (NTRS)

    2003-01-01

    MGS MOC Release No. MOC2-519, 20 October 2003

    This April 2003 Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) high resolution image shows a depression in the martian southern cratered highlands near 1.3oS, 244.3oW. The floor of the depression and some nearby craters are covered by large windblown ripples or small sand dunes. This image of ancient martian terrain covers an area 3 km (1.9 mi) across and is illuminated by sunlight from the upper left.

  7. 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.

  8. 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.

  9. 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.

  10. Large furlable antenna study

    NASA Technical Reports Server (NTRS)

    Campbell, G. K. C.

    1975-01-01

    The parametric study of the performance of large furlable antennas is described and the availability of various size antennas is discussed. Three types of unfurlable reflector designs are considered: the wrapped rib, the polyconic, and the maypole. On the basis of these approaches, a space shuttle launch capability, and state-of-the-art materials, it is possible to design unfurlable reflectors as large as 130 feet (40 meters) in diameter to operate at 10 GHz and 600 feet (183 meters) in diameter at 0.5 GHz. These figures can be increased if very low thermal coefficient of expansion materials can be developed over the next 2-5 years. It is recommended that a special effort be made to develop light weight materials that would provide nearly zero thermal coefficient of expansion and good thermal conductivity within the next 10 years. A conservative prediction of the kinds of unfurlable spacecraft antennas that will be available by 1985 with orbital performance predicted on the basis of test data and with developed manufacturing processes is summarized.

  11. ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern.

    PubMed

    Sakamoto, Kana; Nakasone, Hideki; Togashi, Yuki; Sakata, Seiji; Tsuyama, Naoko; Baba, Satoko; Dobashi, Akito; Asaka, Reimi; Tsai, Chien-Chen; Chuang, Shih-Sung; Izutsu, Koji; Kanda, Yoshinobu; Takeuchi, Kengo

    2016-04-01

    Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+LBCL) is a rare, aggressive B-cell lymphoma with ALK fusion genes. Histopathologically, the ALK immunohistochemical staining pattern is suggestive of the fusion partner of ALK. Here, we examined an ALK+LBCL case showing a unique diffuse cytoplasmic ALK staining pattern and identified EML4-ALK, which has not previously been reported in ALK+LBCL. Furthermore, to clarify whether the prognosis differs depending on the staining pattern, we reviewed 112 previously reported cases, and analyzed immunohistochemical markers and clinical data stratified by the staining pattern. We found that ALK staining can be classified into a granular cytoplasmic staining (GCS) or a non-GCS patterns. Sixty-four adult cases for which both the ALK staining pattern and survival time were reported were further analyzed for survival trends. The non-GCS pattern was significantly associated with inferior overall survival (P = 0.031). This difference remained significant after adjusting for age and clinical stage (hazard ratio 5.08, 95 % CI 1.88-13.7, P = 0.0013). Given that the ALK immunohistochemical staining pattern is associated with the ALK fusion partner, the present results suggest that the prognosis for ALK+LBCL differs depending on the ALK fusion partner. PMID:26781614

  12. Synchronizing large systolic arrays

    SciTech Connect

    Fisher, A.L.; Kung, H.T.

    1982-04-01

    Parallel computing structures consist of many processors operating simultaneously. If a concurrent structure is regular, as in the case of systolic array, it may be convenient to think of all processors as operating in lock step. Totally synchronized systems controlled by central clocks are difficult to implement because of the inevitable problem of clock skews and delays. An alternate means of enforcing necessary synchronization is the use of self-timed, asynchronous schemes, at the cost of increased design complexity and hardware cost. Realizing that different circumstances call for different synchronization methods, this paper provides a spectrum of synchronization models; based on the assumptions made for each model, theoretical lower bounds on clock skew are derived, and appropriate or best-possible synchronization schemes for systolic arrays are proposed. This paper represents a first step towards a systematic study of synchronization problems for large systolic arrays.

  13. 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.

  14. 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.

  15. Large Binocular Telescope Project

    NASA Astrophysics Data System (ADS)

    Hill, John M.; Salinari, Piero

    1998-08-01

    The Large Binocular Telescope (LBT) Project is a collaboration between institutions in Arizona, Germany, Italy, and Ohio. With the addition of the partners from Ohio State and Germany in February 1997, the Large Binocular Telescope Corporation has the funding required to build the full telescope populated with both 8.4 meter optical trans. The first of two 8.4 meter borosilicate honeycomb primary mirrors for LBT was cast at the Steward Observatory Mirror Lab in 1997. The baseline optical configuration of LBT includes adaptive infrared secondaries of a Gregorian design. The F/15 secondaries are undersized to provide a low thermal background focal plane. The interferometric focus combining the light from the two 8.4 meter primaries will reimage the two folded Gregorian focal planes to three central locations. The telescope elevation structure accommodates swing arms which allow rapid interchange of the various secondary and tertiary mirrors. Maximum stiffness and minimal thermal disturbance were important drivers for the design of the telescope in order to provide the best possible images for interferometric observations. 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 was completed in 1997 by ADS Italia (Lecco) and European Industrial Engineering (Mestre). A series of contracts for the fabrication and machining of the telescope structure had been placed at the end of 1997. The final enclosure design was completed at M3 Engineering & Technology (Tucson), EIE and ADS Italia. During 1997, the telescope pier and the concrete ring wall for the rotating enclosure were completed along with the steel structure of the fixed portion of the enclosure. The erection of the steel structure for the rotating portion of the enclosure will begin in the Spring of 1998.

  16. 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. PMID:20517352

  17. 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.

  18. 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.

  19. 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.

  20. Stability of large systems

    NASA Astrophysics Data System (ADS)

    Hastings, Harold

    2007-03-01

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

  1. The Large Millimeter Telescope

    NASA Astrophysics Data System (ADS)

    Hughes, D. H.; Schloerb, F. P.; LMT Project Team

    2009-05-01

    This paper, presented on behalf of the Large Millimeter Telescope (LMT) project team, describes the status and near-term plans for the telescope and its initial instrumentation. The LMT is a bi-national collaboration between México and the USA, led by the Instituto Nacional de Astrofísica, Óptica y Electrónica (INAOE) and the University of Massachusetts at Amherst, to construct, commission and operate a 50 m diameter millimeter-wave radio telescope. Construction activities are nearly complete at the LMT site, at an altitude of ˜ 4600 m on the summit of Sierra Negra, an extinct volcano in the Mexican state of Puebla. Full movement of the telescope, under computer control in both azimuth and elevation, has been achieved. First-light at centimeter wavelengths on astronomical sources was obtained in November 2006. Installation of precision surface segments for millimeter-wave operation is underway, with the inner 32 m diameter of the surface now complete and ready to be used to obtain first-light at millimeter wavelengths in 2008. Installation of the remainder of the reflector will continue during the next year and be completed in 2009 for final commissioning of the antenna. The full LMT antenna, outfitted with its initial complement of scientific instruments, will be a world-leading scientific research facility for millimeter-wave astronomy.

