Randomized phase II study of a bendamustine monotherapy schedule for relapsed or refractory low-grade B-cell non-Hodgkin lymphoma or mantle cell lymphoma (RABBIT-14).

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Itoh, Kuniaki; Igarashi, Tadahiko; Irisawa, Hiroyuki; Aotsuka, Nobuyuki; Masuda, Shinichi; Utsu, Yoshikazu; Tsujimura, Hideki; Tsukasaki, Kunihiro; Wakita, Hisashi

2017-10-30

The aim of this randomized phase II study was to improve the treatment delays and discontinuations associated with bendamustine use by comparing the effect of Benda-14 (intravenous bendamustine, 120 mg/m 2 on days 1 and 15, repeated every 4 weeks for a total of 6 cycles) with those of the standard treatment in relapsed indolent lymphoma and/or mantle cell lymphoma. Forty-six patients were randomly assigned to the treatments from September 2012 to February 2016. Treatment accomplishment rate and median relative dose intensity were similar in both arms: 38 and 63.4% in the Benda-14 arm and 41 and 66.3% in the standard treatment arm, respectively. The overall response rate and median progression-free survival, respectively, were 83% and 21.0 months for Benda-14, and 77% and 15.5 months for the standard treatment. Benda-14 induced favorable responses with less frequent hematological toxicities.

Ibrutinib Is Effective in the Treatment of Autoimmune Haemolytic Anaemia in Mantle Cell Lymphoma

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Aliénor Galinier

2017-01-01

Full Text Available Autoimmune haemolytic anaemia (AIHA in mantle cell lymphoma (MCL is a rare but life-threatening complication. To date, there are no relevant data for treatment of AIHA in MCL. Ibrutinib, which has been approved for relapse/refractory MCL, is an immunomodulatory drug inhibiting Th2 activation and consequently the production of autoantibodies. We report a case of MCL with AIHA in which this form of anaemia was not controlled with the usual chemotherapy. Ibrutinib was used when MCL with AIHA relapsed, and it allowed rapid remission of AIHA and rapid discontinuation of steroid therapy.

Mantle-cell lymphoma.

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Barista, I; Romaguera, J E; Cabanillas, F

2001-03-01

During the past decade, mantle-cell lymphoma has been established as a new disease entity. The normal counterparts of the cells forming this malignant lymphoma are found in the mantle zone of the lymph node, a thin layer surrounding the germinal follicles. These cells have small to medium-sized nuclei, are commonly indented or cleaved, and stain positively with CD5, CD20, cyclin D1, and FMC7 antibodies. Because of its morphological appearance and a resemblance to other low-grade lymphomas, many of which grow slowly, this lymphoma was initially thought to be an indolent tumour, but its natural course was not thoroughly investigated until the 1990s, when the BCL1 oncogene was identified as a marker for this disease. Mantle-cell lymphoma is a discrete entity, unrelated to small lymphocytic or small-cleaved-cell lymphomas.

Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma.

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Tam, Constantine S; Anderson, Mary Ann; Pott, Christiane; Agarwal, Rishu; Handunnetti, Sasanka; Hicks, Rodney J; Burbury, Kate; Turner, Gillian; Di Iulio, Juliana; Bressel, Mathias; Westerman, David; Lade, Stephen; Dreyling, Martin; Dawson, Sarah-Jane; Dawson, Mark A; Seymour, John F; Roberts, Andrew W

2018-03-29

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (Pibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a "real world" study.

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Epperla, Narendranath; Hamadani, Mehdi; Cashen, Amanda F; Ahn, Kwang W; Oak, Eunhye; Kanate, Abraham S; Calzada, Oscar; Cohen, Jonathon B; Farmer, Luke; Ghosh, Nilanjan; Tallarico, Michael; Nabhan, Chadi; Costa, Luciano J; Kenkre, Vaishalee P; Hari, Parameswaran N; Fenske, Timothy S

2017-12-01

Ibrutinib has demonstrated significant activity in relapsed/refractory mantle cell lymphoma (MCL) in clinical trials. However, the impact of hematopoietic cell transplantation on the outcomes of ibrutinib and the predictive factors for ibrutinib response has not been well studied. Hence, we conducted a multicenter retrospective study of MCL patients who received ibrutinib to (1) determine the overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of ibrutinib in routine clinical practice, (2) examine characteristics predictive of response to ibrutinib therapy, and (3) describe the outcomes of patients failing ibrutinib. Ninety-seven patients met the eligibility criteria. Overall response rate and median DOR to ibrutinib were 65% and 17 months, respectively. Only lack of primary refractory disease was predictive of ibrutinib response on multivariate analysis. Twenty-nine patients received postibrutinib therapies, with an ORR of 48% and a median DOR of 3 months. The median OS and PFS for the entire group (n = 97) was 22 and 15 months, respectively. On multivariate analysis, ibrutinib response, low MCL international prognostic index, and absence of primary refractory disease were predictors of better PFS, while ibrutinib response and Eastern Cooperative Oncology Group performance status ≤1 were predictors of better OS. The median OS postibrutinib failure was 2.5 months. Our results confirm the high ORR and DOR of ibrutinib in MCL and that prior hematopoietic cell transplantation does not negatively influence ibrutinib outcomes. Survival following ibrutinib failure is poor with no specific subsequent therapy showing superior activity in this setting. As a result, for select (transplant eligible) patients, allogeneic transplant should be strongly considered soon after ibrutinib response is documented to provide durable responses. Copyright © 2017 John Wiley & Sons, Ltd.

Mantle cell lymphoma-current literature overview.

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Pejcic, Ivica; Petkovic, Ivan; Vrbic, Svetislav; Filipovic, Sladjana; Balic, Mirjana; Cvetanovic, Ana

2014-01-01

Mantle cell lymphoma (MCL) is a distinct subtype of lymphoma identified as a particular entity in the early 1990s. The prognosis of MCL is generally poor, and is considered one of the worst among all B-cell lymphomas. In general, conventional chemotherapy is only palliative and the median duration of remissions is only 1-2 years. With the exception of allogeneic hematopoietic stem cell transplantation (allo-SCT), current treatment approaches are not curative and the corresponding survival curve is characterized by a relatively steep and continuous decline, with a median survival of about 4 years and watch and wait strategy. Optimal first-line therapy in MCL is not established yet. Very intensive regimens, including autologous (auto-SCT) and allo-SCT, seem to be required to improve the outcome. Allogeneic stem cell transplantation is the only therapy that can achieve a plateau in the survival curve, but, however, it is not applicable in most of the cases due to the patients' older age when the disease mostly occurs. Molecular knowledge of MCL has progressed and therefore a large number of molecular targeted therapies have been introduced in relapsed and refractory disease.

[Mantle cell lymphoma: Towards a personalized therapeutic strategy?].

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Navarro Matilla, Belén; García-Marco, José A

2015-06-22

Mantle cell lymphoma (MCL) is a clinically heterogeneous non-Hodgkin lymphoma with an aggressive clinical behaviour and short survival in some cases and an indolent course in others. Advances in the biology and pathogenesis of MCL have unveiled several genes involved in deregulation of cell cycle checkpoints and the finding of subclonal populations with specific recurrent mutations (p53, ATM, NOTCH2) with an impact on disease progression and refractoriness to treatment. Prognostic stratification helps to distinguish between indolent and aggressive forms of MCL. Currently, younger fit patients benefit from more intensive front line chemotherapy regimens and consolidation with autologous transplantation, while older or frail patients are treated with less intensive regimens and rituximab maintenance. For relapsing disease, the introduction of bortezomib and lenalidomide containing regimens and B-cell receptor pathway inhibitors such as ibrutinib and idelalisib in combination with immunochemotherapy have emerged as therapeutic agents with promising clinical outcomes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Detailed Functional and Proteomic Characterization of Fludarabine Resistance in Mantle Cell Lymphoma Cells.

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Lucie Lorkova

Full Text Available Mantle cell lymphoma (MCL is a chronically relapsing aggressive type of B-cell non-Hodgkin lymphoma considered incurable by currently used treatment approaches. Fludarabine is a purine analog clinically still widely used in the therapy of relapsed MCL. Molecular mechanisms of fludarabine resistance have not, however, been studied in the setting of MCL so far. We therefore derived fludarabine-resistant MCL cells (Mino/FR and performed their detailed functional and proteomic characterization compared to the original fludarabine sensitive cells (Mino. We demonstrated that Mino/FR were highly cross-resistant to other antinucleosides (cytarabine, cladribine, gemcitabine and to an inhibitor of Bruton tyrosine kinase (BTK ibrutinib. Sensitivity to other types of anti-lymphoma agents was altered only mildly (methotrexate, doxorubicin, bortezomib or remained unaffacted (cisplatin, bendamustine. The detailed proteomic analysis of Mino/FR compared to Mino cells unveiled over 300 differentially expressed proteins. Mino/FR were characterized by the marked downregulation of deoxycytidine kinase (dCK and BTK (thus explaining the observed crossresistance to antinucleosides and ibrutinib, but also by the upregulation of several enzymes of de novo nucleotide synthesis, as well as the up-regulation of the numerous proteins of DNA repair and replication. The significant upregulation of the key antiapoptotic protein Bcl-2 in Mino/FR cells was associated with the markedly increased sensitivity of the fludarabine-resistant MCL cells to Bcl-2-specific inhibitor ABT199 compared to fludarabine-sensitive cells. Our data thus demonstrate that a detailed molecular analysis of drug-resistant tumor cells can indeed open a way to personalized therapy of resistant malignancies.

Mantle Cell Lymphoma

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... Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma Primary Central Nervous System Lymphoma T-Cell Lymphoma Transformed Mycosis Fungoides Waldenstrom Macroglobulinemia Young Adult Lymphoma Overview Treatment Options Relapsed/Refractory Long-term ...

A rare tumoral combination, synchronous lung adenocarcinoma and mantle cell lymphoma of the pleura

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Foroulis Christophoros N

2008-12-01

Full Text Available Abstract Background Coexistence of adenocarcinoma and mantle cell lymphoma in the same or different anatomical sites is extremely rare. We present a case of incidental discovery of primary lung adenocarcinoma and mantle cell lymphoma involving the pleura, during an axillary thoracotomy performed for a benign condition. Case presentation A 73-year old male underwent bullectomy and apical pleurectomy for persistent pneumothorax. A bulla of the lung apex was resected en bloc with a scar-like lesion of the lung, which was located in proximity with the bulla origin, by a wide wedge resection. Histologic examination of the stripped-off parietal pleura and of the bullectomy specimen revealed the synchronous occurrence of two distinct neoplasms, a lymphoma infiltrating the pleura and a primary, early lung adenocarcinoma. Immunohistochemical and fluorescence in situ hybridization assays were performed. The morphologic, immunophenotypic and genetic findings supported the diagnosis of primary lung adenocarcinoma (papillary subtype coexisting with a non-Hodgkin, B-cell lineage, mantle cell lymphoma involving both, visceral and parietal pleura and without mediastinal lymph node involvement. The neoplastic lymphoid cells showed the characteristic immunophenotype of mantle cell lymphoma and the translocation t(11;14. The patient received 6 cycles of chemotherapy, while pulmonary function tests precluded further pulmonary parenchyma resection (lobectomy for his adenocarcinoma. The patient is alive and without clinical and radiological findings of local recurrence or distant relapse from both tumors 14 months later. Conclusion This is the first reported case of a rare tumoral combination involving simultaneously lung and pleura, emphasizing at the incidental discovery of the two coexisting neoplasms during a procedure performed for a benign condition. Any tissue specimen resected during operations performed for non-tumoral conditions should be routinely sent for

Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells.

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Ma, Jiao; Lu, Pin; Guo, Ailin; Cheng, Shuhua; Zong, Hongliang; Martin, Peter; Coleman, Morton; Wang, Y Lynn

2014-09-01

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach. © 2014 John Wiley & Sons Ltd.

The mantle cells lymphoma: a proposed treatment

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Chavez Martinez, Marlene Elizabeth

2012-01-01

A literature review was performed on mantle cells lymphoma in the therapeutic schemes. The literature that has been used is published in journals of medicine specializing in hematology, oncology, radiation therapy, molecular biology and internal medicine. The literature review was performed to propose a scheme of treatment according to Costa Rica. Epigenetic alterations have been revealed in patients with mantle lymphoma on current researches. The mantle lymphoma pathology has been described in various forms of clinical and histological presentation, stressing the importance of detailing the different methods and diagnostic reports. Working groups have proposed and developed various chemotherapy regimens and concluded that CHOP alone is without effect in mantle cell lymphoma unlike R-hyper-CVAD, CHOP / DHAP, high-dose Ara-C. Researchers have tried to develop new treatments based vaccines, use of modified viruses, specific monoclonal antibodies. The classic treatment has been triple intrathecal therapy. The central nervous system has been one of the most momentous sites of mantle cell lymphoma infiltration because poorer patient prognosis [es

CAR-T cells and allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia.

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Liu, Jun; Zhang, Xi; Zhong, Jiang F; Zhang, Cheng

2017-10-01

Relapsed/refractory acute lymphoblastic leukemia (ALL) has a low remission rate after chemotherapy, a high relapse rate and poor long-term survival even when allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Chimeric antigen receptors redirected T cells (CAR-T cells) can enhance disease remission with a favorable outcome for relapsed/refractory ALL, though some cases quickly relapsed after CAR-T cell treatment. Thus, treatment with CAR-T cells followed by allo-HSCT may be the best way to treat relapsed/refractory ALL. In this review, we first discuss the different types of CAR-T cells. We then discuss the treatment of relapsed/refractory ALL using only CAR-T cells. Finally, we discuss the use of CAR-T cells, followed by allo-HSCT, for the treatment of relapsed/refractory ALL.

How to manage mantle cell lymphoma.

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Dreyling, M; Ferrero, S; Hermine, O

2014-11-01

Mantle cell lymphoma (MCL) is no longer a hopeless disease. Considered to carry a uniformly dismal prognosis so far, during the last years it has been rediscovered as a heterogeneous clinical and biological entity. Such a complexity has been highlighted by molecular genetics, unraveling different pathways of cell survival and progression. Concurrently, the application of new therapeutic paradigms including rituximab, high-dose cytarabine and stem cell transplantation dramatically improved treatment activity and the introduction of innovative targeted molecules has already led to new patient perspectives. In this completely new and continually evolving landscape, the clinical hemato-oncologist might feel disoriented on what are the best current strategies to handle such a critical disease and the gold standard therapeutic options for MCL. Here we address some burning questions on how to manage MCL patients, spacing from prognostic issues to the dilemma of personalized treatment in different scenarios of the disease: how to diagnose an MCL? Which are the fundamental staging procedures? What are the most reliable prognosticators? Is there a place for watch and wait? Which are the best treatment options for younger, elderly and frail patients? Which patients are addressable to high-dose therapy? What is the role of allogeneic transplantation? What is the most appropriate approach for relapsing disease in different categories of patients? What novelties are going to be introduced in the near future? The practical algorithms here discussed represent an evidence-based approach derived from results of multicenter and randomized trials.

Lenalidomide-bendamustine-rituximab in untreated mantle cell lymphoma > 65 years with untreated mantle cell lymphoma

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Albertsson-Lindblad, Alexandra; Kolstad, Arne; Laurell, Anna

2016-01-01

For elderly patients with mantle cell lymphoma (MCL), there is no defined standard therapy. In this multicenter open-label phase I/II trial we evaluated the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment to elderly MCL patients. Patients >65 years with untr......For elderly patients with mantle cell lymphoma (MCL), there is no defined standard therapy. In this multicenter open-label phase I/II trial we evaluated the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment to elderly MCL patients. Patients >65 years...

Aberrant Expression of CD19 and CD43 in a Patient With Therapy-Related Acute Myeloid Leukemia and a History of Mantle Cell Lymphoma

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Yen-Chuan Hsieh

2009-07-01

Full Text Available Mantle cell lymphoma (MCL is an aggressive B cell lymphoma with frequent involvement of the gastrointestinal tract and peripheral blood (PB. In addition to the B cell markers, the neoplastic cells express CD5 and CD43. In patients with a prior history of MCL with PB involvement, the appearance of leukemic cells after chemotherapy usually heralds a relapse, particularly if the leukemic cells express B cell markers and CD43. We report a patient with MCL who presented with multiple lymphomatous polyposis of the intestine. The staging procedures revealed the involvement of lymph nodes, bone marrow and PB. Three years after chemotherapy, thrombocytopenia with the appearance of rare leukemic cells in the PB was noted. Leukemic cells obtained from bone marrow aspirate expressed CD19 and CD43, suggesting a relapse. Detailed cytomorphological and immunophenotypic studies unveiled the myeloid nature of these leukemic cells, and a diagnosis of therapy-related acute myeloid leukemia was made. This case illustrates the importance of morphologic examination and performing a complete antibody panel in the diagnosis of a suspected relapse in patients with a prior history of lymphoma.

Mantle cell lymphoma of the larynx: Primary case report

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Naciri Sarah

2012-07-01

Full Text Available Abstract Introduction Primary laryngeal lymphomas are exceedingly rare. Only about a hundred cases have been reported. They consist mainly of non-Hodgkin lymphoma, especially of diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue. We report the first case of a primary laryngeal mantle cell lymphoma. Case presentation We report a case of a primary mantle cell lymphoma of the larynx in a 70-year-old North African non-smoker male. We present a detailed report of his clinical and paraclinical data as well as treatment options. Conclusions Mantle cell lymphoma is a very aggressive lymphoma subset associated with poor prognosis. Laryngeal mantle cell lymphoma is exceedingly rare. To the best of our knowledge, this is the first case to ever be reported.

Bendamustine HCL for the treatment of relapsed indolent non-Hodgkin’s lymphoma

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Rudolf Weide

2008-09-01

Full Text Available Rudolf WeidePraxisklinik für Hämatologie und Onkologie, Koblenz, GermanyAbstract: Bendamustine is an alkylating agent which also shows properties of a purine analog. Because of its unique mechanism of action it shows activity in relapsed indolent lymphomas which are resistant to alkylating agents, purine analogs, and rituximab. Bendamustine has a favorable toxicity profile causing no alopecia and only a moderate hematotoxicity and gastrointestinal toxicity. Combinations of bendamustine with mitoxantrone and rituximab and with rituximab alone have been shown to be highly active in relapsed/refractory indolent lymphomas and mantle cell lymphomas achieving long lasting complete remissions. Because of only moderate toxicity these combinations can be applied safely in elderly patients who can be treated in an outpatient setting.Keywords: bendamustine, relapsed-indolent, non-Hodgkin’s lymphoma

Novel therapeutic options for relapsed hairy cell leukemia.

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Jain, Preetesh; Polliack, Aaron; Ravandi, Farhad

2015-01-01

The majority of patients with hairy cell leukemia (HCL) achieve a response to therapy with cladribine or pentostatin with or without rituximab. However, late relapses can occur. Treatment of relapsed HCL can be difficult due to a poor tolerance to chemotherapy, increased risk of infections and decreased responsiveness to chemotherapy. The identification of BRAFV600E mutations and the role of aberrant MEK kinase and Bruton's tyrosine kinase (BTK) pathways in the pathogenesis of HCL have helped to develop novel targeted therapies for these patients. Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox), BRAF inhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib. Furthermore, the VH4-34 molecular variant of classic HCL has been identified to be less responsive to chemotherapy. Herein, we review the results of the ongoing clinical trials and potential future therapies for relapsed/refractory HCL.

Early-stage mantle cell lymphoma

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Dabaja, B S; Zelenetz, A D; Ng, A K

2017-01-01

Background: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. Patients and methods: In this 13-institution study, we examined...

Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation.

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Peled, Jonathan U; Devlin, Sean M; Staffas, Anna; Lumish, Melissa; Khanin, Raya; Littmann, Eric R; Ling, Lilan; Kosuri, Satyajit; Maloy, Molly; Slingerland, John B; Ahr, Katya F; Porosnicu Rodriguez, Kori A; Shono, Yusuke; Slingerland, Ann E; Docampo, Melissa D; Sung, Anthony D; Weber, Daniela; Alousi, Amin M; Gyurkocza, Boglarka; Ponce, Doris M; Barker, Juliet N; Perales, Miguel-Angel; Giralt, Sergio A; Taur, Ying; Pamer, Eric G; Jenq, Robert R; van den Brink, Marcel R M

2017-05-20

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Gastric and colonic mantle cell lymphoma - incidental discovery.

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Pitigoi, Dan; Stoica, Victor; Stoia, Razvan; Dobrea, Camelia; Becheanu, Gabriel; Diculescu, Mircea

2009-03-01

A 65-year old patient, with no medical history, was admitted for lower gastrointestinal bleeding. On clinical examination the patient seemed to be in good health. However the examination was completed with a rectosigmoidoscopy revealing the presence of mucosal erosions, ulcerations, multiple papulae. The histopathological examination raised the suspicion of a colonic lymphoma. Gastric biopsies suggested a gastric MALT type lymphoma associated to the colonic lymphoma, but the immunohistochemical profile corresponded to a mantle cell lymphoma. In spite of the general poor prognosis of mantle cell lymphoma, our patient had a good clinical and endoscopic response to the standard cyclophosphamide, vincristine, prednisone (CVP) therapy. The cases of gastric and colonic mantle lymphoma are rare, the response to therapy is poor; fortunately, our patient had a complete resolution after completion of the six cycles of chemotherapy.

A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

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Tucker DL

2015-06-01

Full Text Available David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL and chronic lymphocytic leukemia (CLL, small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which functions by irreversible inhibition of the downstream signaling pathway of the B-cell receptor, which normally promotes cell survival and proliferation. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile even in elderly and multiply pretreated patient cohorts. Although the majority of disease responses tend to be partial, efficacy data have also been encouraging with more than two-thirds of patients with CLL and MCL demonstrating a durable response, even in the high-risk disease setting. Resistance mechanisms are only partially understood and appear to be multifactorial, including the binding site mutation C481S, and escape through other common cell-signaling pathways. This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, both as a single agent and in combination with other therapies, and considers how this drug is likely to be used in future clinical practice. Keywords: ibrutinib, mantle cell lymphoma, chronic lymphocytic leukemia, Bruton’s tyrosine kinase, lymphoproliferative disorders

Prevention and treatment of relapse after stem cell transplantation by cellular therapies.

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Falkenburg, Fred; Ruggiero, Eliana; Bonini, Chaira; Porter, David; Miller, Jeff; Malard, Floran; Mohty, Mohamad; Kröger, Nicolaus; Kolb, Hans Jochem

2018-05-24

Despite recent advances in reducing therapy-related mortality after allogeneic stem cell transplantation (alloSCT) relapse remains the major cause of treatment failure and little progress has been achieved in the last decades. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg/Germany in November 2016 international experts presented and discussed recent developments in the field. Here, the potential of cellular therapies including unspecific and specific T cells, genetically modified T cells, CAR-T cells, NK-cells, and second allografting in prevention and treatment of relapse after alloSCT are summarized.

[Mantle cell lymphoma, response to treatment and prognosis in 45 patients].

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Sorigue, Marc; Sancho, Juan-Manuel; García, Olga; Vila, Jordi; Moreno, Miriam; Ribera, Josep-Maria

2016-07-01

Mantle cell lymphoma (MCL) is a rare lymphoproliferative disorder, with frequent relapses and a poor prognosis. This study analyzes response to treatment and prognosis in a series of MCL patients. Retrospective study of MCL patients diagnosed in a single institution between 1996 and 2013. The cohort was divided according to the treatment received. Forty-five patients were included (32 male) with a median age of 66 years old. Twenty-one received intensive chemotherapy or chemoimmunotherapy (based on high-dose cytarabine), 13 semi-intensive (without high-dose cytarabine), 8 not intensive and 3 did not require treatment. Overall response rate was 85% in the intensive and 77% in the semi-intensive treatment groups. In multivariate analysis, intensive treatment was correlated with a longer progression-free survival (hazard ratio 9.8 [95% CI 2.7-35.5], P=.001) and overall survival (4.5 [1.2-17.8], P=.03). In this retrospective series of MCL patients, intensive treatment was correlated with better outcomes than the other treatment modalities. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Cutaneous lesions as presentation form of mantle cell lymphoma

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Nayra Merino de Paz

2011-12-01

Full Text Available Mantle cell lymphoma is a type of no-Hodgkin lymphoma that affects extranodal areas, especially, bone narrow, digestive tract and Waldeyer ring. Here we report a case of mantle cell lymphoma IV Ann Arbor stage with cutaneous lesions on nasal dorsum and gland as the first manifestations. Skin involvement is a very rare manifestation and less than 20 cases have been reported in the literature. The importance of stablishing multidisciplinary relationships for a global approach has been shown by this clinical case.

Use of acalabrutinib in patients with mantle cell lymphoma.

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Awan, Farrukh T; Jurczak, Wojciech

2018-06-01

Acalabrutinib, a selective Bruton tyrosine kinase (BTK) inhibitor, was granted accelerated approval by the FDA on 31 October 2017 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Areas covered: This narrative review provides an overview of acalabrutinib, its use in clinical practice and potential future developments. Expert commentary: BTK inhibitors have demonstrated efficacy in patients with relapsed or refractory MCL. To prepare patients for therapy, all preexisting infections should be diagnosed and treated, and infection prophylaxis undertaken. Serious adverse reactions are rare with acalabrutinib; however, patients should be made aware of common adverse events such as headaches, which usually resolve within one month without medical treatment. Interaction with other drugs appears to be less of an issue with acalabrutinib than with ibrutinib; however, patients receiving acalabrutinib therapy must be advised not to take any additional medications without first consulting with their treating physician. A key unmet medical need is treatment options for patients in whom BTK inhibitors are discontinued, because of either intolerance or refractory disease. Patients not tolerating ibrutinib could be switched to acalabrutinib, which has improved selectivity and increased tolerability. First-line treatment with acalabrutinib is being investigated.

Synchronous Pulmonary Malignancies: Atypical Presentation of Mantle Cell Lymphoma Masking a Lung Malignancy.

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Masha, Luke; Zinchuk, Andrey; Boosalis, Valia

2015-09-07

We present a case of a pleural space malignancy masked by an atypical presentation of mantle cell lymphoma. Our patient presented with a large pleural effusion and right sided pleural studding, initially attributed to a new diagnosis of mantle cell lymphoma. Rare atypical epithelial cells were also seen amongst the clonal population of lymphocytes. The patient lacked systemic manifestations of mantle cell lymphoma and did not improve with chemotherapy. A pleural biopsy ultimately revealed the presence of an undifferentiated carcinoma, favoring a lung primary. A discussion of synchronous pleural space malignancies involving lymphomas is given.

Mantle Cell Hyperplasia of Peripheral Lymph Nodes as Initial Manifestation of Sickle Cell Disease.

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Monabbati, Ahmad; Noori, Sadat; Safaei, Akbar; Ramzi, Mani; Eghbali, Seyedsajjad; Adib, Ali

2016-01-01

Sickle cell disease (SCD) is a well known hemoglobinopathy with usual manifestations including anemia, hyperbilirubinemia, and vasoocclusive complications. Despite presence of mild splenomegaly in early phase of the disease, lymphadenopathy is not an often finding of SCD. We introduce an undiagnosed case of SCD who presented in third decade of his life with multiple cervical lymphadenopathies and mild splenomegaly persistent for about five years. Histopathologic examination of the resected lymph nodes showed expansion of the mantle cell layers of secondary follicles as well as several monomorphic mantle cell nodules. To rule out possibility of a malignant process involving lymph nodes, an immunohistochemical panel was ordered which was in favor of benign mantle cell hyperplasia. Immunoglobulin gene rearrangement study showed no clonal bands and confirmed benign nature of the process. Respecting mild abnormalities on Complete Blood Count, peripheral blood smear was reviewed revealing some typical sickle red blood cells as well as rare nucleated red blood cells. Solubility test for hemoglobin (HB) S was positive. Hemoglobin electrophoresis confirmed diagnosis of homozygous HbS disease.

The Role of Cyclin D1 in the Chemoresistance of Mantle Cell Lymphoma

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2017-09-01

AWARD NUMBER: W81XWH-15-1-0297 TITLE: The Role of Cyclin D1 in the Chemoresistance of Mantle Cell Lymphoma PRINCIPAL INVESTIGATOR: Vu Ngo...AND SUBTITLE The Role of Cyclin D1 in the Chemoresistance of Mantle Cell Lymphoma 5a. CONTRACT NUMBER The Role of Cyclin D1 in the Chemoresistance of...Mantle Cell Lymphoma 5b. GRANT NUMBER GRANT1173 9905 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Vu Ngo 5e. TASK NUMBER E

Synchronous pulmonary malignancies: atypical presentation of mantle cell lymphoma masking a lung malignancy

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Luke Masha

2015-09-01

Full Text Available We present a case of a pleural space malignancy masked by an atypical presentation of mantle cell lymphoma. Our patient presented with a large pleural effusion and right sided pleural studding, initially attributed to a new diagnosis of mantle cell lymphoma. Rare atypical epithelial cells were also seen amongst the clonal population of lymphocytes. The patient lacked systemic manifestations of mantle cell lymphoma and did not improve with chemotherapy. A pleural biopsy ultimately revealed the presence of an undifferentiated carcinoma, favoring a lung primary. A discussion of synchronous pleural space malignancies involving lymphomas is given.

Treating Multiply Relapsed or Refractory Hairy Cell Leukemia

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In this trial, patients with hairy cell leukemia who have not responded or relapsed after initial chemotherapy will be randomly assigned to receive rituximab combined with either pentostatin or bendamustine.

PD-1hiTIM-3+ T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation

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Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

2015-01-01

Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1 hi TIM-3 + cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1 hi TIM-3 + T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing T N and T EMRA subsets. Importantly, increase of PD-1 hi TIM-3 + cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation

Enhanced gamma interferon responses of mouse spleen cells following immunotherapy for tuberculosis relapse.

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Gil, Olga; Vilaplana, Cristina; Guirado, Evelyn; Díaz, Jorge; Cáceres, Neus; Singh, Mahavir; Cardona, Pere-Joan

2008-11-01

Gamma interferon responses of spleen cells in mice were examined during postchemotherapy relapse of intraperitoneally induced latent tuberculous infection. The mycobacterial extract RUTI, which prevented the relapse, significantly enhanced the immune responses to secreted and structural recombinant mycobacterial antigens, suggesting that RUTI-mediated protection was mediated by activated T cells.

Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part I. Biology of relapse after transplantation.

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Gress, Ronald E; Miller, Jeffrey S; Battiwalla, Minoo; Bishop, Michael R; Giralt, Sergio A; Hardy, Nancy M; Kröger, Nicolaus; Wayne, Alan S; Landau, Dan A; Wu, Catherine J

2013-11-01

In the National Cancer Institute's Second Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Biology of Relapse discussed recent advances in understanding some of the host-, disease-, and transplantation-related contributions to relapse, emphasizing concepts with potential therapeutic implications. Relapse after hematopoietic stem cell transplantation (HSCT) represents tumor escape, from the cytotoxic effects of the conditioning regimen and from immunologic control mediated by reconstituted lymphocyte populations. Factors influencing the biology of the therapeutic graft-versus-malignancy (GVM) effect-and relapse-include conditioning regimen effects on lymphocyte populations and homeostasis, immunologic niches, and the tumor microenvironment; reconstitution of lymphocyte populations and establishment of functional immune competence; and genetic heterogeneity within the malignancy defining potential for clonal escape. Recent developments in T cell and natural killer cell homeostasis and reconstitution are reviewed, with implications for prevention and treatment of relapse, as is the application of modern genome sequencing to defining the biologic basis of GVM, clonal escape, and relapse after HSCT. Published by Elsevier Inc.

IgV H mutations in blastoid mantle cell lymphoma characterize a subgroup with a tendency to more favourable clinical outcome.

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Cogliatti, Sergio B; Bertoni, Francesco; Zimmermann, Dieter R; Henz, Samuel; Diss, Tim C; Ghielmini, Michele; Schmid, Ulrico

2005-07-01

Mantle cell lymphoma (MCL) is associated with a very unfavourable clinical course. This is particularly true for mantle cell lymphoma of the blastoid subtype (MCL-b). In order to define prognostic factors, we analysed the impact of immunoglobulin heavy chain variable (IgV H) gene somatic hypermutations on clinical outcome in a series of 21 cases of morphologically, phenotypically, and genotypically well-characterized MCL-b. Testing and estimation were performed using log-rank statistics and displayed on Kaplan-Meier graphs. Thirteen of 21 cases of MCL-b revealed a homology rate of > or = 99% compared to IgV H germ-line sequences in the databases and were scored as non-mutated. Eight of 21 cases (38%) of MCL-b were mutated. In MCL-b the mutation frequency was usually low and the mutation pattern was only rarely antigen-selected, in contrast to a control group of 11 cases with morphologically almost identical, but phenotypically and genotypically clearly distinguishable, diffuse large B cell lymphoma, derived, most likely, from germinal centre B cells. In our series of 21 MCL-b, positive IgV H mutational status, irrespective of varying homology thresholds, had no statistically significant prognostic impact on event-free or overall survival. However, mutated MCL-b tended to present more frequently at an earlier stage and without bone marrow involvement and to show lower rates of relapse and death, resulting in a more favourable clinical outcome. Copyright 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A rare case of breast carcinoma co-existing with axillary mantle cell lymphoma

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Scally John

2003-12-01

Full Text Available Abstract Background Mantle cell lymphoma (MCL is a rare variety of non-Hodgkin's lymphoma which originates from CD5+ B-cell population in the mantle zones of lymphoid follicles. Coexistence of such tumours in the axillary lymph nodes with invasive breast cancers without prior history of adjuvant chemotherapy or radiotherapy has not been previously reported in literature. Case report We report a rare case of breast cancer co-existing with stage I mantle cell lymphoma of the ipsilateral axillary lymph node detected fortuitously by population screening. Conclusion Though some studies have tried to prove breast carcinomas and lymphomas to share a common molecular or viral link, more research needs to be done to establish whether such a link truly exists.

Immunohistochemical detection of cdc2 is useful in predicting survival in patients with mantle cell lymphoma.

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Hui, David; Reiman, Tony; Hanson, John; Linford, Rick; Wong, Winson; Belch, Andrew; Lai, Raymond

2005-09-01

Recent cDNA microarray studies have reported the prognostic value of several genes in mantle cell lymphoma patients. We aimed to validate the prognostic significance of three of these genes: alpha-tubulin, cdc2, and CENP-F. The protein expression of alpha-tubulin, cdc2, and CENP-F was assessed using immunohistochemistry. Their immunoreactivity in 48 formalin-fixed/paraffin-embedded mantle cell lymphoma tumors was determined by estimating the percentage of positive cells. These results were correlated with the expression of proliferation marker Ki67 and survival. Of these 48 mantle cell lymphoma patients, 41 were men and seven were women. The median age at time of diagnosis was 64.5 years, and the overall median survival was 40 months. In benign lymph nodes, the expression of cdc2 and alpha-tubulin was restricted to the germinal centers; mantle zones were negative. Expression of CENP-F was more uniformly distributed. In mantle cell lymphoma, Ki67 significantly correlated with all three markers (P50%) and cdc2 (>25%) significantly correlated with shorter survival (Por=2 correlated with worse clinical outcome, and high clinical stage (ie 4 vs mantle cell lymphoma patients. Immunohistochemical detection of cdc2 and Ki67 may be a useful and simple method in evaluating the prognosis of mantle cell lymphoma patients.

Topotecan in the treatment of relapsed small cell lung cancer

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Elisabeth Quoix

2008-12-01

Full Text Available Elisabeth QuoixService de Pneumologie, Hôpitaux Universitaires, Strasbourg, FranceAbstract: Small cell lung cancer (SCLC represents about 15% to 20% of all lung cancers. Chemotherapy is the cornerstone of the treatment, cisplatin–etoposide combination being the most used combination as first-line therapy. Despite high initial chemosensitivity, most SCLC patients will experience relapse sooner or later. Unfortunately, second-line chemotherapy does not result in a high response rate like first-line therapy, most patients having developed wide chemoresistance. This chemoresistance is far more important in refractory patients, ie, those who never responded to first-line therapy or who relapsed within 3 months after the end of chemotherapy, than in sensitive patients, ie, those who relapse more than 3 months after the end of chemotherapy. Topotecan, a topoisomerase I inhibitor, is the most studied drug in this second-line setting and has proved its efficacy as a single agent and in combination. A phase III trial comparing oral topotecan to best supportive care (BSC in relapsed SCLC demonstrated a significant survival benefit as well as a better quality of life. Although the usual schedule is 1.5 mg/m2, days 1–5 intravenously, it is not convenient for patients with relapsed SCLC, especially those who are refractory because of their short survival expectation. Oral topotecan is of similar efficacy and much more convenient with limited stay in a treatment unit and has a comparable toxicity profile for these patients with short expected survival. Combination of topotecan with platinum salts or taxanes does not seem to improve further the outcome of the patients and thus single-agent therapy with topotecan is the standard treatment for relapsed SCLC.Keywords: topotecan, small cell lung cancer, chemoresistance

Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality.

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Fenske, Timothy S; Zhang, Mei-Jie; Carreras, Jeanette; Ayala, Ernesto; Burns, Linda J; Cashen, Amanda; Costa, Luciano J; Freytes, César O; Gale, Robert P; Hamadani, Mehdi; Holmberg, Leona A; Inwards, David J; Lazarus, Hillard M; Maziarz, Richard T; Munker, Reinhold; Perales, Miguel-Angel; Rizzieri, David A; Schouten, Harry C; Smith, Sonali M; Waller, Edmund K; Wirk, Baldeep M; Laport, Ginna G; Maloney, David G; Montoto, Silvia; Hari, Parameswaran N

2014-02-01

To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT. For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia.

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Rydström, Anna; Hallner, Alexander; Aurelius, Johan; Sander, Frida Ewald; Bernson, Elin; Kiffin, Roberta; Thoren, Fredrik Bergh; Hellstrand, Kristoffer; Martner, Anna

2017-08-01

Relapse of leukemia in the postchemotherapy phase contributes to the poor prognosis and survival in patients with acute myeloid leukemia (AML). In an international phase IV trial (ClinicalTrials.gov; NCT01347996), 84 patients with AML in first complete remission who had not undergone transplantation received immunotherapy with histamine dihydrochloride (HDC) and low-dose IL-2 with the aim of preventing relapse. The dynamics of myeloid cell counts and expression of activation markers was assessed before and after cycles of immunotherapy and correlated with clinical outcome in terms of relapse risk and survival. During cycles, a pronounced increase in blood eosinophil counts was observed along with a reduction in monocyte and neutrophil counts. A strong reduction of blood monocyte counts during the first HDC/IL-2 treatment cycle predicted leukemia-free survival. The HDC component of the immunotherapy exerts agonist activity at histamine type 2 receptors (H2Rs) that are expressed by myeloid cells. It was observed that the density of H 2 R expression in blood monocytes increased during cycles of immunotherapy and that high monocyte H 2 R expression implied reduced relapse risk and improved overall survival. Several other activation markers, including HLA-DR, CD86, and CD40, were induced in monocytes and dendritic cells during immunotherapy but did not predict clinical outcome. In addition, expression of HLA-ABC increased in all myeloid populations during therapy. A low expression of HLA-ABC was associated with reduced relapse risk. These results suggest that aspects of myeloid cell biology may impact clinical benefit of relapse-preventive immunotherapy in AML. © Society for Leukocyte Biology.

Central nervous system involvement in mantle cell lymphoma : clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network

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Cheah, C. Y.; George, A.; Gine, E.; Chiappella, A.; Kluin-Nelemans, H. C.; Jurczak, W.; Krawczyk, K.; Mocikova, H.; Klener, P.; Salek, D.; Walewski, J.; Szymczyk, M.; Smolej, L.; Auer, R. L.; Ritchie, D. S.; Arcaini, L.; Williams, M. E.; Dreyling, M.; Seymour, J. F.

Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described. We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions.

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation.

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Link, C S; Teipel, R; Heidenreich, F; Rücker-Braun, E; Schmiedgen, M; Reinhardt, J; Oelschlägel, U; von Bonin, M; Middeke, J M; Muetherig, A; Trautmann-Grill, K; Platzbecker, U; Bornhäuser, M; Schetelig, J

2016-06-01

Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

Relapsed Diffuse Large B-Cell Lymphoma Treated by Reduced-Intensity Allogeneic Stem Cell Transplantation with Donor Lymphocyte Infusion

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Chudhry, Q.N.; Ahmed, P.; Ullah, K.; Satti, T.M.; Raza, S.; Mehmood, S.K.; Akram, M.; Ahmed, S.

2010-01-01

A 42 years old male with relapsed diffuse large B-cell lymphoma was given second-line chemotherapy followed by reduced intensity allogeneic stem cell transplantation from HLA matched brother. Twelve weeks post transplant, his disease relapsed evidenced by the appearance of lymphoma cells in the peripheral blood and declining donor chimerism. Donor lymphocyte infusion was given that induced complete lymphoma remission. The patient is well 3 years post transplant with his disease in complete remission. (author)

Conjunctival mass as an initial presentation of mantle cell lymphoma: a case report

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Khanlari Mahsa

2012-12-01

Full Text Available Abstract Background To describe a rare manifestation of mantle cell lymphoma (MCL in conjunctiva, with clinical, hisologic, immunohistologic and genetic findings together with review of the Literature. Case presentation Most ocular adnexal lymphomas are extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT. A few cases of ocular adnexal mantle cell lymphomas have been reported in the literature. We present a case of mantle cell lymphoma presenting as right conjunctival mass of at least three months duration in a 64-year-old man. Histopathologic examination showed a proliferation of monomorphous small-to-medium-sized lymphoid cells with cleaved nuclei in the subconjunctiva. By immunohistochemistry, the infiltrate was positive for CD20, CD5, BCL-2, cyclin D1, and the transcription factor SOX11. Fluorescent in situ hybridization demonstrated the presence of IGH-CCND1 fusion indicating t(11;14. Conclusion A rigorous approach to initial diagnosis and staging of small cell lymphomas of the ocular adnexa is needed. The recognition of ocular MCL requires appropriate immunohistochemical staining and/or genetic confirmation to differentiate this rare form of presentation of MCL from other more frequent small cell lymphomas.

Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network

DEFF Research Database (Denmark)

Hoster, Eva; Klapper, Wolfram; Hermine, Olivier

2014-01-01

PURPOSE: Mantle-cell lymphoma (MCL) is a distinct B-cell lymphoma associated with poor outcome. In 2008, the MCL International Prognostic Index (MIPI) was developed as the first prognostic stratification tool specifically directed to patients with MCL. External validation was planned.......9) and 2.6 (2.0 to 3.3), respectively. MIPI was similarly prognostic for TTF. All four clinical baseline characteristics constituting the MIPI, age, performance status, lactate dehydrogenase level, and WBC count, were confirmed as independent prognostic factors for OS and TTF. The validity of MIPI...

Early lymphocyte recovery as a predictor of outcome, including relapse, after hematopoieticstem cell transplantation

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Juliane Morando

2012-01-01

Full Text Available BACKGROUND: Despite advances in the treatment of acute leukemia, many patients need to undergo hematopoietic stem cell transplantation. Recent studies show that early lymphocyte recovery may be a predictor of relapse and survival in these patients. OBJECTIVE: To analyze the influence of lymphocyte recovery on Days +30 and +100 post-transplant on the occurrence of relapse and survival. METHODS: A descriptive, retrospective study was performed of 137 under 21-year-old patients who were submitted to hematopoietic stem cell transplantation for acute leukemia between 1995 and 2008. A lymphocyte count 0.3 x 10(9/L were considered adequate. Lymphocyte recovery was also analyzed on Day +100 with < 0.75 x 10(9/Land < 0.75 x 10(9/L being considered inadequate and adequate lymphocyte recovery, respectively. RESULTS: There was no significant difference in the occurrence of relapse between patients with inadequate and adequate lymphocyte recovery on Day +30 post-transplant. However, the transplant-related mortality was significantly higher in patients with inadequate recovery on Day +30. Patients with inadequate lymphocyte recovery on Day +30 had worse overall survival and relapse-free survival than patients with adequate recovery. There was no significant difference in the occurrence of infections and acute or chronic graft-versus-host disease. Patients with inadequate lymphocyte recovery on Day +100 had worse overall survival and relapse-free survival and a higher cumulative incidence of relapse. CONCLUSION: The evaluation of lymphocyte recovery on Day +30 is not a good predictor of relapse after transplant however patients with inadequate lymphocyte recovery had worse overall survival and relapse-free survival. Inadequate lymphocyte recovery on Day +100 is correlated with higher cumulative relapse as well as lower overall survival and relapse-free survival.

Mantle cell lymphoma of the gastrointestinal tract presenting with multiple intussusceptions – case report and review of literature

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Abo Stephen M

2009-07-01

Full Text Available Abstract Background Mantle cell lymphoma (MCL is an aggressive type of B-cell non-Hodgkin's lymphoma that originates from small to medium sized lymphocytes located in the mantle zone of the lymph node. Extra nodal involvement is present in the majority of cases, with a peculiar tendency to invade the gastro-intestinal tract in the form of multiple lymphomatous polyposis. MCL can be accurately diagnosed with the use of the highly specific marker Cyclin D1. Few cases of mantle cell lymphoma presenting with intussuception have been reported. Here we present a rare case of multiple intussusceptions caused by mantle cell lymphoma and review the literature of this disease. Case presentation A 68-year-old male presented with pain, tenderness in the right lower abdomen, associated with nausea and non-bilious vomiting. CT scan of abdomen revealed ileo-colic intussusception. Laparoscopy confirmed multiple intussusceptions involving ileo-colic and ileo-ileal segments of gastrointestinal tract. A laparoscopically assisted right hemicolectomy and extended ileal resection was performed. Postoperative recovery was uneventful. The histology and immuno-histochemistry of the excised small and large bowel revealed mantle cell lymphoma with multiple lymphomatous polyposis and positivity to Cyclin D1 marker. The patient was successfully treated with Rituximab-CHOP chemotherapy and remains in complete remission at one-year follow-up. Conclusion This is a rare case of intestinal lymphomatous polyposis due to mantle cell lymphoma presenting with multiple small bowel intussusceptions. Our case highlights laparoscopic-assisted bowel resection as a potential and feasible option in the multi-disciplinary treatment of mantle cell lymphoma.