  2. The Large Millimeter Telescope

    NASA Astrophysics Data System (ADS)

    Schloerb, F. Peter

    2008-07-01

    This paper, presented on behalf of the Large Millimeter Telescope (LMT) project team, describes the status and near-term plans for the telescope and its initial instrumentation. The LMT is a bi-national collaboration between Mexico and the USA, led by the Instituto Nacional de Astrofísica, Optica y Electronica (INAOE) and the University of Massachusetts at Amherst, to construct, commission and operate a 50m-diameter millimeter-wave radio telescope. Construction activities are nearly complete at the 4600m LMT site on the summit of Sierra Negra, an extinct volcano in the Mexican state of Puebla. Full movement of the telescope, under computer control in both azimuth and elevation, has been achieved. First-light at centimeter wavelengths on astronomical sources was obtained in November 2006. Installation of precision surface segments for millimeter-wave operation is underway, with the inner 32m-diameter of the surface now complete and ready to be used to obtain first light at millimeter wavelengths in 2008. Installation of the remainder of the reflector will continue during the next year and be completed in 2009 for final commissioning of the antenna. The full LMT antenna, outfitted with its initial complement of scientific instruments, will be a world-leading scientific research facility for millimeter-wave astronomy.

  3. 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.

  4. Large Deployable Reflectarray Antenna

    NASA Technical Reports Server (NTRS)

    Fang, Houfei; Huang, John; Lou, Michael

    2006-01-01

    A report discusses a 7-meter-diameter reflectarray antenna that has been conceived in a continuing effort to develop large reflectarray antennas to be deployed in outer space. Major underlying concepts were reported in three prior NASA Tech Briefs articles: "Inflatable Reflectarray Antennas" (NPO-20433), Vol. 23, No. 10 (October 1999), page 50; "Tape-Spring Reinforcements for Inflatable Structural Tubes" (NPO-20615), Vol. 24, No. 7 (July 2000), page 58; and "Self-Inflatable/Self-Rigidizable Reflectarray Antenna" (NPO-30662), Vol. 28, No. 1 (January 2004), page 61. Like previous antennas in the series, the antenna now proposed would include a reflectarray membrane stretched flat on a frame of multiple inflatable booms. The membrane and booms would be rolled up and folded for compact stowage during transport. Deployment in outer space would be effected by inflating the booms to unroll and then to unfold the membrane, thereby stretching the membrane out flat to its full size. The membrane would achieve the flatness for a Ka-band application. The report gives considerable emphasis to designing the booms to rigidify themselves upon deployment: for this purpose, the booms could be made as spring-tape-reinforced aluminum laminate tubes like those described in two of the cited prior articles.

  5. Large Format Radiographic Imaging

    SciTech Connect

    J. S. Rohrer; Lacey Stewart; M. D. Wilke; N. S. King; S. A Baker; Wilfred Lewis

    1999-08-01

    Radiographic imaging continues to be a key diagnostic in many areas at Los Alamos National Laboratory (LANL). Radiographic recording systems have taken on many form, from high repetition-rate, gated systems to film recording and storage phosphors. Some systems are designed for synchronization to an accelerator while others may be single shot or may record a frame sequence in a dynamic radiography experiment. While film recording remains a reliable standby in the radiographic community, there is growing interest in investigating electronic recording for many applications. The advantages of real time access to remote data acquisition are highly attractive. Cooled CCD camera systems are capable of providing greater sensitivity with improved signal-to-noise ratio. This paper begins with a review of performance characteristics of the Bechtel Nevada large format imaging system, a gated system capable of viewing scintillators up to 300 mm in diameter. We then examine configuration alternatives in lens coupled and fiber optically coupled electro-optical recording systems. Areas of investigation include tradeoffs between fiber optic and lens coupling, methods of image magnification, and spectral matching from scintillator to CCD camera. Key performance features discussed include field of view, resolution, sensitivity, dynamic range, and system noise characteristics.

  6. [Large granular lymphocyte leukemia].

    PubMed

    Lazaro, Estibaliz; Caubet, Olivier; Menard, Fanny; Pellegrin, Jean-Luc; Viallard, Jean-François

    2007-11-01

    Large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic cells, either CD3(+) (T-cell) or CD3(-) (natural killer, or NK). Both subtypes can manifest as indolent or aggressive disorders. T-LGL leukemia is associated with cytopenias and autoimmune diseases and most often has an indolent course and good prognosis. Rheumatoid arthritis and Felty syndrome are frequent. NK-LGL leukemias can be more aggressive. LGL expansion is currently hypothesized to be a virus (Ebstein Barr or human T-cell leukemia viruses) antigen-driven T-cell response that involves disruption of apoptosis. The diagnosis of T-LGL is suggested by flow cytometry and confirmed by T-cell receptor gene rearrangement studies. Clonality is difficult to determine in NK-LGL but use of monoclonal antibodies specific for killer cell immunoglobulin-like receptor (KIR) has improved this process. Treatment is required when T-LGL leukemia is associated with recurrent infections secondary to chronic neutropenia. Long-lasting remission can be obtained with immunosuppressive treatments such as methotrexate, cyclophosphamide, and cyclosporine A. NK-LGL leukemias may be more aggressive and refractory to conventional therapy. PMID:17596907

  7. 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.

  8. 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

  9. 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. PMID:19531503

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

    SciTech Connect

    Ladanyi, M.

    1994-09-01

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

  11. Large planer for finishing smooth, flat surfaces of large pieces ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Large planer for finishing smooth, flat surfaces of large pieces of metal; in operating condition and used for public demonstrations. - Thomas A. Edison Laboratories, Building No. 5, Main Street & Lakeside Avenue, West Orange, Essex County, NJ

  12. 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. PMID:27431583

  13. Large for gestational age (LGA)

    MedlinePlus

    ... 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 ...

  14. 76 FR 35451 - Oncologic Drugs Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-17

    ... refractory (resistant to previous standard treatments) Hodgkin's lymphoma. During the afternoon session, the... relapsed or refractory systemic anaplastic large cell lymphoma. FDA intends to make background...

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

    PubMed

    Emparan, Roberto; Grumiller, Daniel; Tanabe, Kentaro

    2013-06-21

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

  16. 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.

  17. Analytic bootstrap at large spin

    NASA Astrophysics Data System (ADS)

    Kaviraj, Apratim; Sen, Kallol; Sinha, Aninda

    2015-11-01

    We use analytic conformal bootstrap methods to determine the anomalous dimensions and OPE coefficients for large spin operators in general conformal field theories in four dimensions containing a scalar operator of conformal dimension Δ ϕ . It is known that such theories will contain an infinite sequence of large spin operators with twists approaching 2Δ ϕ + 2 n for each integer n. By considering the case where such operators are separated by a twist gap from other operators at large spin, we analytically determine the n, Δ ϕ dependence of the anomalous dimensions. We find that for all n, the anomalous dimensions are negative for Δ ϕ satisfying the unitarity bound. We further compute the first subleading correction at large spin and show that it becomes universal for large twist. In the limit when n is large, we find exact agreement with the AdS/CFT prediction corresponding to the Eikonal limit of a 2-2 scattering with dominant graviton exchange.