Dynamics of intraocular IFN-γ, IL-17 and IL-10-producing cell populations during relapsing and monophasic rat experimental autoimmune uveitis.

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Ulrike Kaufmann

Full Text Available A major limitation of most animal models of autoimmune diseases is that they do not reproduce the chronic or relapsing-remitting pattern characteristic of many human autoimmune diseases. This problem has been overcome in our rat models of experimentally induced monophasic or relapsing-remitting autoimmune uveitis (EAU, which depend on the inducing antigen peptides from retinal S-Antigen (monophasic EAU or interphotoreceptor retinoid-binding protein (relapsing EAU. These models enable us to compare autoreactive and regulatory T cell populations. Intraocular, but not peripheral T cells differ in their cytokine profiles (IFN-γ, IL-17 and IL-10 at distinct time points during monophasic or relapsing EAU. Only intraocular T cells concomitantly produced IFN-γ, IL-17 and/or IL-10. Monophasic EAU presented rising numbers of cells expressing IFN-γ and IL-17 (Th1/Th17 and cells expressing IL-10 or Foxp3. During relapsing uveitis an increase of intraocular IFN-γ+ cells and a concomitant decrease of IL-17+ cells was detected, while IL-10+ populations remained stable. Foxp3+ cells and cells expressing IL-10, even in combination with IFN-γ or IL-17, increased during the resolution of monophasic EAU, suggesting a regulatory role for these T cells. In general, cells producing multiple cytokines increased in monophasic and decreased in relapsing EAU. The distinct appearance of certain intraocular populations with characteristics of regulatory cells points to a differential influence of the ocular environment on T cells that induce acute and monophasic or relapsing disease. Here we provide evidence that different autoantigens can elicit distinct and differently regulated immune responses. IFN-γ, but not IL-17 seems to be the key player in relapsing-remitting uveitis, as shown by increased, synchronized relapses after intraocular application of IFN-γ. We demonstrated dynamic changes of the cytokine pattern during monophasic and relapsing-remitting disease

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

NARCIS (Netherlands)

Queirós, A.C. (Ana C.); R. Beekman (Renée); Vilarrasa-Blasi, R. (Roser); Duran-Ferrer, M. (Martí); Clot, G. (Guillem); Merkel, A. (Angelika); Raineri, E. (Emanuele); Russiñol, N. (Nuria); Castellano, G. (Giancarlo); S. Bea (Silvia); Navarro, A. (Alba); Kulis, M. (Marta); Verdaguer-Dot, N. (Núria); P. Jares (Pedro); A. Enjuanes (Anna); M.J. Calasanz (Maria); Bergmann, A. (Anke); Vater, I. (Inga); Salaverría, I. (Itziar); H.J.G. van de Werken (Harmen); W.H. Wilson (Wyndham); Datta, A. (Avik); P. Flicek (Paul); Royo, R. (Romina); J.H.A. Martens (Joost); Giné, E. (Eva); Lopez-Guillermo, A. (Armando); H. Stunnenberg (Henk); W. Klapper (Wolfram); C. Pott (Christiane); Heath, S. (Simon); I. Gut (Ivo); R. Siebert (Reiner); G. Campo (Gianluca); J.I. Martin-Subero (J.)

2016-01-01

textabstractWe analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and

Treatment relapsed subcutaneous panniculitis-like T-cell lymphoma together HPS by Cyclosporin A

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Ren'an Chen

2010-11-01

Full Text Available A 25-year-old man was diagnosised subcutaneous panniculitis-like T-cell lymphoma (SPTCL through biopsy of a nodule from the anterior chest. After the treatment with prednisone 90 mg 3 weeks and tapered off in 1 month, the disease released, but relapsed together with symptions of hemophagocytic syndrome eight months after the termination of prednisone. CHOEP recipe was given but with unsatisfactory result until cyclosporine was prescribed. Cyclosporine was removed 6 months later. There is no evidence of clinical relapse 1 year later. This case suggest that cyclosporine could be a selectable treatment even in relapsed SPTCL.

Screening for adenoviruses in haematological neoplasia: High prevalence in mantle cell lymphoma.

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Kosulin, Karin; Rauch, Margit; Ambros, Peter F; Pötschger, Ulrike; Chott, Andreas; Jäger, Ulrich; Drach, Johannes; Nader, Alexander; Lion, Thomas

2014-02-01

Human adenoviruses possess oncogenic capacity which is well documented in mammalian animal models, but their possible implication in human malignancy has remained enigmatic. Following primary infection, adenoviruses can persist in a latent state in lymphocytes where the virus is apparently able to evade immune surveillance. In the present study, we have employed a broad-spectrum adenovirus polymerase chain reaction (PCR) assay to systematically screen more than 200 diagnostic specimens of different lymphoid malignancies including acute lymphocytic leukaemia (n=50), chronic lymphocytic leukaemia (n=50), various types of malignant lymphoma (n=100) and multiple myeloma (n=11) for the presence of adenoviral sequences. While most entities analysed revealed negative findings in virtually all specimens tested, adenoviral DNA was detected in 15/36 (42%) mantle cell lymphomas investigated. The most prevalent adenoviral species detected was C, and less commonly B. Adenovirus-positive findings in patients with mantle cell lymphoma were made at different sites including bone marrow (n=7), intestine (n=5), lymph nodes (n=2) and tonsillar tissue (n=1). The presence of adenoviral sequences identified by PCR was confirmed in individual cells by fluorescence in-situ hybridisation (FISH). The frequent observation of adenoviruses in mantle cell lymphoma is intriguings, and raises questions about their possible involvement in the pathogenesis of this lymphoid malignancy. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Central nervous system relapse in diffuse large B cell lymphoma: Risk factors].

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Sancho, Juan-Manuel; Ribera, Josep-Maria

2016-01-15

Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25-30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis

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Torrealdea Javier

2011-07-01

Full Text Available Abstract Background The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS. Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens that are able to trigger the immune system. Results The model represents five concepts: central tolerance (T-cell generation by the thymus, T-cell activation, T-cell memory, cross-regulation (negative feedback between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion The relapsing dynamic in MS

Retrospective analysis of bendamustine and rituximab use in indolent and mantle cell non-Hodgkin lymphoma based on initial starting dose.

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Bond, David A; Huang, Ying; Ruppert, Amy S; Walker, Alison R; Dotson, Emily K; Roddy, Julianna; Blum, Kristie A; Christian, Beth A

2017-07-01

The initial dose of bendamustine, an alkylating agent used in treating indolent lymphoma (iNHL) and mantle cell lymphoma, is variable in clinical practice. 134 patients treated with bendamustine and rituximab were evaluated for starting dosage, patient characteristics, toxicities, and clinical outcome. The starting dosage ranged from 50 to 90 mg/m 2 . Lower starting dosage (<90 mg/m 2 ) was associated with relapsed disease, increased age and worse performance status (PS), histologic subtype other than follicular lymphoma, baseline renal impairment, and cytopenias. No significant difference was observed in toxicities between patients treated with 90 mg/m 2 compared with lower doses. The starting dose of 90 mg/m 2 was associated with a higher complete response rate (56% vs. 29%) and longer progression free survival (PFS) (39.5 months vs. 19.7 months). However, in a multivariable model, the higher starting dose was not associated with longer PFS in those with similar age, histology, PS, and number of prior therapies.

Non-traditional CD4+CD25-CD69+ regulatory T cells are correlated to leukemia relapse after allogeneic hematopoietic stem cell transplantation.

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Zhao, Xiao-su; Wang, Xu-hua; Zhao, Xiang-yu; Chang, Ying-jun; Xu, Lan-ping; Zhang, Xiao-hui; Huang, Xiao-jun

2014-07-01

Non-traditional CD4+CD25-CD69+ T cells were found to be involved in disease progression in tumor-bearing mouse models and cancer patients recently. We attempted to define whether this subset of T cells were related to leukemia relapse after allogeneic hematopoietic cell transplantation (allo-HSCT). The frequency of CD4+CD25-CD69+ T cells among the CD4+ T cell population from the bone marrow of relapsed patients, patients with positive minimal residual disease (MRD+) and healthy donors was examined by flow cytometry. The CD4+CD25-CD69+ T cells were also stained with the intracellular markers to determine the cytokine (TGF-β, IL-2 and IL-10) secretion. The results showed that the frequency of CD4+CD25-CD69 + T cells was markedly increased in patients in the relapsed group and the MRD + group compared to the healthy donor group. The percentage of this subset of T cells was significantly decreased after effective intervention treatment. We also analyzed the reconstitution of CD4+CD25-CD69+ T cells at various time points after allo-HSCT, and the results showed that this subset of T cells reconstituted rapidly and reached a relatively higher level at +60 d in patients compared to controls. The incidence of either MRD+ or relapse in patients with a high frequency of CD4+CD25-CD69+ T cells (>7%) was significantly higher than that of patients with a low frequency of CD4+CD25-CD69+ T cells at +60 d, +90 d and +270 d after transplant. However, our preliminary data indicated that CD4+CD25-CD69+ T cells may not exert immunoregulatory function via cytokine secretion. This study provides the first clinical evidence of a correlation between non-traditional CD4+CD25-CD69+ Tregs and leukemia relapse after allo-HSCT and suggests that exploration of new methods of adoptive immunotherapy may be beneficial. Further research related to regulatory mechanism behind this phenomenon would be necessary.

Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

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Craddock, Charles; Labopin, Myriam; Robin, Marie

2016-01-01

Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic...... syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixty-nine patients...... conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required....

Tandem autologous-allo-SCT is feasible in patients with high-risk relapsed non-Hodgkin's lymphoma.

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Crocchiolo, R; Castagna, L; Fürst, S; El-Cheikh, J; Faucher, C; Oudin, C; Granata, A; Bouabdallah, R; Coso, D; Chabannon, C; Balzarotti, M; Santoro, A; Blaise, D

2013-02-01

Allo-SCT is used to exploit GVL effect in high-risk relapsed non-Hodgkin's lymphoma (NHL). Here, we retrospectively analyzed 34 high-risk NHL patients who underwent auto-SCT followed closely by reduced-intensity allo-SCT ('tandem auto-allo') from January 2002 to November 2010. The search for an allogeneic donor was started at the beginning of salvage regimen. Median patients' age was 47 (27-68) years; histotypes were: diffuse large B-cell n=5, follicular n=14, transformed follicular n=4, mantle-cell n=5, plasmocytoid lymphoma n=1, anaplastic large T-cell n=2, peripheral T-cell n=3. Donors were HLA-identical siblings (n=29) or 10/10-matched unrelated individuals (n=5). Median interval between auto-SCT and allo-SCT was 77 days (36-197). At a median follow-up of 46 (8-108) months since allo-SCT, 5-year OS is 77% (61-93) and PFS is 68% (51-85). Disease relapse or progression occurred in six patients, 100-day TRM was 0%, 2-year TRM incidence was 6%. In conclusion, tandem transplantation is feasible in high-risk NHL patients having a HLA-identical donor. This approach could represent a suitable therapeutic option for those patients with high-risk NHL potentially benefitting from further therapy after auto-SCT. Donor searches should be started promptly whenever such an approach is chosen.

DNA Superresolution Structure of Reed-Sternberg Cells Differs Between Long-Lasting Remission Versus Relapsing Hodgkin's Lymphoma Patients.

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Righolt, Christiaan H; Knecht, Hans; Mai, Sabine

2016-07-01

Recent developments in microscopy have led to superresolution microscopy images of cells. Structured illumination microscopy was used before to reveal new details in the DNA structure and the structure of the DNA-free space in the DAPI-stained cell nuclei of the Hodgkin's lymphoma HDLM-2 cell line. This study extends this technology to primary pre-treatment classical Hodgkin's lymphoma samples of ten patients. Significant differences in both the DNA structure and the structure of the DNA-free space were detected between lymphocytes and malignant cells. Both types of structures were similar for lymphocytes of different patients. When the patients were un-blinded and grouped based on their clinical outcome, either non-relapsed or relapsed, a significant difference in the DNA structure of their Reed-Sternberg (RS) cells was found. Since, RS cells develop from mono-nucleated Hodgkin (H) cells, these data suggest distinct architectural restructuring of nuclei during RS cell formation in patients going to long-lasting remission versus relapse. J. Cell. Biochem. 117: 1633-1637, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse

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Merlos-Suarez, A.; Barriga, F.M.; Jung, P.; Iglesias, M.; Cespedes, M.V.; Rossell, D.; Sevillano, M.; Hernando-Momblona, X.; da Silva-Diz, V.; Munoz, P.; Clevers, H.; Sancho, E.; Mangues, R.; Batlle, E.

2011-01-01

A frequent complication in colorectal cancer (CRC) is regeneration of the tumor after therapy. Here, we report that a gene signature specific for adult intestinal stem cells (ISCs) predicts disease relapse in CRC patients. ISCs are marked by high expression of the EphB2 receptor, which becomes

Very late relapse in diffuse large B-cell lymphoma represents clonally related disease and is marked by germinal center cell features

NARCIS (Netherlands)

de Jong, Daphne; Glas, Annuska M.; Boerrigter, Lucie; Hermus, Marie-Christine; Dalesio, Otilia; Willemse, Els; Nederlof, Petra M.; Kersten, Marie José

2003-01-01

Patients with diffuse large B-cell lymphoma (DLBCL) rarely show relapse after 4 years of complete remission (CR). In this study, we addressed the following questions: (1) Does late-relapsing DLBCL represent clonally related disease or a second malignancy; and (2) is there a characteristic biologic

Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival.

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McIver, Z A; Yin, F; Hughes, T; Battiwalla, M; Ito, S; Koklanaris, E; Haggerty, J; Hensel, N F; Barrett, A John

2013-09-01

Patients with leukemia relapsing after allogeneic hematopoietic SCT have a dismal prognosis. A second SCT offers a further opportunity for cure, but has a high rate of treatment failure. To determine the utility of this option, we analyzed 59 consecutive patients relapsing after a myeloablative HLA-matched sibling T cell-depleted (TCD) SCT. Twenty-five patients (13 relapsing within 6 months and 12 relapsing between 6 and 170 months after the first SCT) received a T-replete second SCT. Thirty-eight patients relapsing early had a shorter survival than the 21 patients relapsing later (median 96 vs 298 days, P=0.0002). In patients relapsing early, the second SCT did not improve OS compared with patients receiving non-SCT treatments (median survival 109 vs 80 days, P=0.41). In patients relapsing late, despite an early trend in favor of second SCT, survival was comparable for patients receiving a second SCT compared with non retransplanted patients (median survival 363.5 vs 162 days, P=0.49). Disappointingly, our results do not demonstrate an important survival benefit for a second T-replete allogeneic SCT to treat relapse following a TCD SCT.

Relapse of nephrotic syndrome during post-rituximab peripheral blood B-lymphocyte depletion.

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Sato, Mai; Kamei, Koichi; Ogura, Masao; Ishikura, Kenji; Ito, Shuichi

2018-02-01

Rituximab is effective against complicated childhood steroid-dependent nephrotic syndrome (SDNS). Peripheral blood B-lymphocyte (B-cell) depletion is strongly correlated with persistent remission, relapse rarely occurring during B-cell depletion; however, we have encountered several such patients. We retrospectively analyzed the characteristics and clinical course of 82 patients with SDNS treated with rituximab from January 2007 to December 2012 in our institution. Six of 82 patients (7.3%) had relapses during B-cell depletion after receiving rituximab (relapsed group). The remaining 76 patients did not have relapses during B-cell depletion (non-relapsed group). The median time to initial relapse during B-cell depletion was 85 days after receiving rituximab, which is significantly shorter than in the non-relapsed group (410 days, p = 0.0003). The median annual numbers of relapses after receiving rituximab were 2.5 and 0.9 in the relapsed and non-relapsed groups, respectively (p depletion did not differ between the two groups. Relapse during B-cell depletion after receiving rituximab suggests that various pathophysiological mechanisms play a part in childhood nephrotic syndrome.

Relapsing pattern of brain metastasis after brain irradiation in small cell lung cancer

International Nuclear Information System (INIS)

Murakami, Masao; Kuroda, Yasumasa; Okamoto, Yoshiaki; Kono, Koichi; Yoden, Eisaku; Mori, Takeki

1997-01-01

Many reports concerning radiation therapy for brain metastasis have been published, and which of the various methods urged by these reports provide optional control is still controversial. According to developing diagnosis of metastasis in CNS, therapeutic problems should be referred. We reviewed 67 patients with small cell lung cancer and brain metastasis who underwent brain irradiation (Ave. 47 Gy/5W), and all 15 patients with brain relapse after the irradiation. Relapsing patterns in this clinical setting were divided into local regrowth in the same lesions and re-metastasis (reseeding) in other regions, by reviewing follow up CT and MRI studies. Total survival among 15 patients with brain relapse and 52 without relapse was longer in the former cases than the later: 1-, and 2-year survival (47/19%, 13/8%) and MST (10.8/5.7 months), from the initial brain irradiation. The concerned significant factors limited in younger age, low value of LDH and improvement of NF. Of the 15 patients with brain relapse, 4 developed local regrowth and 11 did re-metastasis. The period of remission since brain irradiation were 172±94.4 and 393±281 days, respectively. Lower number of brain metastasis and lower value of LDH were shown in re-metastasis patients. At the time of brain relapse, 11 patients had recurrence of carcinomatous meningitis. 4 patients were treated with whole brain re-irradiation. All patients died of cancer, including 12 of relapsing CNS diseases and 3 of primary lesion and hepatic metastasis. Leukoencephalopathy developed in 2 patients. Survival since the brain relapse was 2 to 238 days without significant difference in cases of local regrowth and re-metastasis. According to our data on relapsing pattern of brain metastasis after conventional fractionated brain irradiation with an objective dose of 50 Gy, 75% of brain relapse were re-metastasis, we appreciate this irradiation for initial brain metastasis if limited to the brain. (author)

Conventional-Dose versus High-Dose Chemotherapy for Relapsed Germ Cell Tumors

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Deaglan J. McHugh

2018-01-01

Full Text Available The majority of metastatic germ cell tumors (GCTs are cured with cisplatin-based chemotherapy, but 20–30% of patients will relapse after first-line chemotherapy and require additional salvage strategies. The two major salvage approaches in this scenario are high-dose chemotherapy (HDCT with autologous stem cell transplant (ASCT or conventional-dose chemotherapy (CDCT. Both CDCT and HDCT have curative potential in the management of relapsed/refractory GCT. However, due to a lack of conclusive randomized trials, it remains unknown whether sequential HDCT or CDCT represents the optimal initial salvage approach, with practice varying between tertiary institutions. This represents the most pressing question remaining for defining GCT treatment standards and optimizing outcomes. The authors review prognostic factors in the initial salvage setting as well as the major studies assessing the efficacy of CDCT, HDCT, or both, describing the strengths and weaknesses that formed the rationale behind the ongoing international phase III “TIGER” trial.

Leuconostoc sp. Meningitis in a Patient Treated with Rituximab for Mantle Cell Lymphoma

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Hrvoje Holik

2015-09-01

Full Text Available We present a 64-year-old man who was treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone chemoimmunotherapy for mantle cell lymphoma and developed purulent meningitis, probably caused by Leuconostoc sp. The patient had severe hypogammaglobulinemia, which is a possible complication of rituximab therapy. To our knowledge and after reviewing the available medical literature, this is the first described case of purulent meningitis caused by Leuconostoc sp. in a patient with mantle cell lymphoma that appeared after treatment with the R-CHOP protocol. The diagnosis of purulent meningitis was based on clinical, laboratory and cytological cerebrospinal fluid findings, in addition to blood culture results in which we isolated Leuconostoc sp. The patient was treated with meropenem with full recovery.

Germ Cell Cancer and Multiple Relapses: Toxicity and Survival

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Lauritsen, Jakob; Kier, Maria G.G.; Mortensen, Mette S.

2015-01-01

Purpose: A small number of patients with germ cell cancer (GCC) receive more than one line of treatment for disseminated disease. The purpose of this study was to evaluate late toxicity and survival in an unselected cohort of patients who experienced relapse after receiving first-line treatment...... for disseminated disease. Methods: From the Danish Testicular Cancer database, we identified all patients who received more than one line of treatment for disseminated disease. Information about late toxicity and mortality was obtained by means of linkage to national registers. Prognostic factors for relapse......, compared with patients treated with only orchiectomy, had an increased risk for a second cancer (hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.5), major cardiovascular disease (HR, 1.9; 95% CI, 1.0 to 3.3), pulmonary disease (HR, 2.0; 95% CI, 1.0 to 3.8), GI disease (HR, 7.3; 95% CI, 3.6 to 14.8), renal...

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

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van Imhoff, Gustaaf W; McMillan, Andrew; Matasar, Matthew J

2017-01-01

Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Pat...

Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

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Kim, Ji Hyun [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Stein, Anthony [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Tsai, Nicole [Department of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Schultheiss, Timothy E. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Palmer, Joycelynne [Department of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Liu, An [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Rosenthal, Joseph [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Department of Pediatrics, City of Hope National Medical Center, Duarte, California (United States); Forman, Stephen J. [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Wong, Jeffrey Y.C., E-mail: jwong@coh.org [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States)

2014-05-01

Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.

Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

International Nuclear Information System (INIS)

Kim, Ji Hyun; Stein, Anthony; Tsai, Nicole; Schultheiss, Timothy E.; Palmer, Joycelynne; Liu, An; Rosenthal, Joseph; Forman, Stephen J.; Wong, Jeffrey Y.C.

2014-01-01

Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk

Primary mantle cell lymphoma of tonsil: Case report

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Knežević Snežana B.

2017-01-01

Full Text Available Introduction: Mantle cell lymphoma is rare type of the mature B cell lymphoma. It includes 4% - 6% of all Non Hodgkin's Lymphomas. Compared to the other subtypes of lymphoma it develops more often in older men, and the median age of patients is 65 years. Primary tonsillar lymphoma accounts for less than 1% of head and neck malignancies. Method: Data obtained from medical records of the patient. Objective: Emphasize the importance of early and accurate diagnosis and early treatment of malignant diseases. Case report: Patient RP, 63 years old, presents with difficult swallowing, hoarseness, enlarged tonsils, snoring. Left tonsil almost sets into the right tonsillar vine, displaces the uvula and covers the isthmus. Respiratory sound is normal, with rhythmic action of the heart and soft abdomen. Good general condition. Echo: enlarged and actively altered lymph glands of the middle right jugular chain, the largest 148x77 mm, on the left side lymph nodes are enlarged, the largest is 143x72 mm. Echo of the abdomen inconspicuous. Lab: WBC 5.9, RBC 5.2, Hb 152, Hct 0.44, SE 10, CK 129, LDH 331, CRP 4.6, ALP 61, fibrinogen 2.4, Ca2+ 2.3, phosphate 0.8; BK, HCV, HBsAg, EB, HIV negative. X-ray of the chest inconspicuous. Admitted to the hematology department of the General Hospital. PH: Immunoproliferative disease. Immunohistochemistry, at the institute of Pathology: IHH CK AE1-AE3, PAX5 +, CD20 +, CD3, bcl2 +, bcl6-, CyklinD1 +, CD23-, CD43 +, MUM1 - / +, Ki67 + in about 20% of the tumor cells. Morphological and immunohistochemical findings: Mantle cell lymphoma. MSCD of the neck, chest and upper abdomen: Left tonsil diameter is 28x32 mm and length is 36mm, with lobular contour and heterogeneous structure, asymmetrically narrowing lumen of the airways to 7 mm. pathologically enlarged submandibular and par jugular lymph nodes (10-15 mm diameter on the left. There were no pathological findings in the lung parenchyma. Abdominal and retroperitoneal lymph nodes

Leydig cell function in boys following treatment for testicular relapse of acute lymphoblastic leukemia

International Nuclear Information System (INIS)

Blatt, J.; Sherins, R.J.; Niebrugge, D.; Bleyer, W.A.; Poplack, D.G.

1985-01-01

Current practice for achieving local control of testicular relapse in males with acute lymphoblastic leukemia (ALL) includes the use of 2,400-rad testicular radiation. Although this therapy is known to cause germ cell depletion, it has been assumed that it does not alter testicular secretion of testosterone. To test this assumption, the authors measured gonadotropin and testosterone levels in seven boys with ALL who had been treated with radiation for clinically apparent testicular relapse. In four of seven boys, testicular relapse was bilateral with overt involvement of one testicle and microscopic involvement of the other. Three of these four boys demonstrated delayed sexual maturation, and in addition to elevated follicle-stimulating hormone (FSH) concentrations, testosterone levels were low and luteinizing hormone levels were elevated compared with controls. These data indicate that boys with overt testicular leukemia who are treated with 2,400-rad testicular radiation are at risk for Leydig cell dysfunction. However, the relative contributions of radiation, prior chemotherapy, and leukemic infiltration to this dysfunction remain to be clarified

HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse.

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Martelli, Massimo F; Di Ianni, Mauro; Ruggeri, Loredana; Falzetti, Franca; Carotti, Alessandra; Terenzi, Adelmo; Pierini, Antonio; Massei, Maria Speranza; Amico, Lucia; Urbani, Elena; Del Papa, Beatrice; Zei, Tiziana; Iacucci Ostini, Roberta; Cecchini, Debora; Tognellini, Rita; Reisner, Yair; Aversa, Franco; Falini, Brunangelo; Velardi, Andrea

2014-07-24

Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation-based regimen. Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow. © 2014 by The American Society of Hematology.

Nacre formation by epithelial cell cultures from mantle of the black-lip pearl oyster, Pinctada margaritifera.

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Jayasankar, Vidya; Vasudevan, Srinivasa Raghavan; Poulose, Suja C; Divipala, Indira

2018-06-12

Mantle tissue from the black-lip pearl oyster, Pinctada margaritifera, was cultured in vitro using sterilized seawater supplemented with 0.1% yeast extract as the culture medium. Granular and agranular epithelial cells, hyalinocytes, and fibroblast-like cells were observed in the initial stages of culture. Epithelial cells later formed pseudopodial cell networks containing clusters of granulated cells, which upon maturation released their colored granules. These granules induced formation of nacre crystal deposits on the bottom of the culture plate. Cultures comprised of only granulated epithelial cells were established through periodic sub-culturing of mantle cells and maintained for over 18 mo in a viable condition. Reverse transcriptase PCR of cultured cells demonstrated gene expression of the shell matrix protein, nacrein. To further evaluate the functional ability of cultured granulated epithelial cells, nuclear shell beads were incubated in culture medium containing these cells to induce nacre formation on the beads. Observation of the bead surface under a stereomicroscope at periodic intervals showed the gradual formation of blackish yellow colored nacre deposits. Examination of the bead surface by scanning electron microscopy and energy dispersive X-ray analysis at periodic intervals revealed a distinct brick and mortar formation characteristic of nacre, comprised of aragonite platelets and matrix proteins. Calcium, carbon, and oxygen were the major elements in all stages examined. Our study shows that mantle epithelial cells in culture retain the ability to secrete nacre and can therefore form the basis for future studies on the biomineralization process and its application in development of sustainable pearl culture.

Receptor units responding to movement in the octopus mantle.

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Boyle, P R

1976-08-01

1. A preparation of the mantle of Octopus which is inverted over a solid support and which exposes the stellate ganglion and associated nerves is described. 2. Afferent activity can be recorded from stellar nerves following electrical stimulation of the pallial nerve. The latency and frequency of the phasic sensory response is correlated with the contraction of the mantle musculature. 3. It is proposed that receptors cells located in the muscle, and their activity following mantle contraction, form part of a sensory feedback system in the mantle. Large, multipolar nerve cells that were found between the two main layers of circular muscle in the mantle could be such receptors.

Cytomegalovirus reactivation is associated with a lower rate of early relapse in myeloid malignancies independent of in-vivo T cell depletion strategy.

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Hilal, Talal; Slone, Stacey; Peterson, Shawn; Bodine, Charles; Gul, Zartash

2017-06-01

The association between cytomegalovirus (CMV) reactivation and relapse risk has not been evaluated in relation to T cell depletion strategies. We evaluated 93 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and analyzed the association between T cell depletion strategies with the cumulative incidence of relapse and CMV reactivation. A total of 33% of patients who received ATG vs. 34% who received alemtuzumab developed CMV reactivation. The cumulative incidence of relapse was 3% at 1year and 20% at 3 years in patients with CMV reactivation vs. 30% at 1year and 38% at 3 years in patients without CMV reactivation (p=0.02). When analyzed separately, this effect persisted in the myeloid, but not the lymphoid group. There was a numerical trend towards increased non-relapse mortality (NRM) in patients with CMV reactivation, especially in the myeloid group. The choice of T cell depleting agent and the rate of CMV reactivation were not associated with different overall survival (OS) rates. These results suggest that the choice of T cell depletion strategy may have similar effects on rates of CMV reactivation, disease relapse, and survival. Further studies examining these variables in patients not exposed to in-vivo T cell depleting agents may be of interest. Copyright © 2017 Elsevier Ltd. All rights reserved.

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies.

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Rule, Simon; Dreyling, Martin; Goy, Andre; Hess, Georg; Auer, Rebecca; Kahl, Brad; Cavazos, Nora; Liu, Black; Yang, Shiyi; Clow, Fong; Goldberg, Jenna D; Beaupre, Darrin; Vermeulen, Jessica; Wildgust, Mark; Wang, Michael

2017-11-01

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non-blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0-1, non-bulky disease and non-blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease. © 2017 John Wiley & Sons Ltd.

Forodesine in the treatment of relapsed/refractory peripheral T-cell lymphoma: an evidence-based review

Directory of Open Access Journals (Sweden)

Makita S

2018-04-01

Full Text Available Shinichi Makita,1 Akiko Miyagi Maeshima,2 Dai Maruyama,1 Koji Izutsu,1 Kensei Tobinai1 1Department of Hematology, 2Department of Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan Abstract: T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma (PTCL generally have a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP/CHOP-like chemotherapy; once relapse occurs, it is mostly regarded as an incurable disease. To overcome the chemorefractoriness of PTCL, several novel agents have been developed. Since the first approval of pralatrexate, a dihydrofolate reductase inhibitor, for relapsed/refractory PTCL by the US Food and Drug Administration, several new agents, such as romidepsin (histone deacetylase inhibitor, brentuximab vedotin (antibody–drug conjugate targeting CD30, chidamide (histone deacetylase inhibitor, and mogamulizumab (anti-CC chemokine receptor 4 monoclonal antibody, have been approved as a therapeutic option for relapsed/refractory PTCL in several countries, including the US, Europe, China, and Japan. Forodesine is a novel, potent purine nucleoside phosphorylase inhibitor that is effective against T-cell malignancies. Although the clinical development of forodesine was discontinued in the US and Europe, a multicenter Phase I/II study of oral forodesine for relapsed PTCL was recently completed in Japan. The overall response rate was 24% (10 of 41 patients, which included four patients with complete response. In general, the toxicity of forodesine is manageable. As the study met the primary end point, forodesine was approved for the treatment of relapsed/refractory PTCL in Japan in March 2017, which was the first approval of forodesine in the world. As forodesine is an oral formulation, it is more convenient than other novel intravenous agents approved for PTCL

Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy.

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Sander, Frida Ewald; Nilsson, Malin; Rydström, Anna; Aurelius, Johan; Riise, Rebecca E; Movitz, Charlotta; Bernson, Elin; Kiffin, Roberta; Ståhlberg, Anders; Brune, Mats; Foà, Robin; Hellstrand, Kristoffer; Thorén, Fredrik B; Martner, Anna

2017-11-01

Regulatory T cells (T regs ) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3 + CD25 high CD4 + T regs during immunotherapy and to determine the potential impact of T regs on relapse risk and survival. We observed a pronounced increase in T reg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating T regs resembled thymic-derived natural T regs (nT regs ), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by T reg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of T reg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of T regs in later treatment cycles and a short T reg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive T regs that may be targeted for improved anti-leukemic efficiency.

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

Science.gov (United States)

Bashford-Rogers, R J M; Nicolaou, K A; Bartram, J; Goulden, N J; Loizou, L; Koumas, L; Chi, J; Hubank, M; Kellam, P; Costeas, P A; Vassiliou, G S

2016-01-01

The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome. PMID:27211266

Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia

DEFF Research Database (Denmark)

Karlsson, Lene; Forestier, Erik; Hasle, Henrik

2017-01-01

Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children...... relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS5y ) was 39 ± 4% for the whole group and 43 ± 4......, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 ± 5%. Four of 19 children (21%) survived without...

Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms’ Tumor: A CIBMTR retrospective analysis

Science.gov (United States)

Malogolowkin, Marcio H.; Hemmer, Michael T.; Le-Rademacher, Jennifer; Hale, Gregory A; Metha, Parinda A.; Smith, Angela R.; Kitko, Carrie; Abraham, Allistair; Abdel-Azim, Hisham; Dandoy, Christopher; Diaz, Miguel Angel; Gale, Robert Peter; Guilcher, Greg; Hayashi, Robert; Jodele, Sonata; Kasow, Kimberly A.; MacMillian, Margaret L.; Thakar, Monica; Wirk, Baldeep M.; Woolfrey, Ann; Thiel, E L

2017-01-01

Despite the dramatic improvement in the overall survival for patients diagnosed with Wilms’ tumor (WT), the outcomes for those that experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). The 5-year estimates for event free survival (EFS) and overall survival (OS) were 36% (95% CI; 29 – 43%) and 45% (95% CI; 38 – 51%) respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality (TRM) showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. Since attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus high-dose chemotherapy followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. Since disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy. PMID:28869618

A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study.

Science.gov (United States)

Fenske, Timothy S; Shah, Namrata M; Kim, Kyung Mann; Saha, Sandeep; Zhang, Chong; Baim, Arielle E; Farnen, John P; Onitilo, Adedayo A; Blank, Jules H; Ahuja, Harish; Wassenaar, Tim; Qamar, Rubina; Mansky, Patrick; Traynor, Anne M; Mattison, Ryan J; Kahl, Brad S

2015-10-01

Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models. The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle. Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination. The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL. © 2015 American Cancer Society.

Influence of chest radiotherapy in frequency and patterns of chest relapse in disseminated small cell lung carcinoma

International Nuclear Information System (INIS)

Mira, J.G.; Livingston, R.B.; Moore, T.N.

1982-01-01

The value of radiotherapy to the chest (RC) in disseminated small cell lung carcinoma (SCLC) has been questioned. Two protocols for disseminated SCLC from the Southwest Oncology Group (SWOG) have been compared. The first one included radiotherapy (RT), 3000 rad in two weeks, to the primary tumor, mediastinum and supraclavicular areas, while the second one deleted any RC. Multidrug chemotherapy (CT) and brain RT were used in both protocols. Nonresponders to CT were removed from the study. Our main findings are as follows: (1) Initial chest relapses (patients with no initial extrathoracic relapse) have increased from 24-55% when RC is not given (P = 0.0001). Overall chest relapse (adding those patients that relapsed simultaneously in the chest plus other sites) in the second protocol was 73%. (2) Amount of response to CT does not influence the chances for relapse. Even complete responders to CT have a high chance for chest relapse. (3) Sites of relapse without RC are mainly in the primary tumor, ipsilateral hilus and mediastinum. (4) With RC, relapses shift to the chest periphery, mostly to the lung outside the radiotherapy field and to the pleura. (5) The two very different CT regimens have produced similar percentages and duration of response. (6) CT schema with periodic reinductions prolongs duration of response and survival over schema with continuous maintenance. Hence, interruption of CT to allow RC does not seem to adversely influence CT efficacy

Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study.

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Gooskens, S L; Furtwängler, R; Spreafico, F; van Tinteren, H; de Kraker, J; Vujanic, G M; Leuschner, I; Coulomb-L'Herminé, A; Godzinski, J; Schleiermacher, G; Stoneham, S; Bergeron, C; Pritchard-Jones, K; Graf, N; van den Heuvel-Eibrink, M M

2014-07-15

Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols. We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012. Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%-32%), and 5-year overall survival (OS) was 26% (95% CI: 10%-42%). In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.

Role of Radiation Therapy in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

DEFF Research Database (Denmark)

Ng, Andrea K; Yahalom, Joachim; Goda, Jayant S

2018-01-01

Approximately 30% to 40% of patients with diffuse large B-cell lymphoma (DLBCL) will have either primary refractory disease or relapse after chemotherapy. In transplant-eligible patients, those with disease sensitive to salvage chemotherapy will significantly benefit from high-dose therapy with a...

Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone

OpenAIRE

Palmerini, E.; Jones, R. L.; Marchesi, E.; Paioli, A.; Cesari, M.; Longhi, A.; Meazza, C.; Coccoli, L.; Fagioli, F.; Asaftei, S.; Grignani, G.; Tamburini, A.; Pollack, S. M.; Picci, P.; Ferrari, S.

2016-01-01

Background Few new compounds are available for relapsed osteosarcoma. We retrospectively evaluated the activity of gemcitabine (G) plus docetaxel (D) in patients with relapsed high-grade osteosarcoma and high-grade spindle cell sarcoma of bone (HGS). Methods Patients receiving G 900?mg/m2 d 1, 8; D 75?mg/m2 d 8, every 21?days were eligible. Primary end-point: progression-free survival (PFS) at 4?months; secondary end-point: overall survival (OS) and response rate. Results Fifty-one patients w...

IIVP salvage regimen induces high response rates in patients with relapsed lymphoma before autologous stem cell transplantation.

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Abali, Huseyin; Oyan, Basak; Koc, Yener; Kars, Ayse; Barista, Ibrahim; Uner, Aysegul; Turker, Alev; Demirkazik, Figen; Tekin, Fatma; Tekuzman, Gulten; Kansu, Emin

2005-06-01

Patients with relapsed lymphoma can be cured with high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). New therapeutic approaches with better cytoreductive capacity are needed for relapsed patients to keep their chance for cure with transplantation. We report 30 patients with relapsed lymphoma, median age 43 years, treated with IIVP salvage regimen consisting of ifosfamide, mesna, idarubicin, and etoposide for 2 or 3 cycles. Seventeen patients had non-Hodgkin lymphoma (NHL) and 13 patients had Hodgkin disease (HD). Fourteen (47%) patients were at their first relapse. Overall response rate was 86.6% (n = 26) with 19 patients (63.3%) achieving complete response. Overall response rate was 92% in patients with HD and 82% in NHL. The most frequent side effects observed were grade III-IV neutropenia (87%) and thrombocytopenia (73%). IIVP regimen is a highly effective salvage therapy for patients with relapsed HD or NHL who are candidates for autologous HSCT. Close follow up is necessary because of the high incidence of grade III-IV hematologic toxicity.

Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children.

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Gabelli, Maria; Zecca, Marco; Messina, Chiara; Carraro, Elisa; Buldini, Barbara; Rovelli, Attilio Maria; Fagioli, Franca; Bertaina, Alice; Lanino, Edoardo; Favre, Claudio; Rabusin, Marco; Prete, Arcangelo; Ripaldi, Mimmo; Barberi, Walter; Porta, Fulvio; Caniglia, Maurizio; Santarone, Stella; D'Angelo, Paolo; Basso, Giuseppe; Locatelli, Franco

2018-06-13

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

[The mantle zone in lymphatic follicles and its stratification].

Science.gov (United States)

Bednár, B

1993-04-01

Ten inguinal lymph nodes and spleens from autopsies were chosen according to age decades in order to get an idea about usual appearance of follicular structures. The group was complemented by 4 palatine tonsils from routine biopsies. Phenotype was ascertained by using about 30 standard markers and results were compared with a basic histocytological picture. The appearance of lymphatic tissue was quite different according to location and age categories, nevertheless, there were common immunophenotypic and structural features of follicular mantle in younger persons. It mostly comprised four cellular layers, more conspicuous at the upper pole of the follicle. An innermost layer was small-celled blastic, MB 2 and IgD positive, the next B monocytoid layer had medium sized cells of a similar phenotype but more alc, phosphatase positive. An inconstant plasmacytoid layer and a clarocellular layer used to be incomplete. It was cytostructurally characteristic but immunohistologically non-standard (faint CD 19 et CD 20 positivity). T 4 lymphocytes and perhaps some other elements leaving germinal centres were admixed into the inner mantle layer. Various small lymphoid cells, especially T 8 lymphocytes and sometimes litoral cells, were admixed into mantle periphery. Mutual exchange of lymphatic cells between the germinal and mantle zones was very scant. The mantle zone is presumed therefore to be independent from the structural and functional point of view as well.

Linking lowermost mantle structure, core-mantle boundary heat flux and mantle plume formation

Science.gov (United States)

Li, Mingming; Zhong, Shijie; Olson, Peter

2018-04-01

The dynamics of Earth's lowermost mantle exert significant control on the formation of mantle plumes and the core-mantle boundary (CMB) heat flux. However, it is not clear if and how the variation of CMB heat flux and mantle plume activity are related. Here, we perform geodynamic model experiments that show how temporal variations in CMB heat flux and pulses of mantle plumes are related to morphologic changes of the thermochemical piles of large-scale compositional heterogeneities in Earth's lowermost mantle, represented by the large low shear velocity provinces (LLSVPs). We find good correlation between the morphologic changes of the thermochemical piles and the time variation of CMB heat flux. The morphology of the thermochemical piles is significantly altered during the initiation and ascent of strong mantle plumes, and the changes in pile morphology cause variations in the local and the total CMB heat flux. Our modeling results indicate that plume-induced episodic variations of CMB heat flux link geomagnetic superchrons to pulses of surface volcanism, although the relative timing of these two phenomena remains problematic. We also find that the density distribution in thermochemical piles is heterogeneous, and that the piles are denser on average than the surrounding mantle when both thermal and chemical effects are included.

Birch's Mantle

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Anderson, D. L.

2002-12-01

Francis Birch's 1952 paper started the sciences of mineral physics and physics of the Earth's interior. Birch stressed the importance of pressure, compressive strain and volume in mantle physics. Although this may seem to be an obvious lesson many modern paradoxes in the internal constitution of the Earth and mantle dynamics can be traced to a lack of appreciation for the role of compression. The effect of pressure on thermal properties such as expansivity can gravitational stratify the Earth irreversibly during accretion and can keep it chemically stratified. The widespread use of the Boussinesq approximation in mantle geodynamics is the antithesis of Birchian physics. Birch pointed out that eclogite was likely to be an important component of the upper mantle. Plate tectonic recycling and the bouyancy of oceanic crust at midmantle depths gives credence to this suggestion. Although peridotite dominates the upper mantle, variations in eclogite-content may be responsible for melting- or fertility-spots. Birch called attention to the Repetti Discontinuity near 900 km depth as an important geodynamic boundary. This may be the chemical interface between the upper and lower mantles. Recent work in geodynamics and seismology has confirmed the importance of this region of the mantle as a possible barrier. Birch regarded the transition region (TR ; 400 to 1000 km ) as the key to many problems in Earth sciences. The TR contains two major discontinuities ( near 410 and 650 km ) and their depths are a good mantle thermometer which is now being exploited to suggest that much of plate tectonics is confined to the upper mantle ( in Birch's terminology, the mantle above 1000 km depth ). The lower mantle is homogeneous and different from the upper mantle. Density and seismic velocity are very insensitive to temperature there, consistent with tomography. A final key to the operation of the mantle is Birch's suggestion that radioactivities were stripped out of the deeper parts of

Isolated Extramedullary Relapse of Acute Leukemia after Allogeneic Stem Cell Transplantation: Different Kinetics and Better Prognosis than Systemic Relapse.

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Shem-Tov, Noga; Saraceni, Francesco; Danylesko, Ivetta; Shouval, Roni; Yerushalmi, Ronit; Nagler, Arnon; Shimoni, Avichai

2017-07-01

Allogeneic stem cell transplantation (SCT) is curative treatment in patients with acute leukemia and myelodysplastic syndrome. However, recurrent disease is the major cause of treatment failure. Isolated extramedullary relapse (iEMR) after SCT is relatively rare and not well characterized. We performed a retrospective analysis of 566 consecutive patients with acute myeloid leukemia (n = 446) and acute lymphoblastic leukemia (ALL; n = 120) after SCT to study the incidence, risk factors, treatment options, and outcome of iEMR. The 5-year cumulative incidence of bone marrow relapse (BMR) and iEMR was 41.0% and 5.8%, respectively. iEMR occurred significantly later than BMR at 10 and 4 months, respectively (P BMR but did not protect against iEMR. Most patients with iEMR received systemic treatment combined with local radiation and donor lymphocyte infusions when feasible. The 3-year survival after relapse was 8.5% and 30.1% after BMR and iEMR, respectively (P = .002). Patients with a first iEMR continued to have recurrent EMRs, and only a minority progressed to BMR. Second iEMR was also common after first BMR and associated with longer survival than second BMR. iEMR is more frequent in patients with ALL and prior extramedullary disease. It occurs later than BMR and more commonly in patients with chronic GVHD, suggesting less effective graft-versus-leukemia effect in extramedullary sites. Second iEMR is common after a first iEMR but also after a first BMR. Long-term survival is feasible with aggressive treatment. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

High-dose myeloablative versus conventional low-dose radioimmunotherapy (RIT) of mantle cell lymphoma (MCL) with the chimeric anti-CD20 antibody C2B8

International Nuclear Information System (INIS)

Behr, T.M.; Gotthardt, M.; Schipperm, M.L.; Gratz, S.; Behe, M.P.; Brittinger, G.; Woermann, B.; Becker, W.