  18. 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. PMID:26823131

  19. 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.…

  20. 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…

  1. Robust large dimension terahertz cloaking.

    PubMed

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

    2012-02-14

    A large scale homogenous invisibility cloak functioning at terahertz frequencies is reported. The terahertz invisibility device features a large concealed volume, low loss, and broad bandwidth. In particular, it is capable of hiding objects with a dimension nearly an order of magnitude larger than that of its lithographic counterpart, but without involving complex and time-consuming cleanroom processing. PMID:22253094

  2. 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…

  3. 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.

  4. 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.

  5. LSD: Large Survey Database framework

    NASA Astrophysics Data System (ADS)

    Juric, Mario

    2012-09-01

    The Large Survey Database (LSD) is a Python framework and DBMS for distributed storage, cross-matching and querying of large survey catalogs (>10^9 rows, >1 TB). The primary driver behind its development is the analysis of Pan-STARRS PS1 data. It is specifically optimized for fast queries and parallel sweeps of positionally and temporally indexed datasets. It transparently scales to more than >10^2 nodes, and can be made to function in "shared nothing" architectures.

  6. 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.

  7. 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.

  8. The MAGNEX large acceptance spectrometer

    SciTech Connect

    Cavallaro, M.; Cappuzzello, F.; Cunsolo, A.; Carbone, D.; Foti, A.

    2010-03-01

    The main features of the MAGNEX large acceptance magnetic spectrometer are described. It has a quadrupole + dipole layout and a hybrid detector located at the focal plane. The aberrations due to the large angular (50 msr) and momentum (+- 13%) acceptance are reduced by an accurate hardware design and then compensated by an innovative software ray-reconstruction technique. The obtained resolution in energy, angle and mass are presented in the paper. MAGNEX has been used up to now for different experiments in nuclear physics and astrophysics confirming to be a multipurpose device.

  9. Detecting communities in large networks

    NASA Astrophysics Data System (ADS)

    Capocci, A.; Servedio, V. D. P.; Caldarelli, G.; Colaiori, F.

    2005-07-01

    We develop an algorithm to detect community structure in complex networks. The algorithm is based on spectral methods and takes into account weights and link orientation. Since the method detects efficiently clustered nodes in large networks even when these are not sharply partitioned, it turns to be specially suitable for the analysis of social and information networks. We test the algorithm on a large-scale data-set from a psychological experiment of word association. In this case, it proves to be successful both in clustering words, and in uncovering mental association patterns.

  10. 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...

  11. 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.

  12. 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)

  13. CERN's Large Hadron Collider project

    NASA Astrophysics Data System (ADS)

    Fearnley, Tom A.

    1997-03-01

    The paper gives a brief overview of CERN's Large Hadron Collider (LHC) project. After an outline of the physics motivation, we describe the LHC machine, interaction rates, experimental challenges, and some important physics channels to be studied. Finally we discuss the four experiments planned at the LHC: ATLAS, CMS, ALICE and LHC-B.

  14. Large area CMOS image sensors

    NASA Astrophysics Data System (ADS)

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

    2011-01-01

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

  15. 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.

  16. 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.

  17. Mass spectrometry of large complexes.

    PubMed

    Bich, Claudia; Zenobi, Renato

    2009-10-01

    Mass spectrometry is becoming a more and more powerful tool for investigating protein complexes. Recent developments, based on different ionization techniques, electrospray, desorption/ionization and others are contributing to the usefulness of MS to describe the organization and structure of large non-covalent assemblies. PMID:19782560

  18. Unusually large submandibular gland stone.

    PubMed

    Al-Hussona, Aws Adel

    2015-01-01

    Submandibular gland calculi is the most common disease of the gland. In this article, we report a case with unusually large stone located at the hilum of the gland causing necrosis of the overlying duct and the oral mucosa (floor of mouth). PMID:25934409

  19. 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.

  20. Galaxy clustering on large scales.

    PubMed

    Efstathiou, G

    1993-06-01

    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

  1. Very Large Scale Integration (VLSI).

    ERIC Educational Resources Information Center

    Yeaman, Andrew R. J.

    Very Large Scale Integration (VLSI), the state-of-the-art production techniques for computer chips, promises such powerful, inexpensive computing that, in the future, people will be able to communicate with computer devices in natural language or even speech. However, before full-scale VLSI implementation can occur, certain salient factors must be…

  2. Large-scale polarimetry of large optical galaxies

    NASA Astrophysics Data System (ADS)

    Sholomitskii, G. B.; Maslov, I. A.; Vitrichenko, E. A.

    1999-11-01

    We present preliminary results of wide-field visual CCD polarimetry for large optical galaxies through a concentric multisector radial-tangential polaroid analyzer mounted at the intermediate focus of a Zeiss-1000 telescope. The mean degree of tangential polarization in a 13-arcmin field, which was determined by processing images with imprinted ``orthogonal'' sectors, ranges from several percent (M 82) and 0.51% (the spirals M 51, M 81) to lower values for elliptical galaxies (M 49, M 87). It is emphasized that the parameters of large-scale polarization can be properly determined by using physical models for galaxies; inclination and azimuthal dependences of the degree of polarization are given for spirals.

  3. 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

  4. 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.

  5. Chunking of Large Multidimensional Arrays

    SciTech Connect

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

    2007-02-28

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

  6. Progress on large area GEMs

    NASA Astrophysics Data System (ADS)

    Villa, Marco; Duarte Pinto, Serge; Alfonsi, Matteo; Brock, Ian; Croci, Gabriele; David, Eric; de Oliveira, Rui; Ropelewski, Leszek; Taureg, Hans; van Stenis, Miranda

    2011-02-01

    The Gas Electron Multiplier (GEM) manufacturing technique has recently evolved to allow the production of large area GEMs. A novel approach based on single mask photolithography eliminates the mask alignment issue, which limits the dimensions in the traditional double mask process. Moreover, a splicing technique overcomes the limited width of the raw material. Stretching and handling issues in large area GEMs have also been addressed. Using the new improvements it was possible to build a prototype triple-GEM detector of ˜2000 cm2 active area, aimed at an application for the TOTEM T1 upgrade. Further refinements of the single mask technique allow great control over the shape of the GEM holes and the size of the rims, which can be tuned as needed. In this framework, simulation studies can help to understand the GEM behavior depending on the hole shape.

  7. 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.

  8. Large aperture scanning airborne lidar

    NASA Technical Reports Server (NTRS)

    Smith, J.; Bindschadler, R.; Boers, R.; Bufton, J. L.; Clem, D.; Garvin, J.; Melfi, S. H.

    1988-01-01

    A large aperture scanning airborne lidar facility is being developed to provide important new capabilities for airborne lidar sensor systems. The proposed scanning mechanism allows for a large aperture telescope (25 in. diameter) in front of an elliptical flat (25 x 36 in.) turning mirror positioned at a 45 degree angle with respect to the telescope optical axis. The lidar scanning capability will provide opportunities for acquiring new data sets for atmospheric, earth resources, and oceans communities. This completed facility will also make available the opportunity to acquire simulated EOS lidar data on a near global basis. The design and construction of this unique scanning mechanism presents exciting technological challenges of maintaining the turning mirror optical flatness during scanning while exposed to extreme temperatures, ambient pressures, aircraft vibrations, etc.

  9. Large Scale Nanolaminate Deformable Mirror

    SciTech Connect

    Papavasiliou, A; Olivier, S; Barbee, T; Miles, R; Chang, K

    2005-11-30

    This work concerns the development of a technology that uses Nanolaminate foils to form light-weight, deformable mirrors that are scalable over a wide range of mirror sizes. While MEMS-based deformable mirrors and spatial light modulators have considerably reduced the cost and increased the capabilities of adaptive optic systems, there has not been a way to utilize the advantages of lithography and batch-fabrication to produce large-scale deformable mirrors. This technology is made scalable by using fabrication techniques and lithography that are not limited to the sizes of conventional MEMS devices. Like many MEMS devices, these mirrors use parallel plate electrostatic actuators. This technology replicates that functionality by suspending a horizontal piece of nanolaminate foil over an electrode by electroplated nickel posts. This actuator is attached, with another post, to another nanolaminate foil that acts as the mirror surface. Most MEMS devices are produced with integrated circuit lithography techniques that are capable of very small line widths, but are not scalable to large sizes. This technology is very tolerant of lithography errors and can use coarser, printed circuit board lithography techniques that can be scaled to very large sizes. These mirrors use small, lithographically defined actuators and thin nanolaminate foils allowing them to produce deformations over a large area while minimizing weight. This paper will describe a staged program to develop this technology. First-principles models were developed to determine design parameters. Three stages of fabrication will be described starting with a 3 x 3 device using conventional metal foils and epoxy to a 10-across all-metal device with nanolaminate mirror surfaces.

  10. Measuring Diameters Of Large Vessels

    NASA Technical Reports Server (NTRS)

    Currie, James R.; Kissel, Ralph R.; Oliver, Charles E.; Smith, Earnest C.; Redmon, John W., Sr.; Wallace, Charles C.; Swanson, Charles P.

    1990-01-01

    Computerized apparatus produces accurate results quickly. Apparatus measures diameter of tank or other large cylindrical vessel, without prior knowledge of exact location of cylindrical axis. Produces plot of inner circumference, estimate of true center of vessel, data on radius, diameter of best-fit circle, and negative and positive deviations of radius from circle at closely spaced points on circumference. Eliminates need for time-consuming and error-prone manual measurements.

  11. 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.

  12. Extremely Large Cusp Diamagnetic Cavities

    NASA Astrophysics Data System (ADS)

    Chen, J.; Fritz, T. A.

    2002-05-01

    Extremely large diamagnetic cavities with a size of as large as 6 Re have been observed in the dayside high-altitude cusp regions. Some of the diamagnetic cavities were independent of the IMF directions, which is unexpected by the current MHD (or ISM) models, suggesting that the cusp diamagnetic cavities are different from the magnetospheric sash, which provides a challenge to the existing MHD (or ISM) models. Associated with these cavities are ions with energies from 40 keV up to 8 MeV. The charge state distribution of these cusp cavity ions was indicative of their seed populations being a mixture of the ionospheric and the solar wind particles. The intensities of the cusp cavity energetic ions were observed to increase by as large as four orders of the magnitudes. During high solar wind pressure period on April 21, 1999, the POLAR spacecraft observed lower ion flux in the dayside high-latitude magnetosheath than that in the neighbouring cusp cavities. These observations indicate that the dayside high-altitude cusp diamagnetic cavity is a key region for transferring the solar wind energy, mass, and momentum into the Earth's magnetosphere. These energetic particles in the cusp diamagnetic cavity together with the cusp's connectivity have significant global impacts on the geospace environment research and will be shedding light on the long-standing unsolved fundamental issue about the origins of the energetic particles in the ring current and in upstream ion events.

  13. Extremely large cusp diamagnetic cavities

    NASA Astrophysics Data System (ADS)

    Chen, J.; Fritz, T.; Siscoe, G.

    Extremely large diamagnetic cavities with a size of as large as 6 Re have been observed in the dayside high-altitude cusp regions. These diamagnetic cavities are always there day by day. Some of the diamagnetic cavities have been observed in the morningside during intervals when the IMF By component was positive (duskward), suggesting that the cusp diamagnetic cavities are different from the magnetospheric sash predicted by MHD simulations. Associated with these cavities are ions with energies from 40 keV up to 8 MeV. The charge state distribution of these cusp cavity ions was indicative of their seed populations being a mixture of the ionospheric and the solar wind particles. The intensities of the cusp cavity energetic ions were observed to increase by as large as four orders of the magnitudes. These observations indicate that the dayside high-altitude cusp diamagnetic cavity is a key region for transferring the solar wind energy, mass, and momentum into the Earth's magnetosphere. These energetic particles in the cusp diamagnetic cavity together with the cusp's connectivity to the entire magnetopause may have significant global impacts on the geospace environment. They will possibly be shedding light on the long-standing unsolved fundamental issue about the origins of the energetic particles in the ring current and in the regions upstream of the subsolar magnetopause where energetic ion events frequently are observed.

  14. Deflectometric measurement of large mirrors

    NASA Astrophysics Data System (ADS)

    Olesch, Evelyn; Häusler, Gerd; Wörnlein, André; Stinzing, Friedrich; van Eldik, Christopher

    2014-06-01

    We discuss the inspection of large-sized, spherical mirror tiles by `Phase Measuring Deflectometry' (PMD). About 10 000 of such mirror tiles, each satisfying strict requirements regarding the spatial extent of the point-spread-function (PSF), are planned to be installed on the Cherenkov Telescope Array (CTA), a future ground-based instrument to observe the sky in very high energy gamma-rays. Owing to their large radii of curvature of up to 60 m, a direct PSF measurement of these mirrors with concentric geometry requires large space. We present a PMD sensor with a footprint of only 5×2×1.2 m3 that overcomes this limitation. The sensor intrinsically acquires the surface slope; the shape data are calculated by integration. In this way, the PSF can be calculated for real case scenarios, e.g., when the light source is close to infinity and off-axis. The major challenge is the calibration of the PMD sensor, specifically because the PSF data have to be reconstructed from different camera views. The calibration of the setup is described, and measurements presented and compared to results obtained with the direct approach.

  15. 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

  16. 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.