2002-01-01

CD20 has been used as target molecule for low-dose as well as high-dose, myeloablative RIT of B-cell NHL. MCL is an especially aggressive, prognostically unfavorable form of B-cell NHL. The aim of this study was to investigate whether high-dose, myeloablative RIT with the 131 I-labeled chimeric anti-CD20 antibody C2B8 (rituxan, Mabthera, Roche) may be therapeutically more effective than conventional low-dose therapy in MCL. A total of twelve patients with chemorefractory or relapsed mantle cell lymphoma were studied so far (all of them having relapsed after high-dose chemotherapy, seven of them combined with 12 Gy TBI). A diagnostic-dosimetric study was performed with 10 mCi of 131 I-C2B8 at a protein dose of 2.5 mg/kg. In case of splenic pooling, the protein dose was increased until a more 'favorable' biodistribution was obtained. Therapy was performed with conventional (30-75 mCi; n=4) or myeloablative activities (261-515 mCi; n=8) of 131 I-C2B8 at the previously optimized protein dose, aiming at whole-body doses of ≤ 0.8 Gy (for low-dose RIT) or lung doses of ≤ 27 Gy (for high-dose RIT). Clinical follow-up was obtained for up to 42 months. Overall, in 11 patients the 2.5 mg/kg protein dose was used, whereas in one patient with marked splenomegaly, 10 mg/kg were necessary to overcome the splenic antigenic sink. In the high-dose patients, non-hematologic toxicity was restricted to mild to moderate nausea, fever, transient bilirubin or liver enzyme elevations. Despite thyroid blocking, 6/8 high-dose (in contrast to 0/4 low-dose) patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. The response rate in the low-dose arm was only 1(PR)/4, whereas 7/8 high-dose patients experienced complete and the remainder a partial remission. 6 high-dose patients are still in CR (one of them relapsed locally at 3 months, one systemically at 26 months after RIT), and 7 are still alive for up to 42+ months. In contrast to low-dose therapy

A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Science.gov (United States)

2018-04-11

CD20 Positive; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Transformed Indolent Non-Hodgkin Lymphoma

Relapsing-Remitting MS (RRMS)

Medline Plus

Full Text Available ... defined attacks of new or increasing neurologic symptoms. These attacks – also called relapses or exacerbations – are followed ... as well as the nerve fibers themselves. During these inflammatory attacks, activated immune cells cause small, localized ...

Relapsing tumefactive lesion in an adult with medulloblastoma previously treated with chemoradiotherapy and stem cell transplant.

Science.gov (United States)

Mahta, Ali; Qu, Yan; Nastic, Denis; Sundstrom, Maria; Kim, Ryan Y; Saria, Marlon; Santagata, Sandro; Kesari, Santosh

2012-04-01

Herein, we present an adult case of medulloblastoma who received chemotherapy, radiation therapy and stem cell transplantation, and underwent multiple surgical resections for what were thought to be recurrences; however pathology confirmed a diagnosis of relapsing tumefactive lesions. This phenomenon seems to be a consequence of stem cell transplantation rather than a simple radiation treatment effect.

17-AAG enhances the cytotoxicity of flavopiridol in mantle cell lymphoma via autophagy suppression.

Science.gov (United States)

Xiao, Y; Guan, J

2015-01-01

Flavopiridol, a cyclin-dependent kinase inhibitor (CDKI), shows promising anti-tumor activity in hematologic malignancies. However, Flavopiridol-induced protective autophagy may lead to drug resistance. Here we found that Hsp90 inhibitor 17-AAG can sensitize mantle cell lymphoma (MCL) cells to flavopiridol by suppressing flavopiridol-triggered protective autophagy. The suppressing effect of 17-AAG on autophgy was mediated by Beclin1 degradation and ERK inactivation. Furthermore, 17-AAG enhanced flavopiridol-induced apoptosis and growth suppression in MCL cells. Our study may provide some insights into CDKI -targeted chemotherapies.

Effect of Radiotherapy Dose and Volume on Relapse in Merkel Cell Cancer of the Skin

International Nuclear Information System (INIS)

Foote, Matthew; Harvey, Jennifer; Porceddu, Sandro

2010-01-01

Purpose: To assess the effect of radiotherapy (RT) dose and volume on relapse patterns in patients with Stage I-III Merkel cell carcinoma (MCC). Patients and Methods: This was a retrospective analysis of 112 patients diagnosed with MCC between January 2000 and December 2005 and treated with curative-intent RT. Results: Of the 112 evaluable patients, 88% had RT to the site of primary disease for gross (11%) or subclinical (78%) disease. Eighty-nine percent of patients had RT to the regional lymph nodes; in most cases (71%) this was for subclinical disease in the adjuvant or elective setting, whereas 21 patients (19%) were treated with RT to gross nodal disease. With a median follow-up of 3.7 years, the 2-year and 5-year overall survival rates were 72% and 53%, respectively, and the 2-year locoregional control rate was 75%. The in-field relapse rate was 3% for primary disease, and relapse was significantly lower for patients receiving ≥50Gy (hazard ratio [HR] = 0.22; 95% confidence interval [CI], 0.06-0.86). Surgical margins did not affect the local relapse rate. The in-field relapse rate was 11% for RT to the nodes, with dose being significant for nodal gross disease (HR = 0.24; 95% CI, 0.07-0.87). Patients who did not receive elective nodal RT had a much higher rate of nodal relapse compared with those who did (HR = 6.03; 95% CI, 1.34-27.10). Conclusion: This study indicates a dose-response for subclinical and gross MCC. Doses of ≥50Gy for subclinical disease and ≥55Gy for gross disease should be considered. The draining nodal basin should be treated in all patients.

Carbonate stability in the reduced lower mantle

Science.gov (United States)

Dorfman, Susannah M.; Badro, James; Nabiei, Farhang; Prakapenka, Vitali B.; Cantoni, Marco; Gillet, Philippe

2018-05-01

Carbonate minerals are important hosts of carbon in the crust and mantle with a key role in the transport and storage of carbon in Earth's deep interior over the history of the planet. Whether subducted carbonates efficiently melt and break down due to interactions with reduced phases or are preserved to great depths and ultimately reach the core-mantle boundary remains controversial. In this study, experiments in the laser-heated diamond anvil cell (LHDAC) on layered samples of dolomite (Mg, Ca)CO3 and iron at pressure and temperature conditions reaching those of the deep lower mantle show that carbon-iron redox interactions destabilize the MgCO3 component, producing a mixture of diamond, Fe7C3, and (Mg, Fe)O. However, CaCO3 is preserved, supporting its relative stability in carbonate-rich lithologies under reducing lower mantle conditions. These results constrain the thermodynamic stability of redox-driven breakdown of carbonates and demonstrate progress towards multiphase mantle petrology in the LHDAC at conditions of the lowermost mantle.

Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer: a phase II study of the German Testicular Cancer Study Group

OpenAIRE

Kollmannsberger, C; Rick, O; Klaproth, H; Kubin, T; Sayer, H G; Hentrich, M; Welslau, M; Mayer, F; Kuczyk, M; Spott, C; Kanz, L; Bokemeyer, C

2002-01-01

Despite generally high cure rates in patients with metastatic germ cell cancer, patients with progressive disease on first-line cisplatin-based chemotherapy or with relapsed disease following high-dose salvage therapy exhibit a very poor prognosis. Irinotecan has shown antitumour activity in human testicular tumour xenografts in nude mice. We have performed a phase II study examining the single agent activity of irinotecan in patients with metastatic relapsed or cisplatin-refractory germ cell...

High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients.

Science.gov (United States)

Pan, J; Yang, J F; Deng, B P; Zhao, X J; Zhang, X; Lin, Y H; Wu, Y N; Deng, Z L; Zhang, Y L; Liu, S H; Wu, T; Lu, P H; Lu, D P; Chang, A H; Tong, C R

2017-12-01

Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal residual disease by flow cytometry (FCM-MRD + ) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 10 5 /kg and were eventually settled at 1 × 10 5 /kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD + patients achieved MRD - . All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD - with a median follow-up time of 206 (45-427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 10 5 /kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.

[Cytostructure of the mantle zone in lymphatic tissue].

Science.gov (United States)

Bednár, B

1993-04-01

Four cellular layers of the follicular mantle zone in palatine tonsil lymphatic tissue were studied by electron microscopy after simultaneous immunophenotypical investigation. The first layer of the mantle zone consisting of small blastic cells was analogous to the small (centrocytoid) blastic layer of germinal centres. The second B monocytoid layer was lacking analogy in basic series of lymphocytes and seemed to be an independent morphological and probably functional unit. Plasmacytoid and clarocellular elements in outer layers of follicular mantle zone were in a way similar to T plasmacytoid and clarocellular components of Sézary syndrome infiltrates but considering transitional forms they had a local origin from incompletely transformed elements of B monocytoid layer. Inner follicular mantle zone was discussed as a source of incompletely transformed B lymphocytes for further mantle layers where their immunophenotypical modulation is taking place according to actual need. Outer mantle layers are aggressive against damaged epithelial and litoral structures and may be instrumental in a common reaction of B and T components.

Central diabetes insipidus as a very late relapse limited to the pituitary stalk in Langerhans cell histiocytosis.

Science.gov (United States)

Nakagawa, Shunsuke; Shinkoda, Yuichi; Hazeki, Daisuke; Imamura, Mari; Okamoto, Yasuhiro; Kawakami, Kiyoshi; Kawano, Yoshifumi

2016-07-01

Central diabetes insipidus (CDI) and relapse are frequently seen in multifocal Langerhans cell histiocytosis (LCH). We present two females with multifocal LCH who developed CDI 9 and 5 years after the initial diagnosis, respectively, as a relapse limited to the pituitary stalk. Combination chemotherapy with cytarabine reduced the mass in the pituitary stalk. Although CDI did not improve, there has been no anterior pituitary hormone deficiency (APHD), neurodegenerative disease in the central nervous system (ND-CNS) or additional relapse for 2 years after therapy. It was difficult to predict the development of CDI in these cases. CDI might develop very late in patients with multifocal LCH, and therefore strict follow-up is necessary, especially with regard to symptoms of CDI such as polydipsia and polyuria. For new-onset CDI with LCH, chemotherapy with cytarabine might be useful for preventing APHD and ND-CNS.

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

DEFF Research Database (Denmark)

Eskelund, Christian W.; Dahl, Christina; Hansen, Jakob W.

2017-01-01

Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM...

Outcome After First Relapse in Children With Acute Lymphoblastic Leukemia : A Report Based on the Dutch Childhood Oncology Group (DCOG) Relapse ALL 98 Protocol

NARCIS (Netherlands)

van den Berg, H.; de Groot-Kruseman, H. A.; Damen-Korbijn, C. M.; de Bont, E. S. J. M.; Schouten-van Meeteren, A. Y. N.; Hoogerbrugge, P. M.

Background. We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late

Outcome after first relapse in children with acute lymphoblastic leukemia: a report based on the Dutch Childhood Oncology Group (DCOG) relapse all 98 protocol

NARCIS (Netherlands)

Berg, H. van den; Groot-Kruseman, H.A. de; Damen-Korbijn, C.M.; Bont, E.S. de; Schouten-van Meeteren, A.Y.; Hoogerbrugge, P.M.

2011-01-01

BACKGROUND: We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late

Outcome After First Relapse in Children With Acute Lymphoblastic Leukemia: A Report Based on the Dutch Childhood Oncology Group (DCOG) Relapse ALL 98 Protocol

NARCIS (Netherlands)

van den Berg, H.; de Groot-Kruseman, H. A.; Damen-Korbijn, C. M.; de Bont, E. S. J. M.; Schouten-van Meeteren, A. Y. N.; Hoogerbrugge, P. M.

2011-01-01

Background. We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late

Effects of iron on the lattice thermal conductivity of Earth's deep mantle and implications for mantle dynamics.

Science.gov (United States)

Hsieh, Wen-Pin; Deschamps, Frédéric; Okuchi, Takuo; Lin, Jung-Fu

2018-04-17

Iron may critically influence the physical properties and thermochemical structures of Earth's lower mantle. Its effects on thermal conductivity, with possible consequences on heat transfer and mantle dynamics, however, remain largely unknown. We measured the lattice thermal conductivity of lower-mantle ferropericlase to 120 GPa using the ultrafast optical pump-probe technique in a diamond anvil cell. The thermal conductivity of ferropericlase with 56% iron significantly drops by a factor of 1.8 across the spin transition around 53 GPa, while that with 8-10% iron increases monotonically with pressure, causing an enhanced iron substitution effect in the low-spin state. Combined with bridgmanite data, modeling of our results provides a self-consistent radial profile of lower-mantle thermal conductivity, which is dominated by pressure, temperature, and iron effects, and shows a twofold increase from top to bottom of the lower mantle. Such increase in thermal conductivity may delay the cooling of the core, while its decrease with iron content may enhance the dynamics of large low shear-wave velocity provinces. Our findings further show that, if hot and strongly enriched in iron, the seismic ultralow velocity zones have exceptionally low conductivity, thus delaying their cooling.

Mantle cell lymphoma pathogenesis: another turn of the screw to cyclin D1 overexpression

OpenAIRE

Albero Gallego, Robert

2017-01-01

[eng] Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm derived from mature B cells characterized by the presence of the t(11;14)(q13;q32) translocation that leads to the overexpression of Cyclin D1. Cyclin D1 plays a well-established role in G1/S progression, although other functions including transcription or DNA damage response (DDR) can be regulated by this cyclin. Therefore, the main goal of this thesis is the characterization of the cyclin D1 non-canonical function in MCL a...

Mantle cell lymphoma pathogenesis: another turn of the screw to cyclin D1 overexpression

OpenAIRE

Albero Gallego, Robert

2017-01-01

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm derived from mature B cells characterized by the presence of the t(11;14)(q13;q32) translocation that leads to the overexpression of Cyclin D1. Cyclin D1 plays a well-established role in G1/S progression, although other functions including transcription or DNA damage response (DDR) can be regulated by this cyclin. Therefore, the main goal of this thesis is the characterization of the cyclin D1 non-canonical function in MCL and lymp...

[Ibrutinib: A new drug of B-cell malignancies].

Science.gov (United States)

Thieblemont, Catherine

2015-06-01

Ibrutinib (Imbruvica®) is a first-in-class, orally administered once-daily, that inhibits B-cell antigen receptor signaling downstream of Bruton's tyrosine kinase (BTK). Ibrutinib has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. In clinical studies, ibrutinib induced an impressive overall response rate (68%) in patients with relapsed/refractory MCL (phase II study). In CLL, ibrutinib has shown to significantly improve progression-free survival, response rate and overall survival in patients with relapsed/refractory CLL, including in those with del 17p. Ibrutinib had an acceptable tolerability profile. Less than 10% of patients discontinued their treatment because of adverse events. Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma. An approval extension has already been enregistered for Waldenström disease in USA in January 2015. Given its efficacy and tolerability, ibrutinib is an emerging treatment option for patients with B-cell malignancies. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse.

Science.gov (United States)

Ogden, Angela; Rida, Padmashree C G; Knudsen, Beatrice S; Kucuk, Omer; Aneja, Ritu

2015-10-28

Although docetaxel significantly improves survival in a variety of malignancies, its clinical utility is severely restricted by acquired chemoresistance and disease relapse. To uncover the mechanisms underlying these all too common occurrences, an abundance of research has focused on mutations and gene expression patterns; however, these findings are yet to translate into improved outcomes for patients being administered this drug. These analyses have overlooked a promising lead in the quest to discern key mediators of resistance and relapse following docetaxel therapy: polyploidization. This process is manifested following docetaxel-mediated mitotic arrest by the appearance of giant, multinucleated cells, which slipped from mitosis without undergoing cytokinesis. Polyploid cells generally possess supernumerary centrosomes, are chromosomally instable, and resist chemotherapy. We thus suspect that chemoresistance and relapse following treatment with docetaxel might be combatted by co-administration of centrosome declustering drugs, which could selectively destroy polyploid cells given that normal cells do not possess amplified centrosomes, an intriguing paradigm that warrants further investigation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes.

Science.gov (United States)

Cheah, C Y; Chihara, D; Romaguera, J E; Fowler, N H; Seymour, J F; Hagemeister, F B; Champlin, R E; Wang, M L

2015-06-01

Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Case report: partial relapse of Bell's palsy following superficial radiotherapy to a basal cell carcinoma in the temple

International Nuclear Information System (INIS)

Brincat, Stephen; Mantell, B.S.

1986-01-01

A patient who developed a partial relapse of Bell's palsy following superficial radiotherapy to a basal cell carcinoma in the temple is reported. Nerves injured by Bell's palsy may be more susceptible to radiation induced damage. (author)

Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

Science.gov (United States)

2015-08-18

Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; HIV Infection; Intraocular Lymphoma; Multicentric Angiofollicular Lymphoid Hyperplasia; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

Long-term follow-up of patients receiving allogeneic stem cell transplant for chronic lymphocytic leukaemia: mixed T-cell chimerism is associated with high relapse risk and inferior survival.

Science.gov (United States)

Thompson, Philip A; Stingo, Francesco; Keating, Michael J; Wierda, William G; O'Brien, Susan M; Estrov, Zeev; Ledesma, Celina; Rezvani, Katayoun; Qazilbash, Muzaffar; Shah, Nina; Parmar, Simrit; Popat, Uday; Anderlini, Paolo; Yago, Nieto; Ciurea, Stefan O; Kebriaei, Partow; Champlin, Richard; Shpall, Elizabeth J; Hosing, Chitra M

2017-05-01

There is limited information regarding the immunological predictors of post-allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T-cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post-alloSCT and the ability of post-transplant immunomodulation to treat relapse. Mixed T-cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post-alloSCT; upon 3- and 6-month landmark analysis, this was associated with inferior progression-free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P CLL. © 2017 John Wiley & Sons Ltd.

Relapsed Acute Promyelocytic Leukemia Lacks "Classic" Leukemic Promyelocyte Morphology and Can Create Diagnostic Challenges.

Science.gov (United States)

Dayton, Vanessa J; McKenna, Robert W; Yohe, Sophia L; Dolan, Michelle M; Courville, Elizabeth; Alvarez, Harold; Linden, Michael A

2017-01-01

Although current therapies for acute promyelocytic leukemia (APL), such as all- trans retinoic acid and arsenic trioxide, usually result in remission, some patients relapse. Early recognition of relapse is critical for prompt intervention. In this study, we systematically reviewed morphologic, immunophenotypic, and cytogenetic findings in paired diagnostic and relapsed APL cases and describe and quantify the changes in blast morphology at relapse. By electronic database search, we identified eight paired diagnostic and relapsed APL cases for which peripheral blood or bone marrow smears were available for review. For two cases, diagnostic material was available for relapse after hematopoietic cell transplantation. Neoplastic hypergranular or microgranular promyelocytes with indented or bivalve nuclei predominated at diagnosis in all patients. Most patients had undifferentiated blasts at relapse and/or hypergranular blast equivalents with round to oval nuclei. Classic acute promyelocytic leukemia cells with bivalve nuclei and bundles of cytoplasmic Auer rods were easily identifiable in fewer than half of cases at diagnosis and rare to absent in all relapsed cases. Morphologic features of relapsed APL overlap with other types of acute myeloid leukemia, creating diagnostic challenges, especially if no history is available when relapsing patients seek treatment for care. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Mineralogy of the Hydrous Lower Mantle

Science.gov (United States)

Shim, S. H.; Chen, H.; Leinenweber, K. D.; Kunz, M.; Prakapenka, V.; Bechtel, H.; Liu, Z.

2017-12-01

The hydrous ringwoodite inclusions found in diamonds suggest water storage in the mantle transition zone. However, water storage in the lower mantle remains unclear. Bridgmanite and magnesiowustite appear to have very little storage capacity for water. Here, we report experimental results indicating significant changes in the lower-mantle mineralogy under the presence of water. We have synthesized Mg2SiO4 ringwoodite with 2 wt% water in multi-anvil press at 20 GPa and 1573 K at ASU. The hydrous ringwoodite sample was then loaded to diamond anvil cells with Ar or Ne as a pressure medium. We heated the pure hydrous ringwoodite samples at lower-mantle pressure using a CO2 laser heating system at ASU. We measured X-ray diffraction patterns at the GSECARS sector of the Advanced Photon Source (APS) and 12.2.2 sector of the Advanced Light Source (ALS). For the separate Pt-mixed samples, we have conducted in situ heating at the beamlines using near IR laser heating systems. We measured the infrared spectra of the heated samples at high pressure and after pressure quench at 1.4.4 sector of ALS. In the in situ experiments with hydrous ringwoodite + Pt mixture as a starting material, we found formation of stishovite together with bridgmanite and periclase during heating with a near IR laser beams at 1300-2500 K and 35-66 GPa. However, some hydrous ringwoodite still remains even after a total of 45 min of heating. In contrast, the hydrous ringwoodite samples heated without Pt by CO2 laser beams are transformed completely to bridgmanite, periclase and stishovite at 31-55 GPa and 1600-1900 K. We have detected IR active OH mode of stishovite from the samples heated at lower-mantle pressures. The unit-cell volume of stishovite measured after pressure quench is greater than that of dry stishovite by 0.3-0.6%, supporting 0.5-1 wt% of H2O in stishovite in these samples. Stishovite is a thermodynamically forbidden phase in the dry lower mantle because of the existence of periclase and

PET/CT before autologous stem cell transplantation predicts outcome in refractory/relapsed follicular lymphoma

Energy Technology Data Exchange (ETDEWEB)

Alcantara, Marion; Tilly, Herve [Universite de Rouen, Service d' Hematologie, Centre Henri Becquerel, Rouen (France); Dupuis, Jehan; Haioun, Corinne [CHU Henri Mondor et Universite Paris-Est, Assistance Publique - Hopitaux de Paris, Unite Hemopathies Lymphoides, Marechal de Lattre de Tassigny (France); Mareschal, Sylvain; Dubois, Sydney [Centre Henri Becquerel, IRIB, Unite Inserm U918, Rouen (France); Julian, Anne [CHU Purpan, Service de Medecine Nucleaire, Toulouse (France); Cottereau, Anne Segolene; Becker, Stephanie [Centre Henri Becquerel, Service de Medecine Nucleaire, Rouen (France); Oberic, Lucie; Huynh, Anne; Laurent, Guy; Ysebaert, Loic [IUCT-Oncopole, Departement d' Hematologie, Toulouse (France); Meignan, Michel [CHU Henri-Mondor, Service de Medecine Nucleaire, Paris (France)

2014-09-20

Salvage of young patients with follicular lymphoma (FL) after R-CHOP includes salvage immunochemotherapy followed by autologous stem cell transplantation (ASCT). Previous studies dealing with relapsed Hodgkin lymphoma have shown the prognostic value of PET/CT prior to ASCT. We retrospectively analysed 59 patients with refractory/relapsed FL after first-line R-CHOP who were chemosensitive (as evaluated by CT) to the salvage treatment and who proceeded to ASCT. The role of PET/CT in this setting to define chemosensitivity is not definitely established. So we focused on the prognostic value of PET/CT performed after salvage treatment, before ASCT. The estimated 3-year progression-free survival (PFS) and overall survival were 63.1 % (50.9-78.3 %) and 90.5 % (82.8 - 98.8 %), respectively, and did not differ significantly according to their Follicular Lymphoma International Prognostic Index at relapse, conditioning regimen, or type of salvage. PFS was significantly lower in PET/CT-positive patients, according to the International Harmonization Project revised response criteria, with a 3-year PFS of 45.5 % (26.6 - 77.8 %) versus 72.6 % (58.5 - 90.0 %; p = 0.039). To better refine prognosis, we applied two types of thresholds: a Deauville five-point scale positive threshold of ≥3 (3-year PFS of 74.9 %, range 61.0 - 92.1 % %, versus 42.8 %, range 24.7 - 74.4 %; p = 0.02), and a ≥70 % ∇SUV{sub max} threshold between presalvage and pre-ASCT PET/CT (3-year PFS of 72.4 %, range 57.5 - 91.3 % versus 13.3 %, 2.2 - 81.7 %; p < 10{sup -3}). The PET/CT findings before ASCT were independently correlated with PFS in our series. PET/CT negativity before ASCT is a desirable and achievable goal in the management of chemosensitive FL relapsing after first-line R-CHOP. (orig.)