  17. Radiosurgery for Large Brain Metastases

    SciTech Connect

    Han, Jung Ho; Kim, Dong Gyu; Chung, Hyun-Tai; Paek, Sun Ha; Park, Chul-Kee; Jung, Hee-Won

    2012-05-01

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

  18. Challenges for Large Scale Simulations

    NASA Astrophysics Data System (ADS)

    Troyer, Matthias

    2010-03-01

    With computational approaches becoming ubiquitous the growing impact of large scale computing on research influences both theoretical and experimental work. I will review a few examples in condensed matter physics and quantum optics, including the impact of computer simulations in the search for supersolidity, thermometry in ultracold quantum gases, and the challenging search for novel phases in strongly correlated electron systems. While only a decade ago such simulations needed the fastest supercomputers, many simulations can now be performed on small workstation clusters or even a laptop: what was previously restricted to a few experts can now potentially be used by many. Only part of the gain in computational capabilities is due to Moore's law and improvement in hardware. Equally impressive is the performance gain due to new algorithms - as I will illustrate using some recently developed algorithms. At the same time modern peta-scale supercomputers offer unprecedented computational power and allow us to tackle new problems and address questions that were impossible to solve numerically only a few years ago. While there is a roadmap for future hardware developments to exascale and beyond, the main challenges are on the algorithmic and software infrastructure side. Among the problems that face the computational physicist are: the development of new algorithms that scale to thousands of cores and beyond, a software infrastructure that lifts code development to a higher level and speeds up the development of new simulation programs for large scale computing machines, tools to analyze the large volume of data obtained from such simulations, and as an emerging field provenance-aware software that aims for reproducibility of the complete computational workflow from model parameters to the final figures. Interdisciplinary collaborations and collective efforts will be required, in contrast to the cottage-industry culture currently present in many areas of computational

  19. The Large Synoptic Survey Telescope

    NASA Astrophysics Data System (ADS)

    Axelrod, T. S.

    2006-07-01

    The Large Synoptic Survey Telescope (LSST) is an 8.4 meter telescope with a 10 square degree field degree field and a 3 Gigapixel imager, planned to be on-sky in 2012. It is a dedicated all-sky survey instrument, with several complementary science missions. These include understanding dark energy through weak lensing and supernovae; exploring transients and variable objects; creating and maintaining a solar system map, with particular emphasis on potentially hazardous objects; and increasing the precision with which we understand the structure of the Milky Way. The instrument operates continuously at a rapid cadence, repetitively scanning the visible sky every few nights. The data flow rates from LSST are larger than those from current surveys by roughly a factor of 1000: A few GB/night are typical today. LSST will deliver a few TB/night. From a computing hardware perspective, this factor of 1000 can be dealt with easily in 2012. The major issues in designing the LSST data management system arise from the fact that the number of people available to critically examine the data will not grow from current levels. This has a number of implications. For example, every large imaging survey today is resigned to the fact that their image reduction pipelines fail at some significant rate. Many of these failures are dealt with by rerunning the reduction pipeline under human supervision, with carefully ``tweaked'' parameters to deal with the original problem. For LSST, this will no longer be feasible. The problem is compounded by the fact that the processing must of necessity occur on clusters with large numbers of CPU's and disk drives, and with some components connected by long-haul networks. This inevitably results in a significant rate of hardware component failures, which can easily lead to further software failures. Both hardware and software failures must be seen as a routine fact of life rather than rare exceptions to normality.

  20. 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.

  1. Uncertainties in large space systems

    NASA Technical Reports Server (NTRS)

    Fuh, Jon-Shen

    1988-01-01

    Uncertainties of a large space system (LSS) can be deterministic or stochastic in nature. The former may result in, for example, an energy spillover problem by which the interaction between unmodeled modes and controls may cause system instability. The stochastic uncertainties are responsible for mode localization and estimation errors, etc. We will address the effects of uncertainties on structural model formulation, use of available test data to verify and modify analytical models before orbiting, and how the system model can be further improved in the on-orbit environment.

  2. Microfluidic large-scale integration.

    PubMed

    Thorsen, Todd; Maerkl, Sebastian J; Quake, Stephen R

    2002-10-18

    We developed high-density microfluidic chips that contain plumbing networks with thousands of micromechanical valves and hundreds of individually addressable chambers. These fluidic devices are analogous to electronic integrated circuits fabricated using large-scale integration. A key component of these networks is the fluidic multiplexor, which is a combinatorial array of binary valve patterns that exponentially increases the processing power of a network by allowing complex fluid manipulations with a minimal number of inputs. We used these integrated microfluidic networks to construct the microfluidic analog of a comparator array and a microfluidic memory storage device whose behavior resembles random-access memory. PMID:12351675

  3. 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.

  4. 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.

  5. 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.

  6. Large-mode enhancement cavities.

    PubMed

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

    2013-05-01

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

  7. 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.

  8. How Large Asexual Populations Adapt

    NASA Astrophysics Data System (ADS)

    Desai, Michael

    2007-03-01

    We often think of beneficial mutations as being rare, and of adaptation as a sequence of selected substitutions: a beneficial mutation occurs, spreads through a population in a selective sweep, then later another beneficial mutation occurs, and so on. This simple picture is the basis for much of our intuition about adaptive evolution, and underlies a number of practical techniques for analyzing sequence data. Yet many large and mostly asexual populations -- including a wide variety of unicellular organisms and viruses -- live in a very different world. In these populations, beneficial mutations are common, and frequently interfere or cooperate with one another as they all attempt to sweep simultaneously. This radically changes the way these populations adapt: rather than an orderly sequence of selective sweeps, evolution is a constant swarm of competing and interfering mutations. I will describe some aspects of these dynamics, including why large asexual populations cannot evolve very quickly and the character of the diversity they maintain. I will explain how this changes our expectations of sequence data, how sex can help a population adapt, and the potential role of ``mutator'' phenotypes with abnormally high mutation rates. Finally, I will discuss comparisons of these predictions with evolution experiments in laboratory yeast populations.

  9. 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.

  10. Electron Collisions with Large Molecules

    NASA Astrophysics Data System (ADS)

    McKoy, Vincent

    2006-10-01

    In recent years, interest in electron-molecule collisions has increasingly shifted to large molecules. Applications within the semiconductor industry, for example, require electron collision data for molecules such as perfluorocyclobutane, while almost all biological applications involve macromolecules such as DNA. A significant development in recent years has been the realization that slow electrons can directly damage DNA. This discovery has spurred studies of low-energy collisions with the constituents of DNA, including the bases, deoxyribose, the phosphate, and larger moieties assembled from them. In semiconductor applications, a key goal is development of electron cross section sets for plasma chemistry modeling, while biological studies are largely focused on understanding the role of localized resonances in inducing DNA strand breaks. Accurate calculations of low-energy electron collisions with polyatomic molecules are computationally demanding because of the low symmetry and inherent many-electron nature of the problem; moreover, the computational requirements scale rapidly with the size of the molecule. To pursue such studies, we have adapted our computational procedure, known as the Schwinger multichannel method, to run efficiently on highly parallel computers. In this talk, we will present some of our recent results for fluorocarbon etchants used in the semiconductor industry and for constituents of DNA and RNA. In collaboration with Carl Winstead, California Institute of Technology.

  11. 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.

  12. 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.

  13. 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. PMID:27126244

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. Large scale topography of Io

    NASA Technical Reports Server (NTRS)

    Gaskell, R. W.; Synnott, S. P.

    1987-01-01

    To investigate the large scale topography of the Jovian satellite Io, both limb observations and stereographic techniques applied to landmarks are used. The raw data for this study consists of Voyager 1 images of Io, 800x800 arrays of picture elements each of which can take on 256 possible brightness values. In analyzing this data it was necessary to identify and locate landmarks and limb points on the raw images, remove the image distortions caused by the camera electronics and translate the corrected locations into positions relative to a reference geoid. Minimizing the uncertainty in the corrected locations is crucial to the success of this project. In the highest resolution frames, an error of a tenth of a pixel in image space location can lead to a 300 m error in true location. In the lowest resolution frames, the same error can lead to an uncertainty of several km.

  19. Safe handling of large animals.

    PubMed

    Grandin, T

    1999-01-01

    The major causes of accidents with cattle, horses, and other grazing animals are: panic due to fear, male dominance aggression, or the maternal aggression of a mother protecting her newborn. Danger is inherent when handling large animals. Understanding their behavior patterns improves safety, but working with animals will never be completely safe. Calm, quiet handling and non-slip flooring are beneficial. Rough handling and excessive use of electric prods increase chances of injury to both people and animals, because fearful animals may jump, kick, or rear. Training animals to voluntarily cooperate with veterinary procedures reduces stress and improves safety. Grazing animals have a herd instinct, and a lone, isolated animal can become agitated. Providing a companion animal helps keep an animal calm. PMID:10329901

  20. Biotherapies in large vessel vasculitis.

    PubMed

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

    2016-06-01

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

  1. Analysis of large urban fires

    SciTech Connect

    Kang, S.W.; Reitter, T.A.; Takata, A.N.

    1984-11-01

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

  2. Intergalactic shells at large redshift

    NASA Technical Reports Server (NTRS)

    Shull, J. M.; Silk, J.

    1981-01-01

    The intergalactic shells produced by galactic explosions at large redshift, whose interiors cool by inverse Compton scattering off the cosmic background radiation, have a characteristic angular size of about 1 arcmin at peak brightness. At z values lower than 2, the shells typically have a radius of 0.5 Mpc, a velocity of about 50 km/sec, a metal abundance of about 0.0001 of cosmic values, and strong radiation in H I(Lyman-alpha), He II 304 A, and the IR fine-structure lines of C II and Si II. The predicted extragalactic background emission from many shells, strongly peaked toward the UV, sets an upper limit to the number of exploding sources at z values of about 10. Shell absorption lines of H I, C II, Si II, and Fe II, which may be seen at more recent epochs in quasar spectra, may probe otherwise invisible explosions in the early universe.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  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 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

  11. 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.

  12. Anthropogenic triggering of large earthquakes.

    PubMed

    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

  13. Amplification of large artificial chromosomes.

    PubMed Central

    Smith, D R; Smyth, A P; Moir, D T

    1990-01-01

    Yeast artificial chromosome cloning is an attractive technology for genomic mapping studies because very large DNA segments can be readily propagated. However, detailed analyses often require the extensive application of blotting-hybridization techniques because artificial chromosomes are normally present at only one copy per haploid genome. We have developed a cloning vector and host strain that alleviate this problem by permitting copy number amplification of artificial chromosomes. The vector includes a conditional centromere that can be turned on or off by changing the carbon source. Strong selective pressure for extra copies of the artificial chromosome can be applied by selecting for the expression of a heterologous thymidine kinase gene. When this system was used, artificial chromosomes ranging from about 100 to 600 kilobases in size were readily amplified 10- to 20-fold. The selective conditions did not induce obvious rearrangements in any of the clones tested. Reactivation of the centromere in amplified artificial chromosome clones resulted in stable maintenance of an elevated copy number for 20 generations. Applications of copy number control to various aspects of artificial chromosome analysis are addressed. Images PMID:2236036

  14. Large Scale Homing in Honeybees

    PubMed Central

    Pahl, Mario; Zhu, Hong; Tautz, Jürgen; Zhang, Shaowu

    2011-01-01

    Honeybee foragers frequently fly several kilometres to and from vital resources, and communicate those locations to their nest mates by a symbolic dance language. Research has shown that they achieve this feat by memorizing landmarks and the skyline panorama, using the sun and polarized skylight as compasses and by integrating their outbound flight paths. In order to investigate the capacity of the honeybees' homing abilities, we artificially displaced foragers to novel release spots at various distances up to 13 km in the four cardinal directions. Returning bees were individually registered by a radio frequency identification (RFID) system at the hive entrance. We found that homing rate, homing speed and the maximum homing distance depend on the release direction. Bees released in the east were more likely to find their way back home, and returned faster than bees released in any other direction, due to the familiarity of global landmarks seen from the hive. Our findings suggest that such large scale homing is facilitated by global landmarks acting as beacons, and possibly the entire skyline panorama. PMID:21602920

  15. The Mass of Large Impactors

    NASA Technical Reports Server (NTRS)

    Parisi, M. G.; Brunini, A.

    1996-01-01

    By means of a simplified dynamical model, we have computed the eccentricity change in the orbit of each giant planet, caused by a single, large impact at the end of the accretion process. In order to set an upper bound on this eccentricity change, we have considered the giant planets' present eccentricities as primordial ones. By means of this procedure, we were able to obtain an implicit relation for the impactor masses and maximum velocities. We have estimated by this method the maximum allowed mass to impact Jupiter to be approx. 1.136 x 10(exp -1), being in the case of Neptune approx. 3.99 x 10(exp -2) (expressed in units of each planet final mass). Due to the similar present eccentricities of Saturn, Uranus and Jupiter, the constraint masses and velocities of the bodies to impact them (in units of each planet final mass and velocity respectively) are almost the same for the three planets. These results are in good agreement with those obtained by Lissauer and Safronov. These bounds might be used to derive the mass distribution of planetesimals in the early solar system.

  16. 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.

  17. How Large Should Whales Be?

    PubMed Central

    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. PMID:23342050

  18. Large N{sub c}

    SciTech Connect

    Jenkins, Elizabeth E.

    2009-12-17

    The 1/N{sub c} expansion of QCD with N{sub c} = 3 has been successful in explaining a wide variety of QCD phenomenology. Here I focus on the contracted spin-flavor symmetry of baryons in the large-N{sub c} limit and deviations from spin-flavor symmetry due to corrections suppressed by powers of 1/N{sub c}. Baryon masses provide an important example of the 1/N{sub c} expansion, and successful predictions of masses of heavy-quark baryons continue to be tested by experiment. The ground state charmed baryon masses have all been measured, and five of the eight ground state bottom baryon masses have been found. Results of the 1/N{sub c} expansion can aid in the discovery of the remaining bottom baryons. The brand new measurement of the {omega}{sub b}{sup -} mass by the CDF collaboration conflicts with the original D0 discovery value and is in excellent agreement with the prediction of the 1/N{sub c} expansion.