Iron-carbonate interaction at Earth's core-mantle boundary

Science.gov (United States)

Dorfman, S. M.; Badro, J.; Nabiei, F.; Prakapenka, V.; Gillet, P.

2015-12-01

Carbon storage and flux in the deep Earth are moderated by oxygen fugacity and interactions with iron-bearing phases. The amount of carbon stored in Earth's mantle versus the core depends on carbon-iron chemistry at the core-mantle boundary. Oxidized carbonates subducted from Earth's surface to the lowermost mantle may encounter reduced Fe0 metal from disproportionation of Fe2+ in lower mantle silicates or mixing with the core. To understand the fate of carbonates in the lowermost mantle, we have performed experiments on sandwiches of single-crystal (Ca0.6Mg0.4)CO3 dolomite and Fe foil in the laser-heated diamond anvil cell at lower mantle conditions of 49-110 GPa and 1800-2500 K. Syntheses were conducted with in situ synchrotron X-ray diffraction to identify phase assemblages. After quench to ambient conditions, samples were sectioned with a focused Ga+ ion beam for composition analysis with transmission electron microscopy. At the centers of the heated spots, iron melted and reacted completely with the carbonate to form magnesiowüstite, iron carbide, diamond, magnesium-rich carbonate and calcium carbonate. In samples heated at 49 and 64 GPa, the two carbonates exhibit a eutectoid texture. In the sample heated at 110 GPa, the carbonates form rounded ~150-nm-diameter grains with a higher modal proportion of interspersed diamonds. The presence of reduced iron in the deep lower mantle and core-mantle boundary region will promote the formation of diamonds in carbonate-bearing subducted slabs. The complete reaction of metallic iron to oxides and carbides in the presence of mantle carbonate supports the formation of these phases at the Earth's core-mantle boundary and in ultra-low velocity zones.

Potent anti-leukemia activities of humanized CD19-targeted CAR-T cells in patients with relapsed/refractory acute lymphoblastic leukemia.

Science.gov (United States)

Cao, Jiang; Wang, Gang; Cheng, Hai; Wei, Chen; Qi, Kunming; Sang, Wei; Zhenyu, Li; Shi, Ming; Li, Huizhong; Qiao, Jianlin; Pan, Bin; Zhao, Jing; Wu, Qingyun; Zeng, Lingyu; Niu, Mingshan; Jing, Guangjun; Zheng, Junnian; Xu, Kailin

2018-04-10

Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The immune response induced by murine single-chain variable fragment (scFv) of the CAR may limit CAR-T cell persistence and thus increases the risk of leukemia relapse. In this study, we developed a novel humanized scFv from the murine FMC63 antibody. A total of 18 R/R ALL patients with or without prior murine CD19 CAR-T therapy were treated with humanized CD19-targeted CAR-T cells (hCART19s). After lymphodepletion chemotherapy with cyclophosphamide and fludarabine, the patients received a single dose (1 × 10 6 /kg) of autologous hCART19s infusion. Among the 14 patients without previous CAR-T therapy, 13 (92.9%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, whereas 1 of the 3 patients who failed a second murine CAR-T infusion achieved CR after hCART19s infusion. At day 180, the overall and leukemia-free survival rates were 65.8% and 71.4%, respectively. The cumulative incidence of relapse was 22.6%, and the non-relapse mortality rate was 7.1%. During treatment, 13 patients developed grade 1-2 cytokine release syndrome (CRS), 4 patients developed grade 3-5 CRS, and 1 patient experienced reversible neurotoxicity. These results indicated that hCART19s could induce remission in patients with R/R B-ALL, especially in patients who received a reinfusion of murine CAR-T. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

DEFF Research Database (Denmark)

Casneuf, Tineke; Xu, Xu Steven; Adams, Homer C

2017-01-01

Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and......, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy...

Allogeneic stem cell transplantation in children with acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and review of the literature.

Science.gov (United States)

Yoshihara, T; Morimoto, A; Kuroda, H; Imamura, T; Ishida, H; Tsunamoto, K; Naya, M; Hibi, S; Todo, S; Imashuku, S

2006-01-01

The prognosis of patients with acute lymphoblastic leukemia (ALL) and central nervous system (CNS) relapse has historically been very poor. Although chemo-radiotherapy has improved outcomes, some patients still have a poor prognosis after CNS relapse. Therefore, allogeneic hematopoietic stem cell transplantation (allo-SCT) has recently become an option for treatment of CNS leukemia; however, information, particularly on the long-term outcome of transplant recipients, is limited. We performed allo-SCT in eight pediatric patients with ALL (n=7) or T-cell type non-Hodgkin's lymphoma (n=1), who had isolated CNS relapse. All patients survived for a median of 70.5 (range, 13-153) months after SCT. Sequelae developed late in some patients: mental retardation (IQ=47) in one patient, severe alopecia in two patients, limited chronic graft-versus-host-disease in three patients, and amenorrhea and/or hypothyroidism in three patients. Except for a pre-school child with post transplant CNS relapse, six out of seven patients show normal school/social performance. Our results clearly indicate a high cure rate of isolated CNS relapse by allo-SCT in pediatric lymphoid malignancies; however, there needs to be further studies to determine which are the appropriate candidates for transplantation and what is the best transplant regimen to achieve high cure rate and maintain good quality of life.

Relapsed or refractory pediatric acute lymphoblastic leukemia: current and emerging treatments.

Science.gov (United States)

Martin, Alissa; Morgan, Elaine; Hijiya, Nobuko

2012-12-01

Relapsed acute lymphoblastic leukemia (ALL) represents a major cause of morbidity and mortality in pediatrics. With contemporary chemotherapy, >85% of patients with newly diagnosed ALL survive. Unfortunately, 20% of these patients will relapse and for these children, outcomes remain poor despite our best known chemotherapy protocols. Most of these children will achieve a second complete remission, but maintaining this remission remains difficult. Because relapsed ALL is such a significant cause of morbidity and mortality, it is the focus of much research interest. Efforts have been made and continue to focus on understanding the underlying biology that drives relapse. The role of hematopoietic stem cell transplantation in relapsed ALL remains unclear, but many clinicians still favor this for high-risk patients given the poor prognosis with current chemotherapy alone. It is important to use new drugs with little cross-resistance in the treatment of relapsed ALL. New classes of agents are currently being studied. We also discuss prognostic factors and the biology of relapsed ALL.

Improved survival of multiple myeloma patients with late relapse after high-dose treatment and stem cell support, a population-based study of 348 patients in Denmark in 1994-2004

DEFF Research Database (Denmark)

Vangsted, Annette Juul; Klausen, Tobias W; Andersen, Niels F

2010-01-01

To analyse if patients with early relapse after high-dose chemotherapy with stem cell support (HDT) benefit from new treatment strategies in a population-based setting.......To analyse if patients with early relapse after high-dose chemotherapy with stem cell support (HDT) benefit from new treatment strategies in a population-based setting....

Monoclonal Antibody Therapy Before Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoid Malignancies

Science.gov (United States)

2017-10-10

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

Long-term outcomes of high dose treatment and autologous stem cell transplantation in follicular and mantle cell lymphomas – a single centre experience

Directory of Open Access Journals (Sweden)

Boltezar Lucka

2016-06-01

Full Text Available Advanced follicular lymphoma (FL and mantle cell lymphoma (MCL are incurable diseases with conventional treatment. The high dose treatment (HDT with autologous stem cell transplantation (ASCT, however, offers a certain proportion of these patients the prospect of a prolonged disease-free and overall survival. The aim of this study was to investigate the event free survival (EFS and overall survival (OS in patients with FL and MCL treated with ASCT.

Papilledema secondary to a superior sagittal sinus thrombosis. Mantle cell lymphoma paraneoplastic syndrome.

Science.gov (United States)

Platas-Moreno, I; Antón-Benito, A; Pérez-Cid-Rebolleda, M T; Rosado Sierra, M B

2016-01-01

A 46 year old patient presented with visual loss in the left eye during the previous months. Ophthalmoscopic examination and magnetic resonance angiography found the presence of papilledema due to thrombosis in superior sagittal sinus. The examination findings revealed a mantle cell lymphoma. Cerebral venous thrombosis is an unusual cause of papilledema. This type of thrombosis may be secondary to hyper-viscosity within a context of a paraneoplastic syndrome. Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

Plasma Riboflavin Level is Associated with Risk, Relapse, and Survival of Esophageal Squamous Cell Carcinoma.

Science.gov (United States)

Li, Shan-Shan; Xu, Yi-Wei; Wu, Jian-Yi; Tan, Hua-Zhen; Wu, Zhi-Yong; Xue, Yu-Jie; Zhang, Jian-Jun; Li, En-Min; Xu, Li-Yan

2017-01-01

Riboflavin is an essential micronutrient for normal cellular activity, and deficiency may result in disease, such as cancer. We performed a case-control study to explore the association of riboflavin levels with risk and prognosis of esophageal squamous cell carcinoma (ESCC). Plasma riboflavin levels, as measured by enzyme-linked immunosorbent assay (ELISA), in ESCC patients were significantly lower than in those of healthy controls (7.04 ± 6.34 ng/ml vs. 9.32 ± 12.40 ng/ml; P riboflavin level and risk of ESCC (odds ratio (OR) = 0.97, 95% confidence interval (CI) = 0.95-0.99, P =  0.02). The 5-year relapse-free and overall survival rates were significantly lower when riboflavin levels were ≤0.8 ng/ml than >0.8 ng/ml (relapse-free survival rate: 29.4% vs. 54.8%; overall survival rate: 28.6% vs. 55.6%). Plasma riboflavin level was an independent protective factor for both relapse-free (hazard ratio (HR) = 0.325, 95% CI = 0.161-0.657, P = 0.002) and overall survival of ESCC patients (HR = 0.382, 95% CI = 0.190-0.768, P = 0.007). In conclusion, plasma riboflavin levels are significantly related to risk and prognosis of ESCC patients, suggesting that moderate supplementation of riboflavin will decrease risk and prevent recurrence of ESCC and also improve prognosis of ESCC patients.

Treatment strategies in patients with AML or high-risk myelodysplastic syndrome relapsed after Allo-SCT.

Science.gov (United States)

Sauer, T; Silling, G; Groth, C; Rosenow, F; Krug, U; Görlich, D; Evers, G; Albring, J; Besoke, R; Mesters, R M; Müller-Tidow, C; Kessler, T; Büchner, T; Berdel, W E; Stelljes, M

2015-04-01

Non-relapse mortality after Allo-SCT has significantly decreased over the last years. Nevertheless, relapse remains a major cause for post SCT mortality in patients with AML and high-risk myelodysplastic syndrome (MDS). In this retrospective single-center analysis, we have analyzed the treatment outcomes of 108 patients with AML or MDS, who relapsed after Allo-SCT. Seventy of these patients (65%) were treated with salvage therapies containing chemotherapy alone, allogeneic cell-based treatment or the combination of both. Thirty-eight patients (35%) received palliative treatment. Median OS after diagnosis of relapse was 130 days. Compared with patients who received chemotherapy alone, response to salvage therapy was significantly improved in patients treated with a combination of chemo- and allogeneic cell-based therapy (CR rate 57% vs 13%, P=0.002). Among risk factors concerning pretreatment characteristics, disease status before first Allo-SCT, and details of transplantation, only the time interval from Allo-SCT to relapse was an independent predictor of response to salvage therapy and OS. These data confirmed that time to relapse after transplantation is an important prognostic factor. Up to now, only patients eligible for treatment regimens containing allogeneic cell-based interventions achieved relevant response rates.

Radioimmunotherapy for first-line and relapse treatment of aggressive B-cell non-Hodgkin lymphoma: an analysis of 215 patients registered in the international RIT-Network

Energy Technology Data Exchange (ETDEWEB)

Hohloch, Karin; Lankeit, H.K.; Truemper, L. [Georg August University, Hematology and Oncology, Goettingen (Germany); Zinzani, P.L. [University of Bologna, Institute of Hematology and Medical Oncology ' ' L. e A. Seragnoli' ' , Bologna (Italy); Scholz, C.W. [Charite, University Berlin, Hematology, Oncology and Tumor Immunology, Berlin (Germany); Lorsbach, M.; Windemuth-Kieselbach, C. [Alcedis GmbH, Giessen (Germany)

2014-08-15

Very few reliable clinical data about the use of radioimmunotherapy in aggressive B-cell lymphoma exist. Patients with aggressive B-cell lymphoma registered in the international RIT-Network were analysed with regard to prior treatment, response and side effects. The RIT-Network is a web-based registry that collects observational data from radioimmunotherapy-treated patients with malignant lymphoma across 13 countries. This analysis included 215 with aggressive B-cell lymphoma out of 232 patients registered in the RIT-Network. Histological subtypes were as follows: 190 diffuse large B-cell, 15 primary mediastinal, 9 anaplastic large cell, and 1 intravascular lymphoma. The median age of the patients was 62 years (range 17 - 88), with 27 % above the age of 70 years. Radioimmunotherapy was mainly used as consolidation after first-line or second-line chemotherapy (56.1 %), as part of third-line to eighth-line therapy for relapse (16.4 %), and in refractory disease (12.2 %). Grade IV neutropenia and thrombopenia and grade III anaemia were observed. The median time to recovery of blood count was 81 days (range 0 - 600 days). The overall response rate was 63.3 %. The complete response rate was 76.4 % in patients treated as part of first-line therapy, and 44.3 % in patients with relapse. Mean overall survival in first-line therapy patients was 32.7 months and 14.0 months in patients with relapse or refractory disease, respectively. Most patients with aggressive B-cell lymphoma in the RIT-Network received radioimmunotherapy as consolidation after first-line therapy with excellent complete remission and overall survival rates compared to published data. In relapsed aggressive B-cell lymphoma, radioimmunotherapy is a safe and feasible treatment leading to satisfactory response rates with acceptable toxicity. (orig.)

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group.

Science.gov (United States)

Buckstein, Rena; Kuruvilla, John; Chua, Neil; Lee, Christina; Macdonald, David A; Al-Tourah, Abdulwahab J; Foo, Alison H; Walsh, Wendy; Ivy, S Percy; Crump, Michael; Eisenhauer, Elizabeth A

2011-05-01

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3-4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity.

Global map of physical interactions among differentially expressed genes in multiple sclerosis relapses and remissions.

Science.gov (United States)

Tuller, Tamir; Atar, Shimshi; Ruppin, Eytan; Gurevich, Michael; Achiron, Anat

2011-09-15

Multiple sclerosis (MS) is a central nervous system autoimmune inflammatory T-cell-mediated disease with a relapsing-remitting course in the majority of patients. In this study, we performed a high-resolution systems biology analysis of gene expression and physical interactions in MS relapse and remission. To this end, we integrated 164 large-scale measurements of gene expression in peripheral blood mononuclear cells of MS patients in relapse or remission and healthy subjects, with large-scale information about the physical interactions between these genes obtained from public databases. These data were analyzed with a variety of computational methods. We find that there is a clear and significant global network-level signal that is related to the changes in gene expression of MS patients in comparison to healthy subjects. However, despite the clear differences in the clinical symptoms of MS patients in relapse versus remission, the network level signal is weaker when comparing patients in these two stages of the disease. This result suggests that most of the genes have relatively similar expression levels in the two stages of the disease. In accordance with previous studies, we found that the pathways related to regulation of cell death, chemotaxis and inflammatory response are differentially expressed in the disease in comparison to healthy subjects, while pathways related to cell adhesion, cell migration and cell-cell signaling are activated in relapse in comparison to remission. However, the current study includes a detailed report of the exact set of genes involved in these pathways and the interactions between them. For example, we found that the genes TP53 and IL1 are 'network-hub' that interacts with many of the differentially expressed genes in MS patients versus healthy subjects, and the epidermal growth factor receptor is a 'network-hub' in the case of MS patients with relapse versus remission. The statistical approaches employed in this study enabled us

Activated mesenchymal stem cell administration inhibits chronic alcohol drinking and suppresses relapse-like drinking in high-alcohol drinker rats.

Science.gov (United States)

Ezquer, Fernando; Quintanilla, María Elena; Morales, Paola; Ezquer, Marcelo; Lespay-Rebolledo, Carolyne; Herrera-Marschitz, Mario; Israel, Yedy

2017-10-18

Neuroinflammation has been reported to follow chronic ethanol intake and may perpetuate alcohol consumption. Present studies determined the effect of human mesenchymal stem cells (hMSCs), known for their anti-inflammatory action, on chronic ethanol intake and relapse-like ethanol intake in a post-deprivation condition. Rats were allowed 12-17 weeks of chronic voluntary ethanol (10% and 20% v/v) intake, after which a single dose of activated hMSCs (5 × 10 5 ) was injected into a brain lateral ventricle. Control animals were administered vehicle. After assessing the effect of hMSCs on chronic ethanol intake for 1 week, animals were deprived of ethanol for 2 weeks and thereafter an ethanol re-access of 60 min was allowed to determine relapse-like intake. A single administration of activated hMSCs inhibited chronic alcohol consumption by 70% (P 80 mg/dl. The single hMSC administration reduced relapse-like blood ethanol levels to 20 mg/dl. Chronic ethanol intake increased by 250% (P chronic ethanol intake, an effect that was fully abolished by the administration of hMSCs. This study supports the neuroinflammation-chronic ethanol intake hypothesis and suggest that mesenchymal stem cell administration may be considered in the treatment of alcohol use disorders. © 2017 Society for the Study of Addiction.

Relapsing-Remitting MS (RRMS)

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Full Text Available ... MS Relapsing-remitting MS (RRMS) Share this page Facebook Twitter Email Relapsing-remitting MS (RRMS) Relapsing-remitting ... Here Start Here Colophon Stay Informed Join Us Facebook Twitter LinkedIn YouTube Pinterest MS Connection About the ...

Relapsing-Remitting MS (RRMS)

Medline Plus

Full Text Available ... Relapsing-remitting MS (RRMS) Share this page Facebook Twitter Email Relapsing-remitting MS (RRMS) Relapsing-remitting MS ( ... Start Here Colophon Stay Informed Join Us Facebook Twitter LinkedIn YouTube Pinterest MS Connection About the Society ...

Density Anomalies in the Mantle and the Gravitational Core-Mantle Interaction

Science.gov (United States)

Kuang, Weijia; Liu, Lanbo

2003-01-01

Seismic studies suggest that the bulk of the mantle is heterogeneous, with density variations in depth as well as in horizontal directions (latitude and longitude). This density variation produces a three- dimensional gravity field throughout the Earth. On the other hand, the core density also varies in both time and space, due to convective core flow. Consequently, the fluid outer core and the solid mantle interact gravitationally due to the mass anomalies in both regions. This gravitational core-mantle interaction could play a significant role in exchange of angular momentum between the core and the mantle, and thus the change in Earth's rotation on time scales of decades and longer. Aiming at estimating the significance of the gravitational core-mantle interaction on Earth's rotation variation, we introduce in our MoSST core dynamics model a heterogeneous mantle, with a density distribution derived from seismic results. In this model, the core convection is driven by the buoyancy forces. And the density variation is determined dynamically with the convection. Numerical simulation is carried out with different parameter values, intending to extrapolate numerical results for geophysical implications.

Uranium in mantle processes

International Nuclear Information System (INIS)

Cortini, M.

1984-01-01

(1) Metasomatism is an effective process in the mantle. It controls the distribution of U, Th and Pb in the mantle before the onset of magma formation. (2) Radioactive disequilibria demonstrate that magma formation is an open-system very fast process in which Ra, U and Th are extracted in large amounts from a mantle source that is geochemically distinct from the mantle fraction from which the melt is formed. (3) Because the enrichment of U, Th and Ra in the magma is so fast, the concept of mineral-melt partition coefficient is not valid for these elements during magma formation. (4) Metasomatism seems to generally produce an increase in μ and a decrease in K of the metasomatized mantle region. (5) Magma formation at oceanic ridges and islands seems to generally produce a decrease in K, in its mantle source region. (6) The major source of U, Th, Ra and Pb in a magma probably is the metasomatic mantle component. Instead, the major source of Sr and Nd in a magma is the non-metasomatic, more 'refractory' mantle component. (7) This proposed model is testable. It predicts isotopic disequilibrium of Pb between coexisting minerals and whole rocks, and a correlation of Pb with Th isotopes. (author)

Case report: partial relapse of Bell's palsy following superficial radiotherapy to a basal cell carcinoma in the temple

Energy Technology Data Exchange (ETDEWEB)

Brincat, S.; Mantell, B.S.

1986-07-01

A patient who developed a partial relapse of Bell's palsy following superficial radiotherapy to a basal cell carcinoma in the temple is reported. Nerves injured by Bell's palsy may be more susceptible to radiation induced damage.

Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma.

Science.gov (United States)

Moccia, Alden A; Hitz, Felicitas; Hoskins, Paul; Klasa, Richard; Power, Maryse M; Savage, Kerry J; Shenkier, Tamara; Shepherd, John D; Slack, Graham W; Song, Kevin W; Gascoyne, Randy D; Connors, Joseph M; Sehn, Laurie H

2017-02-01

The optimal choice of salvage therapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) remains unknown. Based on promising results of phase II trials, the preferred salvage regimen in British Columbia since 2002 has been the out-patient regimen, gemcitabine, dexamethasone, and cisplatin (GDP). We conducted a retrospective analysis including all patients with relapsed/refractory DLBCL or HL who received GDP as salvage therapy between September 2002 and June 2010. We identified 235 patients: 152 DLBCL, 83 HL. Overall response rates were 49% and 71% for patients with DLBCL and HL, respectively. Within the transplant-eligible population, 52% of patients with DLBCL and 96% of patients with HL proceeded to stem cell transplantation. The 2-year progression-free survival and overall survival were 21% and 28% in the DLBCL cohort, and 58% and 85% in the HL group. GDP is an effective and well-tolerated out-patient salvage regimen for relapsed/refractory DLBCL and HL.

Upper mantle fluids evolution, diamond formation, and mantle metasomatism

Science.gov (United States)

Huang, F.; Sverjensky, D. A.

2017-12-01

During mantle metasomatism, fluid-rock interactions in the mantle modify wall-rock compositions. Previous studies usually either investigated mineral compositions in xenoliths and xenocrysts brought up by magmas, or examined fluid compositions preserved in fluid inclusions in diamonds. However, a key study of Panda diamonds analysed both mineral and fluid inclusions in the diamonds [1] which we used to develop a quantitative characterization of mantle metasomatic processes. In the present study, we used an extended Deep Earth Water model [2] to simulate fluid-rock interactions at upper mantle conditions, and examine the fluids and mineral assemblages together simultaneously. Three types of end-member fluids in the Panda diamond fluid inclusions include saline, rich in Na+K+Cl; silicic, rich in Si+Al; and carbonatitic, rich in Ca+Mg+Fe [1, 3]. We used the carbonatitic end-member to represent fluid from a subducting slab reacting with an excess of peridotite + some saline fluid in the host environment. During simultaneous fluid mixing and reaction with the host rock, the logfO2 increased by about 1.6 units, and the pH increased by 0.7 units. The final minerals were olivine, garnet and diamond. The Mg# of olivine decreased from 0.92 to 0.85. Garnet precipitated at an early stage, and its Mg# also decreased with reaction progress, in agreement with the solid inclusions in the Panda diamonds. Phlogopite precipitated as an intermediate mineral and then disappeared. The aqueous Ca, Mg, Fe, Si and Al concentrations all increased, while Na, K, and Cl concentrations decreased during the reaction, consistent with trends in the fluid inclusion compositions. Our study demonstrates that fluids coming from subducting slabs could trigger mantle metasomatism, influence the compositions of sub-lithospherc cratonic mantle, precipitate diamonds, and change the oxygen fugacity and pH of the upper mantle fluids. [1] Tomlinson et al. EPSL (2006); [2] Sverjensky, DA et al., GCA (2014

Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT.

Science.gov (United States)

Konuma, Takaaki; Ooi, Jun; Takahashi, Satoshi; Tomonari, Akira; Tsukada, Nobuhiro; Kato, Seiko; Sato, Aki; Monma, Fumihiko; Kasahara, Senji; Uchimaru, Kaoru; Iseki, Tohru; Tojo, Arinobu; Asano, Shigetaka

2009-06-01

There are many reports of second allogeneic stem cell transplantation (allo-SCT) using cord blood (CB) for graft failure after initial allo-SCT. However, the efficacy of second allo-SCT using CB for patients with leukemia relapsed after initial allo-SCT is unknown. We report the results of second allo-SCT using CB in seven adult patients with leukemia relapsed after initial allo-SCT. All patients received a myeloablative conditioning regimen including oral busulfan 16 mg/kg, intravenously fludarabine 100mg/m(2) and cyclophosphamide 120 mg/kg. All but one patient had myeloid reconstitution and four patients remain alive at between 4 and 40 months after second SCT. We conclude that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT.

Patterns and Timing of Initial Relapse in Patients Subsequently Undergoing Transplantation for Hodgkin's Lymphoma

International Nuclear Information System (INIS)

Dhakal, Sughosh; Biswas, Tithi; Liesveld, Jane L.; Friedberg, Jonathan W.; Phillips, Gordon L.; Constine, Louis S.

2009-01-01

Purpose: To evaluate the patterns and timing of initial recurrence in patients with Hodgkin's lymphoma (HL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplantation to enhance our understanding of the natural history of this disease and its modern treatment strategies and to direct approaches to disease surveillance. Methods and Materials: The records of 69 patients with HL who had undergone high-dose chemotherapy with autologous stem cell transplantation in our center between May 1992 and June 2006 were analyzed. The initial diagnosis had been made between April 1982 and January 2005 at a median patient age of 33 years (range, 19-65). The patients were segregated according to the initial stage (Stage I-II vs. III-IV). Results: Early-stage HL patients developed a relapse at a median of 2.1 years (range, 0.5-10.3), with 91% of relapses at the initial disease site, 71% of which (65% overall) were only in previously involved sites. Advanced-stage HL patients developed a relapse at a median of 1.5 years (range, 0.6-10.5), with 97% at the initial site, 71% of which (69% overall) were only in previously involved sites. Single-site relapses occurred in 47% of early- vs. 26% of advanced-stage patients, and extranodal relapses occurred in 12% of early- vs. 31% of advanced-stage patients. Conclusions: Almost all patients with HL who develop relapse and subsequently undergo high-dose chemotherapy with autologous stem cell transplantation initially developed recurrence in previously involved disease sites. Early-stage HL relapses often occurred in single sites, and advanced-stage disease relapses were more likely in multiple and extranodal sites. The interval to recurrence was brief, suggesting that the frequency of screening should be the greatest in the early post-therapy years.

Thoracic radiation therapy (RT) before autologous bone marrow transplantation (ABMT) in relapsed or refractory Hodgkin's disease (HD)

International Nuclear Information System (INIS)

Tsang, Richard W.; Gospodarowicz, Mary K.; Sutcliffe, Simon B.; Crump, Michael; Keating, Armand

1997-01-01

Purpose: To assess the relationship between peri-ABMT RT and treatment-related mortality in patients receiving high-dose chemotherapy (HDCT) and ABMT for recurrent/refractory HD. Materials and Methods: Between 12/1986 and 12/1992, 90 patients (pts) with HD were treated with HDCT (etoposide 60 mg/kg, melphalan 160 mg/m 2 ) +ABMT in Toronto. Fifty-nine of these had all or part of their treatment (RT and/or CT) at the PMH, and they form the basis of this report. HDCT + ABMT was performed for refractory (11 pts) or relapsed (48 pts) HD. The median age at ABMT was 29 (range 16-47), F:M ratio was 1:1.2. Salvage chemotherapy consisted of DHAP (36), mini-BEAM (7), both (8), other chemotherapy (5), and no chemotherapy (3). RT have been incorporated in the salvage treatment with the intent to achieve complete disease control of active disease at relapse or disease progression. RT was given pre-ABMT in 33 pts (3 mantle, 8 mantle with lung, 7 modified mantle excluding axillae, 4 involved field, 1 mantle with TBI, 1 TBI, and 9 non-thoracic), and post-ABMT in 4 pts (2 mantle, 2 modified mantle). Planned RT tumor dose was 35 Gy over 4 weeks (median 35 Gy, range 25-40 Gy), lower doses were used for lung RT (15-17.5 Gy). Treatment-related (TR) mortality was defined as any death occurring within 100 days of ABMT. Autopsies were performed for all patients with TR deaths. Results: We observed 36 deaths, and 10 of these were treatment-related (TR) deaths. With an average follow-up of 4.9 years (range 1.2-7.4 years), the actuarial overall survival was 52% ± 13% at 3 years, and 41% ± 14% at 5 years. Among the 24 patients who received thoracic RT before ABMT, there were 8 TR deaths, with 3 solely attributable to radiation pneumonitis. The remaining 5 TR deaths all had respiratory failure as a major medical problem with complicating sepsis and pancytopenia. The interval from RT to ABMT was shorter for 8 patients dying of TR death (mean 37 days; range 0-103 days), than for the 16 pts with

[Relapse: causes and consequences].

Science.gov (United States)

Thomas, P

2013-09-01

Relapse after a first episode of schizophrenia is the recurrence of acute symptoms after a period of partial or complete remission. Due to its variable aspects, there is no operational definition of relapse able to modelise the outcome of schizophrenia and measure how the treatment modifies the disease. Follow-up studies based on proxys such as hospital admission revealed that 7 of 10 patients relapsed after a first episode of schizophrenia. The effectiveness of antipsychotic medications on relapse prevention has been widely demonstrated. Recent studies claim for the advantages of atypical over first generation antipsychotic medication. Non-adherence to antipsychotic represents with addictions the main causes of relapse long before some non-consensual factors such as premorbid functioning, duration of untreated psychosis and associated personality disorders. The consequences of relapse are multiple, psychological, biological and social. Pharmaco-clinical studies have demonstrated that the treatment response decreases with each relapse. Relapse, even the first one, will contribute to worsen the outcome of the disease and reduce the capacity in general functionning. Accepting the idea of continuing treatment is a complex decision in which the psychiatrist plays a central role besides patients and their families. The development of integrated actions on modifiable risk factors such as psychosocial support, addictive comorbidities, access to care and the therapeutic alliance should be promoted. Relapse prevention is a major goal of the treatment of first-episode schizophrenia. It is based on adherence to the maintenance treatment, identification of prodromes, family active information and patient therapeutical education. Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.

Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China

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Yuankai Shi

2017-03-01

Full Text Available Abstract The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL. This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256, the overall response rate (ORR and disease control rate (DCR were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127. For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS was 129 (95% CI 82 to 194 days for the monotherapy group and 152 (95% CI 93 to 201 days for the combined therapy group (P = 0.3266. Most adverse events (AEs were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2% and neutropenia (6.2%. For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%, neutropenia (12.6%, anemia (7.1%, and fatigue (5.5%. This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.

Individualized rituximab treatment for relapsing neuromyelitis optica: a pediatric case report.

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He, Dian; Yu, YunLi; Yan, WeiBo; Dai, QingQing; Xu, Zhu; Chu, Lan

2014-08-01

Neuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system. Current therapeutic approaches are based on small uncontrolled trials, case series, or case reports. There are only a few case reports describing rituximab for pediatric neuromyelitis optica. A 7-year-old girl with neuromyelitis optica had high disease activity with recurrent myelitis and steroid dependence. A remarkable increase of CD19(+) B-cell count in the peripheral blood mononuclear cells and seropositivity for anti-aquaporin 4 antibody were detected at each attack. After induction therapy with rituximab, the CD19(+) B-cell number was significantly reduced and sustained at low levels. The level of serum anti-aquaporin 4 antibody normalized. She was relapse-free over 1-year follow-up period. An individualized maintenance therapy scheme is underway. Treatment with rituximab for relapsing neuromyelitis optica requires an individualized regimen to optimize the frequency and dosage of administration to maximize efficacy yet minimize overtreatment and cost. Personal levels of CD19(+) B cells in peripheral blood mononuclear cells at previous attacks and responsiveness to rituximab in induction therapy may be two useful indicators in establishing individualized maintenance therapy schemes for relapsing neuromyelitis optica. Copyright © 2014 Elsevier Inc. All rights reserved.

Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group.

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Itonaga, H; Sawayama, Y; Taguchi, J; Honda, S; Taniguchi, H; Makiyama, J; Matsuo, E; Sato, S; Ando, K; Imanishi, D; Imaizumi, Y; Yoshida, S; Hata, T; Moriuchi, Y; Fukushima, T; Miyazaki, Y

2015-04-01

Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (PSCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.

Dehydration of δ-AlOOH in the lower mantle

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Piet, H.; Shim, S. H.; Tappan, J.; Leinenweber, K. D.; Greenberg, E.; Prakapenka, V. B.

2017-12-01

Hydrous phase δ-AlOOH is an important candidate for water transport and storage in the Earth's deep mantle [1]. Knowing the conditions, under which it is stable and dehydrated, is therefore important for understanding the water transportation to the deep mantle or even to the core. A few experimental studies [1, 2] have shown that δ-AlOOH may be stable in cold descending slabs while it is dehydrated into a mixture of corundum and water under normal mantle conditions, up to 25 GPa. A subsequent study [3] reported the stability of δ-AlOOH in cold descending slabs to the core-mantle boundary conditions (2300 K at 135 GPa). However, the dehydration of δ-AlOOH has not bee directly observed in the experiments conducted at pressures above 25 GPa. We have synthesized δ-AlOOH from diaspore and Al(OH)3 in multi-anvil press at ASU. The sample was mixed with Au for coupling with near IR laser beams and loaded in diamond-anvil cells. We performed the laser-heated diamond anvil cell experiments at the 13IDD beamline of the Advanced Photon Source and ASU. At APS, we measured X-ray diffraction patterns at in situ high pressure and temperature. We observed the appearance of the corundum diffraction lines at 1700-2000 K and 55-90 GPa, indicating the dehydration of δ-AlOOH to Al2O3+ H2O. We found that the transition occurs over a broad range of temperature (500 K). We also observed that the dehydration of δ-AlOOH was accompanied by sudden change in laser coupling, most likely due to the release of fluids. The property change also helps us to determine the dehydration at ASU without in situ XRD. Our new experimental results indicate that δ-AlOOH would be stable in most subducting slabs in the deep mantle. However, because the dehydration occurs very close to the temperatures expected for the lower mantle, its stability is uncertain in the normal mantle. [1] Ohtani et al. 2001, Stability field of new hydrous phase, delta-AlOOH, Geophysical Research Letters 28, 3991-3993. [2

miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator

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Husby, Simon; Ralfkiær, Ulrik Methner; Garde, Christian

2015-01-01

Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling...... by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance....

Predicting Relapse among Young Adults: Psychometric Validation of the Advanced Warning of Relapse (AWARE) Scale

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Kelly, John F.; Hoeppner, Bettina B.; Urbanoski, Karen A.; Slaymaker, Valerie

2011-01-01

Objective Failure to maintain abstinence despite incurring severe harm is perhaps the key defining feature of addiction. Relapse prevention strategies have been developed to attenuate this propensity to relapse, but predicting who will, and who will not, relapse has stymied attempts to more efficiently tailor treatments according to relapse risk profile. Here we examine the psychometric properties of a promising relapse risk measure - the Advance WArning of RElapse scale (AWARE) scale (Miller and Harris, 2000) in an understudied but clinically important sample of young adults. Method Inpatient youth (N=303; Age 18-24; 26% female) completed the AWARE scale and the Brief Symptom Inventory-18 (BSI) at the end of residential treatment, and at 1-, 3-, and 6-months following discharge. Internal and convergent validity was tested for each of these four timepoints using confirmatory factor analysis and correlations (with BSI scores). Predictive validity was tested for relapse 1, 3, and 6 months following discharge, as was incremental utility, where AWARE scores were used as predictors of any substance use while controlling for treatment entry substance use severity and having spent time in a controlled environment following treatment. Results Confirmatory factor analysis revealed a single, internally consistent, 25-item factor that demonstrated convergent validity and predicted subsequent relapse alone and when controlling for other important relapse risk predictors. Conclusions The AWARE scale may be a useful and efficient clinical tool for assessing short-term relapse risk among young people and, thus, could serve to enhance the effectiveness of relapse prevention efforts. PMID:21700396

Predicting relapse among young adults: psychometric validation of the Advanced WArning of RElapse (AWARE) scale.

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Kelly, John F; Hoeppner, Bettina B; Urbanoski, Karen A; Slaymaker, Valerie

2011-10-01

Failure to maintain abstinence despite incurring severe harm is perhaps the key defining feature of addiction. Relapse prevention strategies have been developed to attenuate this propensity to relapse, but predicting who will, and who will not, relapse has stymied attempts to more efficiently tailor treatments according to relapse risk profile. Here we examine the psychometric properties of a promising relapse risk measure-the Advance WArning of RElapse (AWARE) scale (Miller & Harris, 2000) in an understudied but clinically important sample of young adults. Inpatient youth (N=303; Ages 18-24; 26% female) completed the AWARE scale and the Brief Symptom Inventory-18 (BSI) at the end of residential treatment, and at 1-, 3-, and 6-months following discharge. Internal and convergent validity was tested for each of these four timepoints using confirmatory factor analysis and correlations (with BSI scores). Predictive validity was tested for relapse 1, 3, and 6 months following discharge, as was incremental utility, where AWARE scores were used as predictors of any substance use while controlling for treatment entry substance use severity and having spent time in a controlled environment following treatment. Confirmatory factor analysis revealed a single, internally consistent, 25-item factor that demonstrated convergent validity and predicted subsequent relapse alone and when controlling for other important relapse risk predictors. The AWARE scale may be a useful and efficient clinical tool for assessing short-term relapse risk among young people and, thus, could serve to enhance the effectiveness of relapse prevention efforts. Copyright © 2011 Elsevier Ltd. All rights reserved.

Prolonged Survival of a Refractory Acute Myeloid Leukemia Patient after a Third Hematopoietic Stem Cell Transplantation with Umbilical Cord Blood following a Second Relapse

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Suk-young Lee

2014-01-01

Full Text Available Although hematopoietic stem cell transplantation (HSCT has been considered to be the only way for potential cure of relapsed acute myeloid leukemia (AML, there has been no report on a third HSCT in patients with multiple relapsed AML. Here, we report a case of 53-year-old female who received a successful third allogeneic HSCT after relapse of AML following a second allogeneic HSCT. She was treated with a toxicity reduced conditioning regimen and received direct intrabone cord blood transplantation (CBT using a single unit of 5/6 HLA-matched cord blood as a graft source. Graft-versus-host disease prophylaxis was performed with a single agent of tacrolimus to increase graft-versus-leukemia effect. She is in remission for 8 months since the direct intrabone CBT. This report highlights not only the importance of individually adjusted approach but also the need for further investigation on the role of HSCT as a treatment modality in patients with refractory or multiple relapsed AML.

Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses.

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Rolla, Simona; De Mercanti, Stefania Federica; Bardina, Valentina; Horakova, Dana; Habek, Mario; Adamec, Ivan; Cocco, Eleonora; Annovazzi, Pietro; Vladic, Anton; Novelli, Francesco; Durelli, Luca; Clerico, Marinella

2017-12-15

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia.

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Davila, Marco L; Brentjens, Renier J

2016-10-01

Immunotherapy has demonstrated significant potential for the treatment of patients with chemotherapy-resistant hematologic malignancies and solid tumors. One type of immunotherapy involves the adoptive transfer of T cells that have been genetically modified with a chimeric antigen receptor (CAR) to target a tumor. These hybrid proteins are composed of the antigen-binding domains of an antibody fused to T-cell receptor signaling machinery. CAR T cells that target CD19 recently have made the jump from the laboratory to the clinic, and the results have been remarkable. CD19-targeted CAR T cells have induced complete remissions of disease in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), who have an expected complete response rate of 30% in response to chemotherapy. The high efficacy of CAR T cells in B-ALL suggests that regulatory approval of this therapy for this routinely fatal leukemia is on the horizon. We review the preclinical development of CAR T cells and their early clinical application for lymphoma. We also provide a comprehensive analysis of the use of CAR T cells in patients with B-ALL. In addition, we discuss the unique toxicities associated with this therapy and the management schemes that have been developed.

Dynamical geochemistry of the mantle

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G. F. Davies

2011-09-01

Full Text Available The reconciliation of mantle chemistry with the structure of the mantle inferred from geophysics and dynamical modelling has been a long-standing problem. This paper reviews three main aspects. First, extensions and refinements of dynamical modelling and theory of mantle processing over the past decade. Second, a recent reconsideration of the implications of mantle heterogeneity for melting, melt migration, mantle differentiation and mantle segregation. Third, a recent proposed shift in the primitive chemical baseline of the mantle inferred from observations of non-chondritic ¹⁴²Nd in the Earth. It seems most issues can now be resolved, except the level of heating required to maintain the mantle's thermal evolution.

A reconciliation of refractory trace elements and their isotopes with the dynamical mantle, proposed and given preliminary quantification by Hofmann, White and Christensen, has been strengthened by work over the past decade. The apparent age of lead isotopes and the broad refractory-element differences among and between ocean island basalts (OIBs and mid-ocean ridge basalts (MORBs can now be quantitatively accounted for with some assurance.

The association of the least radiogenic helium with relatively depleted sources and their location in the mantle have been enigmatic. The least radiogenic helium samples have recently been recognised as matching the proposed non-chondritic primitive mantle. It has also been proposed recently that noble gases reside in a so-called hybrid pyroxenite assemblage that is the result of melt from fusible pods reacting with surrounding refractory peridotite and refreezing. Hybrid pyroxenite that is off-axis may not remelt and erupt at MORs, so its volatile constituents would recirculate within the mantle. Hybrid pyroxenite is likely to be denser than average mantle, and thus some would tend to settle in the D" zone at the base of the mantle, along with some old subducted

Daily corticosteroids reduce infection-associated relapses in frequently relapsing nephrotic syndrome: a randomized controlled trial.

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Gulati, Ashima; Sinha, Aditi; Sreenivas, Vishnubhatla; Math, Aparna; Hari, Pankaj; Bagga, Arvind

2011-01-01

Relapses of nephrotic syndrome often follow minor infections, commonly of the upper respiratory tract. Daily administration of maintenance prednisolone during intercurrent infections was examined to determine whether the treatment reduces relapse rates in children with frequently relapsing nephrotic syndrome. In a randomized controlled trial (nonblind, parallel group, tertiary-care hospital), 100 patients with idiopathic, frequently relapsing nephrotic syndrome eligible for therapy with prolonged low-dose, alternate-day prednisolone with or without levamisole were randomized to either receive their usual dose of alternate-day prednisolone daily for 7 days during intercurrent infections (intervention group) or continue alternate-day prednisolone (controls). Primary outcome was assessed by comparing the rates of infection-associated relapses at 12-month follow-up. Secondary outcomes were the frequency of infections and the cumulative amount of prednisolone received in both groups. Patients in the intervention group showed significantly lower infection-associated (rate difference, 0.7 episodes/patient per year; 95% confidence intervals [CI] 0.3, 1.1) and lower total relapse rates (0.9 episodes/patient per year, 95% CI 0.4, 1.4) without increase in steroid toxicity. Poisson regression, adjusted for occurrence of infections, showed that daily administration of prednisolone during infections independently resulted in 59% reduction in frequency of relapses (rate ratio, 0.41; 95% CI 0.3, 0.6). For every six patients receiving this intervention, one showed a reduction of relapse frequency to less than three per year. Daily administration of maintenance doses of prednisolone, during intercurrent infections, significantly reduces relapse rates and the proportion of children with frequently relapsing nephrotic syndrome.