  19. 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

  20. 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.

  1. 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.

  2. 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. PMID:23342050

  3. Large Isotope Spectrometer for Astromag

    NASA Technical Reports Server (NTRS)

    Binns, W. R.; Klarmann, J.; Israel, M. H.; Garrard, T. L.; Mewaldt, R. A.; Stone, E. C.; Ormes, J. F.; Streitmatter, R. E.; Rasmussen, I. L.; Wiedenbeck, M. E.

    1990-01-01

    The Large Isotope Spectrometer for Astromag (LISA) is an experiment designed to measure the isotopic composition and energy spectra of cosmic rays for elements extending from beryllium through zinc. The overall objectives of this investigation are to study the origin and evolution of galactic matter; the acceleration, transport, and time scales of cosmic rays in the galaxy; and search for heavy antinuclei in the cosmic radiation. To achieve these objectives, the LISA experiment will make the first identifications of individual heavy cosmic ray isotopes in the energy range from about 2.5 to 4 GeV/n where relativistic time dilation effects enhance the abundances of radioactive clocks and where the effects of solar modulation and cross-section variations are minimized. It will extend high resolution measurements of individual element abundances and their energy spectra to energies of nearly 1 TeV/n, and has the potential for discovering heavy anti-nuclei which could not have been formed except in extragalactic sources.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Phase II Pediatric Study With Dabrafenib in HGG Patients

    ClinicalTrials.gov

    2016-03-09

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

  9. 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.

  10. 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.

  11. The Large Synoptic Survey Telescope

    NASA Astrophysics Data System (ADS)

    Ivezic, Zeljko

    2007-05-01

    The Large Synoptic Survey Telescope (LSST) is currently by far the most ambitious proposed ground-based optical survey. With initial funding from the US National Science Foundation (NSF), Department of Energy (DOE) laboratories and private sponsors, the design and development efforts are well underway at many institutions, including top universities and leading national laboratories. The main science themes that drive the LSST system design are Dark Energy and Matter, the Solar System Inventory, Transient Optical Sky and the Milky Way Mapping. The LSST system, with its 8.4m telescope and 3,200 Megapixel camera, will be sited at Cerro Pachon in northern Chile, with the first light scheduled for 2014. In a continuous observing campaign, LSST will cover the entire available sky every three nights in two photometric bands to a depth of V=25 per visit (two 15 second exposures), with exquisitely accurate astrometry and photometry. Over the proposed survey lifetime of 10 years, each sky location would be observed about 1000 times, with the total exposure time of 8 hours distributed over six broad photometric bandpasses (ugrizY). This campaign will open a movie-like window on objects that change brightness, or move, on timescales ranging from 10 seconds to 10 years, and will produce a catalog containing over 10 billion galaxies and a similar number of stars. The survey will have a data rate of about 30 TB/night, and will collect over 60 PB of raw data over its lifetime, resulting in an incredibly rich and extensive public archive that will be a treasure trove for breakthroughs in many areas of astronomy and astrophysics.

  12. Fronts in Large Marine Ecosystems

    NASA Astrophysics Data System (ADS)

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

    2009-04-01

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

  13. 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.

  14. India's National Large Solar Telescope

    NASA Astrophysics Data System (ADS)

    Hasan, S. S.

    2012-12-01

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

  15. 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

  16. Interface structure at large supercooling

    NASA Astrophysics Data System (ADS)

    Misbah, C.; Müller-Krumbhaar, H.; Temkin, D. E.

    1991-04-01

    The front dynamics during the growth of a pure substance in the large undercooling limit including interface kinetics is analyzed. There exists a critical dimensionless undercooling Δ_s(>1) above which a planar front is linearly stable. For Δ < Δ_s the planar front is unstable against short wavenumbers k's perturbations, 01). Pour le front est instable vis-à-vis des perturbations de petit vecteur d'onde, 0

  17. 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.

  18. Investing in a Large Stretch Press

    NASA Technical Reports Server (NTRS)

    Choate, M.; Nealson, W.; Jay, G.; Buss, W.

    1986-01-01

    Press for forming large aluminum parts from plates provides substantial economies. Study assessed advantages and disadvantages of investing in large stretch-forming press, and also developed procurement specification for press.

  19. 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.

  20. 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

  1. 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…

  2. 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.

  3. 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...

  4. Large N reduction on coset spaces

    SciTech Connect

    Kawai, Hikaru; Shimasaki, Shinji; Tsuchiya, Asato

    2010-04-15

    As an extension of our previous work concerning the large N reduction on group manifolds, we study the large N reduction on coset spaces. We show that large N field theories on coset spaces are described by certain corresponding matrix models. We also construct Chern-Simons-like theories on group manifolds and coset spaces, and give their reduced models.

  5. 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.

  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. Shape control of large space structures

    NASA Technical Reports Server (NTRS)

    Hagan, M. T.

    1982-01-01

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

  9. 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.

  10. Improved Large-Field Focusing Schlieren System

    NASA Technical Reports Server (NTRS)

    Weinstein, Leonard M.

    1993-01-01

    System used to examine complicated two- and three-dimensional flows. High-brightness large-field focusing schlieren system incorporates Fresnel lens instead of glass diffuser. In system with large field of view, image may also be very large. Relay optical subsystem minifies large image while retaining all of light. Facilities candidates for use of focusing schlieren include low-speed wind and water tunnels. Heated or cooled flow tracers or injected low- or high-density tracers used to make flows visible for photographic recording.

  11. 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…

  12. How Do People Apprehend Large Numerosities?

    ERIC Educational Resources Information Center

    Sophian, Catherine; Chu, Yun

    2008-01-01

    People discriminate remarkably well among large numerosities. These discriminations, however, need not entail numerical representation of the quantities being compared. This research evaluated the role of both non-numerical and numerical information in adult judgments of relative numerosity for large-numerosity spatial arrays. Results of…

  13. Fabrication of large ceramic electrolyte disks

    NASA Technical Reports Server (NTRS)

    Ring, S. A.

    1972-01-01

    Process for sintering compressed ceramic powders produces large ceramic disks for use as electrolytes in high-temperature electrolytic cells. Thin, strain-free uniformly dense disks as large as 30 cm squared have been fabricated by slicing ceramic slugs produced by this technique.

  14. Densifying forest biomass into large round bales

    SciTech Connect

    Fridley, J.; Burkhardt, T.H.

    1981-01-01

    A large round-bale hay baler was modified to examine the concept of baling forest biomass in large round bales. Material baled, feed orientation, and baler belt tension were varied to observe their effects on the baling process and bale density. The torque and power required to drive the baler were measured. 10 refs.

  15. Large-Scale Reform Comes of Age

    ERIC Educational Resources Information Center

    Fullan, Michael

    2009-01-01

    This article reviews the history of large-scale education reform and makes the case that large-scale or whole system reform policies and strategies are becoming increasingly evident. The review briefly addresses the pre 1997 period concluding that while the pressure for reform was mounting that there were very few examples of deliberate or…

  16. Large Lecture Format: Some Lessons Learned.

    ERIC Educational Resources Information Center

    Kryder, LeeAnne G.

    2002-01-01

    Shares some surprising results from a business communication program's recent experiment in using a large lecture format to teach an upper-division business communication course: approximately 90-95% of the students liked the large lecture format, and the quality of their communication deliverables was as good as that produced by students who took…

  17. Large-scale infrared scene projectors

    NASA Astrophysics Data System (ADS)

    Murray, Darin A.

    1999-07-01

    Large-scale infrared scene projectors, typically have unique opto-mechanical characteristics associated to their application. This paper outlines two large-scale zoom lens assemblies with different environmental and package constraints. Various challenges and their respective solutions are discussed and presented.

  18. 75 FR 73983 - Assessments, Large Bank Pricing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-30

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

  19. 76 FR 17521 - Assessments, Large Bank Pricing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-30

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

  20. The algebras of large N matrix mechanics

    SciTech Connect

    Halpern, M.B.; Schwartz, C.

    1999-09-16

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

  1. 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...

  2. 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…

  3. Perception for a large deployable reflector telescope

    NASA Technical Reports Server (NTRS)

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

    1984-01-01

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

  4. 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.

  5. 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…

  6. ARPACK: Solving large scale eigenvalue problems

    NASA Astrophysics Data System (ADS)

    Lehoucq, Rich; Maschhoff, Kristi; Sorensen, Danny; Yang, Chao

    2013-11-01

    ARPACK is a collection of Fortran77 subroutines designed to solve large scale eigenvalue problems. The package is designed to compute a few eigenvalues and corresponding eigenvectors of a general n by n matrix A. It is most appropriate for large sparse or structured matrices A where structured means that a matrix-vector product w

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Do large hiatal hernias affect esophageal peristalsis?

    PubMed Central

    Roman, Sabine; Kahrilas, Peter J; Kia, Leila; Luger, Daniel; Soper, Nathaniel; Pandolfino, John E

    2013-01-01

    Background & Aim Large hiatal hernias can be associated with a shortened or tortuous esophagus. We hypothesized that these anatomic changes may alter esophageal pressure topography (EPT) measurements made during high-resolution manometry (HRM). Our aim was to compare EPT measures of esophageal motility in patients with large hiatal hernias to those of patients without hernia. Methods Among 2000 consecutive clinical EPT, we identified 90 patients with large (>5 cm) hiatal hernias on endoscopy and at least 7 evaluable swallows on EPT. Within the same database a control group without hernia was selected. EPT was analyzed for lower esophageal sphincter (LES) pressure, Distal Contractile Integral (DCI), contraction amplitude, Contractile Front Velocity (CFV) and Distal Latency time (DL). Esophageal length was measured on EPT from the distal border of upper esophageal sphincter to the proximal border of the LES. EPT diagnosis was based on the Chicago Classification. Results The manometry catheter was coiled in the hernia and did not traverse the crural diaphragm in 44 patients (49%) with large hernia. Patients with large hernias had lower average LES pressures, lower DCI, slower CFV and shorter DL than patients without hernia. They also exhibited a shorter mean esophageal length. However, the distribution of peristaltic abnormalities was not different in patients with and without large hernia. Conclusions Patients with large hernias had an alteration of EPT measurements as a consequence of the associated shortened esophagus. However, the distribution of peristaltic disorders was unaffected by the presence of hernia. PMID:22508779

  12. On the distinction between large deformation and large distortion for anisotropic materials

    SciTech Connect

    BRANNON,REBECCA M.

    2000-02-24

    A motion involves large distortion if the ratios of principal stretches differ significantly from unity. A motion involves large deformation if the deformation gradient tensor is significantly different from the identity. Unfortunately, rigid rotation fits the definition of large deformation, and models that claim to be valid for large deformation are often inadequate for large distortion. An exact solution for the stress in an idealized fiber-reinforced composite is used to show that conventional large deformation representations for transverse isotropy give errant results. Possible alternative approaches are discussed.

  13. 1919 + 742 - A large double radio source

    NASA Astrophysics Data System (ADS)

    Strom, R. G.; Eckart, A.; Biermann, P.

    1985-10-01

    A 49-cm map of the source 1919 + 742 (previously catalogued as 4C74.24 and NB74.26) shows it to be a large double. Although the optical identification is unclear, there are several candidate objects near the source centroid which appear to be members of a small group of galaxies. The absence of bright identification candidates argues for a moderately distant, and hence intrinsically large (750 kpc overall size for z = 0.1) object. The spectrum between 80 and 600 MHz is determined, some intrinsic properties are derived, and these are briefly discussed in the context of other large sources.

  14. 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.

  15. 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.

  16. 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.

  17. Microwave sintering of large alumina bodies

    SciTech Connect

    Blake, R.D.; Katz, J.D.

    1993-05-01

    The application of microwaves as an energy source for materials processing of large alumina bodies at elevated temperatures has been limited to date. Most work has concerned itself with small laboratory samples. The nonuniformity of the microwave field within a cavity subjects large alumina bodies to areas of concentrated energy, resulting in uneven heating and subsequent cracking. Smaller bodies are not significantly affected by field nonuniformity due to their smaller mass. This work will demonstrate a method for microwave sintering of large alumina bodies while maintaining their structural integrity. Several alumina configurations were successfully sintered using a method which creates an artificial field or environment within the microwave cavity.

  18. Microwave sintering of large alumina bodies

    SciTech Connect

    Blake, R.D.; Katz, J.D.

    1993-01-01

    The application of microwaves as an energy source for materials processing of large alumina bodies at elevated temperatures has been limited to date. Most work has concerned itself with small laboratory samples. The nonuniformity of the microwave field within a cavity subjects large alumina bodies to areas of concentrated energy, resulting in uneven heating and subsequent cracking. Smaller bodies are not significantly affected by field nonuniformity due to their smaller mass. This work will demonstrate a method for microwave sintering of large alumina bodies while maintaining their structural integrity. Several alumina configurations were successfully sintered using a method which creates an artificial field or environment within the microwave cavity.

  19. Synthesis of small and large scale dynamos

    NASA Astrophysics Data System (ADS)

    Subramanian, Kandaswamy

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

  20. Efficient generation of large random networks

    NASA Astrophysics Data System (ADS)

    Batagelj, Vladimir; Brandes, Ulrik

    2005-03-01

    Random networks are frequently generated, for example, to investigate the effects of model parameters on network properties or to test the performance of algorithms. Recent interest in the statistics of large-scale networks sparked a growing demand for network generators that can generate large numbers of large networks quickly. We here present simple and efficient algorithms to randomly generate networks according to the most commonly used models. Their running time and space requirement is linear in the size of the network generated, and they are easily implemented.