The regulatory BCL2 promoter polymorphism (-938C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma.

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Lehnerdt, G F; Franz, P; Bankfalvi, A; Grehl, S; Kelava, A; Nückel, H; Lang, S; Schmid, K W; Siffert, W; Bachmann, H S

2009-06-01

Expression of the antiapoptotic and antiproliferative protein B-cell lymphoma 2 (Bcl-2) has been repeatedly shown to be associated with better locoregional control and patients' survival in oropharyngeal squamous cell carcinoma (OSCC). A regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generates significantly different BCL2 promoter activities and has been associated with outcome in different malignancies. The aim of the present study was to analyze the possible influence of the (-938C>A) SNP on survival of patients suffering from OSCC. One hundred and thirty-three patients with primary OSCC were retrospectively investigated. Bcl-2 expression of tumor cells was demonstrated by means of immunohistochemistry. Both the Bcl-2 expression and the (-938C>A) genotypes were correlated with the patients' survival. The (-938C>A) SNP was significantly related to Bcl-2 expression (P = 0.008). Kaplan-Meier curves revealed a significant association of the -938 SNP with relapse-free (P = 0.0283) and overall survival (P = 0.0247). Multiple Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for relapse [hazard ratio (HR) 1.898, P = 0.021] as well as for death in OSCC patients (HR 1.897, P = 0.013). The (-938C>A) SNP represents a potential novel prognostic marker in patients with OSCC that could help to identify a group of patients at high risk for relapse and death.

Absolute lymphocyte count predicts response to rituximab-containing salvage treatment for relapsed/refractory B-cell non-Hodgkin's lymphoma with prior rituximab exposure

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Man-Hsin Hung

2013-04-01

Conclusion: Our study results show that for patients with relapsed/refractory B-cell NHL, rituximab-containing salvage treatment is feasible and generally tolerable. A high ALC-R value was significantly associated with a better response to this treatment.

Social settings and addiction relapse.

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Walton, M A; Reischl, T M; Ramanthan, C S

1995-01-01

Despite addiction theorists' acknowledgment of the impact of environmental factors on relapse, researchers have not adequately investigated these influences. Ninety-six substance users provided data regarding their perceived risk for relapse, exposure to substances, and involvement in reinforcing activities. These three setting attributes were assessed in their home, work, and community settings. Reuse was assessed 3 months later. When controlling for confounding variables, aspects of the home settings significantly distinguished abstainers from reusers; perceived risk for relapse was the strongest predictor of reuse. Exposure to substances and involvement in reinforcing activities were not robust reuse indicators. The work and community settings were not significant determinants of reuse. These findings offer some initial support for the utility of examining social settings to better understand addiction relapse and recovery. Identification of setting-based relapse determinants provides concrete targets for relapse prevention interventions.

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

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2018-04-10

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

A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib.

Science.gov (United States)

Lee, Chung-Shien; Rattu, Mohammad A; Kim, Sara S

2016-02-01

Ibrutinib, a Bruton's kinase inhibitor, was granted an accelerated approval by the US Food and Drug Administration in November, 2013, for the treatment of relapsed or refractory mantle cell lymphoma and subsequently for the treatment of relapsed refractory chronic lymphocytic leukemia in February, 2014. In the pivotal phase 2 study of 111 patients with relapsed or refractory mantle cell lymphoma, the overall response rate in patients who received ibrutinib 560 mg daily was 68%. The median progression-free survival was 13.9 months, and the overall survival was 58% at 18 months. In a recently published phase 3 trial (RESONATE) that compared ibrutinib and ofatumumab for the treatment of relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, ibrutinib at the daily dosage of 420 mg demonstrated a significantly higher overall response rate (43% in ibrutinib vs. 4% in ofatumumab) and a significantly improved overall survival at 12 months (90% ibrutinib vs. 81% ofatumumab). Similar clinical benefits were shown regardless of del (17 p). Ibrutinib was well tolerated, and dose-limiting toxicity was not observed. Ibrutinib has shown durable remission, improved progression-free survival and overall survival, and favorable safety profile in indolent B-cell lymphoid malignancies. Ibrutinib, as a monotherapy, is an effective treatment modality as a salvage therapy for treatment of mantle cell lymphoma and chronic lymphocytic leukemia / small lymphocytic lymphoma, particularly in older patients (age ≥70 years) who are not a candidate for intensive chemotherapy and/or those with del (17 p). In patients with chronic lymphocytic leukemia and del (17 p), the current practice guideline recommends ibrutinib as an upfront treatment option. Current on-going trials will further define its role as upfront therapy and/or as a combination therapy in indolent B-cell lymphoid malignancies. © The Author(s) 2014.

Role of routine imaging in detecting recurrent lymphoma; a review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma

DEFF Research Database (Denmark)

El-Galaly, Tarec Christoffer; Mylam, Karen Juul; Bøgsted, Martin

2014-01-01

After first-line therapy, patients with Hodgkin and aggressive non-Hodgkin lymphomas are followed closely for early signs of relapse. The current follow-up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore a retrospective...... multicenter study of relapsed Hodgkin and aggressive non-Hodgkin lymphomas (nodal T-cell and diffuse large B-cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002-2011 and relapsed after achieving complete remission on first-line therapy. Characteristics and outcome...... of imaging-detected relapses were compared to other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient-reported symptoms alone...

Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

International Nuclear Information System (INIS)

Knecht, Hans; Righolt, Christiaan; Mai, Sabine

2013-01-01

In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells are rare and generally make up <3% of the total cellular mass of the affected lymph nodes. During recent years, the introduction of laser micro-dissection techniques at the single cell level has substantially improved our understanding of the molecular pathogenesis of HL. Gene expression profiling, comparative genomic hybridization analysis, micro-RNA expression profiling and viral oncogene sequencing have deepened our knowledge of numerous facets of H- and RS-cell gene expression deregulation. The question remains whether disturbed signaling pathways and deregulated transcription factors are at the origin of refractory/relapsing Hodgkin’s lymphoma or whether these hallmarks are at least partially related to another major factor. We recently showed that the 3D nuclear organization of telomeres and chromosomes marked the transition from H- to RS-cells in HL cell lines. This transition is associated with progression of telomere dysfunction, shelterin disruption and progression of complex chromosomal rearrangements. We reported analogous findings in refractory/relapsing HL and identified the shelterin proteins TRF1, TRF2 and POT1 as targets of the LMP1 oncogene in post-germinal center B-cells. Here we summarize our findings, including data not previously published, and propose a model in which progressive disruption of nuclear integrity, a form of genomic instability, is the key-player in refractory/relapsing HL. Therapeutic approaches should take these findings into account

Relapsing-Remitting MS (RRMS)

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Full Text Available ... Clinicians Publications for Your Patients MS Navigator Program Programs and Services for Your Patients Contact Us Clinical Fellows ... Relapsing-remitting MS (RRMS) Relapsing-remitting ...

Mantle dynamics following supercontinent formation

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Heron, Philip J.

This thesis presents mantle convection numerical simulations of supercontinent formation. Approximately 300 million years ago, through the large-scale subduction of oceanic sea floor, continental material amalgamated to form the supercontinent Pangea. For 100 million years after its formation, Pangea remained relatively stationary, and subduction of oceanic material featured on its margins. The present-day location of the continents is due to the rifting apart of Pangea, with supercontinent dispersal being characterized by increased volcanic activity linked to the generation of deep mantle plumes. The work presented here investigates the thermal evolution of mantle dynamics (e.g., mantle temperatures and sub-continental plumes) following the formation of a supercontinent. Specifically, continental insulation and continental margin subduction are analyzed. Continental material, as compared to oceanic material, inhibits heat flow from the mantle. Previous numerical simulations have shown that the formation of a stationary supercontinent would elevate sub-continental mantle temperatures due to the effect of continental insulation, leading to the break-up of the continent. By modelling a vigorously convecting mantle that features thermally and mechanically distinct continental and oceanic plates, this study shows the effect of continental insulation on the mantle to be minimal. However, the formation of a supercontinent results in sub-continental plume formation due to the re-positioning of subduction zones to the margins of the continent. Accordingly, it is demonstrated that continental insulation is not a significant factor in producing sub-supercontinent plumes but that subduction patterns control the location and timing of upwelling formation. A theme throughout the thesis is an inquiry into why geodynamic studies would produce different results. Mantle viscosity, Rayleigh number, continental size, continental insulation, and oceanic plate boundary evolution are

The Cost of Relapse in Schizophrenia.

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Pennington, Mark; McCrone, Paul

2017-09-01

Schizophrenia is a chronic and debilitating mental illness characterised by periods of relapse that require resource intensive management. Quantifying the cost of relapse is central to the evaluation of the cost effectiveness of treating schizophrenia. We aimed to undertake a comprehensive search of the available literature on the cost of relapse. We performed a search on multiple databases (MEDLINE, Embase, PsycINFO and Health Management Information Consortium) for any study reporting a cost of relapse or data from which such a cost could be calculated. Costs are reported in 2015 international dollars. We found 16 studies reporting costs associated with relapse over a defined period of time and identified a cost associated with hospitalisation for relapse in 43 studies. Eight clinical decision analyses also provided cost estimates. Studies from the US report excess costs of relapse of $6033-$32,753 (2015 Purchasing Power Parity dollars [PPP$]) over periods of 12-15 months. European studies report excess costs of $8665-$18,676 (2015 PPP$) over periods of 6-12 months. Estimates of the cost of hospitalisation for relapse are more diverse, and associated with marked differences in typical length of stay across jurisdictions. Wide ranges in the estimated cost of relapse may reflect differences in sample section and relapse definition as well as practice styles and differences in resource costs. Selection of the most appropriate cost estimate should be guided by the definition of relapse and the analysis setting.

Diagnosis of mantle cell lymphoma and detection of bcl-1 gene rearrangement

International Nuclear Information System (INIS)

Lee, Seung Sook; Cho, Kyung Ja; Lee, Sun Joo

1996-12-01

We reclassified a large series of non-Hogkin's lymphoma diagnosed at Korea Cancer Center Hospital from 1991 to 1995, according to REAL classification, and compared the efficacy of immunohistochemical study for cyclin D1 protein and PCR for bcl-1 gene rearrangement to diagnose mantle cell lymphoma (MCL). By REAL classification, 7 %, diffuse large B-cell lymphoma was the most common type (51.8%) and was followed by peripheral T-cell lymphoma-unspecified (10%) and angiocentric lymphoma (7.5%). The most reliable histologic finding was mitosis to make a differential diagnosis. Mitoses of MCL were 17/10 HPF in average and all the cases showed more than 10/10 HPF. Immunophenotypic study alone cannot lead to a differential diagnosis between MCL and SLL, and the overexpression of cyclin D1 was the most important for diagnosis of MCL . Both immunohistochemistry for cyclin D1 and PCR for bcl-1 were specific for MCL and immunohistochemistry was more sensitive than PCR. Statistical analysis showed a different survival rate between MCL and the other low-grade B-cell lymphomas (SLL + MALT + LPL) and a difference between MCL and SLL. Immunohistochemical detection of cyclin D1 has a practical usefulness in making routine diagnosis of MCL. The initial accurate diagnosis of MCL will help clinicians make a proper management. (author). 27 refs., 6 tabs., 4 figs

Diagnosis of mantle cell lymphoma and detection of bcl-1 gene rearrangement

Energy Technology Data Exchange (ETDEWEB)

Lee, Seung Sook; Cho, Kyung Ja; Lee, Sun Joo [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

1996-12-01

We reclassified a large series of non-Hogkin`s lymphoma diagnosed at Korea Cancer Center Hospital from 1991 to 1995, according to REAL classification, and compared the efficacy of immunohistochemical study for cyclin D1 protein and PCR for bcl-1 gene rearrangement to diagnose mantle cell lymphoma (MCL). By REAL classification, 7 %, diffuse large B-cell lymphoma was the most common type (51.8%) and was followed by peripheral T-cell lymphoma-unspecified (10%) and angiocentric lymphoma (7.5%). The most reliable histologic finding was mitosis to make a differential diagnosis. Mitoses of MCL were 17/10 HPF in average and all the cases showed more than 10/10 HPF. Immunophenotypic study alone cannot lead to a differential diagnosis between MCL and SLL, and the overexpression of cyclin D1 was the most important for diagnosis of MCL . Both immunohistochemistry for cyclin D1 and PCR for bcl-1 were specific for MCL and immunohistochemistry was more sensitive than PCR. Statistical analysis showed a different survival rate between MCL and the other low-grade B-cell lymphomas (SLL + MALT + LPL) and a difference between MCL and SLL. Immunohistochemical detection of cyclin D1 has a practical usefulness in making routine diagnosis of MCL. The initial accurate diagnosis of MCL will help clinicians make a proper management. (author). 27 refs., 6 tabs., 4 figs.

Relapsing-Remitting MS (RRMS)

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Full Text Available ... for You and Your Practice Publications for Clinicians Publications for Your Patients MS Navigator Program Programs and Services for Your Patients ... Relapsing-remitting MS (RRMS) Relapsing-remitting MS ( ...

P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines

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Shirsath Nitesh P

2012-10-01

Full Text Available Abstract Background Mantle cell lymphoma (MCL is a well-defined aggressive lymphoid neoplasm characterized by proliferation of mature B-lymphocytes that have a remarkable tendency to disseminate. This tumor is considered as one of the most aggressive lymphoid neoplasms with poor responses to conventional chemotherapy and relatively short survival. Since cyclin D1 and cell cycle control appears as a natural target, small-molecule inhibitors of cyclin-dependent kinases (Cdks and cyclins may play important role in the therapy of this disorder. We explored P276-00, a novel selective potent Cdk4-D1, Cdk1-B and Cdk9-T1 inhibitor discovered by us against MCL and elucidated its potential mechanism of action. Methods The cytotoxic effect of P276-00 in three human MCL cell lines was evaluated in vitro. The effect of P276-00 on the regulation of cell cycle, apoptosis and transcription was assessed, which are implied in the pathogenesis of MCL. Flow cytometry, western blot, immunoflourescence and siRNA studies were performed. The in vivo efficacy and effect on survival of P276-00 was evaluated in a Jeko-1 xenograft model developed in SCID mice. PK/PD analysis of tumors were performed using LC-MS and western blot analysis. Results P276-00 showed a potent cytotoxic effect against MCL cell lines. Mechanistic studies confirmed down regulation of cell cycle regulatory proteins with apoptosis. P276-00 causes time and dose dependent increase in the sub G1 population as early as from 24 h. Reverse transcription PCR studies provide evidence that P276-00 treatment down regulated transcription of antiapoptotic protein Mcl-1 which is a potential pathogenic protein for MCL. Most importantly, in vivo studies have revealed significant efficacy as a single agent with increased survival period compared to vehicle treated. Further, preliminary combination studies of P276-00 with doxorubicin and bortezomib showed in vitro synergism. Conclusion Our studies thus provide

Heat transfer correlations in mantle tanks

DEFF Research Database (Denmark)

Furbo, Simon; Knudsen, Søren

2005-01-01

on calculations with a CFD-model, which has earlier been validated by means of experiments. The CFD-model is used to determine the heat transfer between the solar collector fluid in the mantle and the walls surrounding the mantle in all levels of the mantle as well as the heat transfer between the wall...... transfer correlations are suitable as input for a detailed simulation model for mantle tanks. The heat transfer correlations determined in this study are somewhat different from previous reported heat transfer correlations. The reason is that this study includes more mantle tank designs and operation......Small solar domestic hot water systems are best designed as low flow systems based on vertical mantle tanks. Theoretical investigations of the heat transfer in differently designed vertical mantle tanks during different operation conditions have been carried out. The investigations are based...

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

Science.gov (United States)

Laubach, J; Garderet, L; Mahindra, A; Gahrton, G; Caers, J; Sezer, O; Voorhees, P; Leleu, X; Johnsen, H E; Streetly, M; Jurczyszyn, A; Ludwig, H; Mellqvist, U-H; Chng, W-J; Pilarski, L; Einsele, H; Hou, J; Turesson, I; Zamagni, E; Chim, C S; Mazumder, A; Westin, J; Lu, J; Reiman, T; Kristinsson, S; Joshua, D; Roussel, M; O'Gorman, P; Terpos, E; McCarthy, P; Dimopoulos, M; Moreau, P; Orlowski, R Z; Miguel, J S; Anderson, K C; Palumbo, A; Kumar, S; Rajkumar, V; Durie, B; Richardson, P G

2016-05-01

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Patterns and Timing of Failure for Diffuse Large B-Cell Lymphoma After Initial Therapy in a Cohort Who Underwent Autologous Bone Marrow Transplantation for Relapse

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Dhakal, Sughosh; Bates, James E. [Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York (United States); Casulo, Carla; Friedberg, Jonathan W.; Becker, Michael W.; Liesveld, Jane L. [Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York (United States); Constine, Louis S., E-mail: louis_constine@urmc.rochester.edu [Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York (United States)

2016-10-01

Purpose: To evaluate the location and timing of initial recurrence in patients with diffuse large B-cell lymphoma (DLBCL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplant (HDC/ASCT), to direct approaches for disease surveillance, elucidate the patterns of failure of contemporary treatment strategies, and guide adjuvant treatment decisions. Methods and Materials: We analyzed consecutive patients with DLBCL who underwent HDC/ASCT between May 1992 and March 2014 at our institution. Of the 187 evaluable patients, 8 had incomplete data, and 79 underwent HDC/ASCT as a component of initial treatment for de novo or refractory DLBCL and were excluded from further analysis. Results: The median age was 50.8 years; the median time to relapse was 1.3 years. Patients were segregated according to the initial stage at diagnosis, with early stage (ES) defined as stage I/II and advanced stage (AS) defined as stage III/IV. In total, 40.4% of the ES and 75.5% of the AS patients relapsed in sites of initial disease; 68.4% of those with ES disease and 75.0% of those with AS disease relapsed in sites of initial disease only. Extranodal relapses were common (44.7% in ES and 35.9% in AS) and occurred in a variety of organs, although gastrointestinal tract/liver (n=12) was most frequent. Conclusions: Most patients with DLBCL who relapse and subsequently undergo HDC/ASCT initially recur in the previously involved disease site(s). Time to recurrence is brief, suggesting that frequency of screening is most justifiably greatest in the early posttherapy years. © 2016 Elsevier Inc.

Daunorubicin, Cytarabine, and Cladribine Regimen Plus Radiotherapy and Donor Lymphocyte Infusion for Extramedullary Relapse of Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation

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Marco Sanna

2013-01-01

Full Text Available Myeloid sarcoma is a rare tumor consisting of myeloid blasts that involve anatomic sites outside the bone marrow. Fatal prognosis is inevitable in patients with extramedullary relapse after hematopoietic stem cell transplantation (HSCT, and no standard treatments are available yet. We report the first case of extramedullary relapse after HSCT treated with a combination of daunorubicin, cytarabine, and cladribine (DAC regimen plus radiotherapy and donor lymphocyte infusion (DLI. This treatment induced a new and durable remission in our patient. The favorable toxicity profile and the reduced cost make this combination worthy of further investigations.

Gemcitabine, dexamethasone, and cisplatin (GDP) as salvage chemotherapy for patients with relapsed or refractory peripheral T cell lymphoma-not otherwise specified.

Science.gov (United States)

Qi, Fei; Dong, Mei; He, Xiaohui; Li, Yexiong; Wang, Weihu; Liu, Peng; Yang, Jianliang; Gui, Lin; Zhang, Changgong; Yang, Sheng; Zhou, Shengyu; Shi, Yuankai

2017-02-01

Standard therapeutic options for patients with relapsed or refractory peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) remain unclear. There are few large cohort studies specifically focused on gemcitabine-based chemotherapy for PTCL-NOS. We retrospectively reviewed patients with relapsed or refractory PTCL-NOS who received salvage GDP (gemcitabine, dexamethasone, and cisplatin) chemotherapy at the Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China, from May 2008 to August 2014. Twenty-five patients were enrolled and analyzed. The median number of cycles of GDP chemotherapy per patient was four (range, 2-8 cycles). Overall response rate was 64.0% (16/25) with five achieved complete remission or complete remission unconfirmed. After a median follow-up of 9 months, median overall survival (OS) and progression-free survival after relapse or progression (second-PFS) were 9.3 and 5.4 months. One-year PFS rate and 1-year OS rate were 27.4% and 43.9%, respectively. Median second-PFS was significantly longer in patients sensitive to GDP than the ones resistant to the treatment (10.3 vs. 2.8 months, p GDP including neutropenia (8/25), thrombocytopenia (5/25), and anemia (4/25). Taken together, our study suggests that GDP is an effective and optional salvage regimen for relapsed or refractory PTCL-NOS.

Evolution of the earliest mantle caused by the magmatism-mantle upwelling feedback: Implications for the Moon and the Earth

Science.gov (United States)

Ogawa, M.

2017-12-01

The two most important agents that cause mantle evolution are magmatism and mantle convection. My earlier 2D numerical models of a coupled magmatism-mantle convection system show that these two agents strongly couple each other, when the Rayleigh number Ra is sufficiently high: magmatism induced by a mantle upwelling flow boosts the upwelling flow itself. The mantle convection enhanced by this positive feedback (the magmatism-mantle upwelling, or MMU, feedback) causes vigorous magmatism and, at the same time, strongly stirs the mantle. I explored how the MMU feedback influences the evolution of the earliest mantle that contains the magma ocean, based on a numerical model where the mantle is hot and its topmost 1/3 is partially molten at the beginning of the calculation: The evolution drastically changes its style, as Ra exceeds the threshold for onset of the MMU feedback, around 107. At Ra 107, however, the mantle remains compositionally more homogeneous in spite of the widespread magmatism, and the deep mantle remains hotter than the shallow mantle, because of the strong convective stirring caused by the feedback. The threshold value suggests that the mantle of a planet larger than Mars evolves in a way substantially different from that in the Moon does. Indeed, in my earlier models, magmatism makes the early mantle compositionally stratified in the Moon, but the effects of strong convective stirring overwhelms that of magmatism to keep the mantle compositionally rather homogeneous in Venus and the Earth. The MMU feedback is likely to be a key to understanding why vestiges of the magma ocean are so scarce in the Earth.

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.

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Scheijen, Blanca; Boer, Judith M; Marke, René; Tijchon, Esther; van Ingen Schenau, Dorette; Waanders, Esmé; van Emst, Liesbeth; van der Meer, Laurens T; Pieters, Rob; Escherich, Gabriele; Horstmann, Martin A; Sonneveld, Edwin; Venn, Nicola; Sutton, Rosemary; Dalla-Pozza, Luciano; Kuiper, Roland P; Hoogerbrugge, Peter M; den Boer, Monique L; van Leeuwen, Frank N

2017-03-01

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia ( P =0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival ( P =0.0003) and a higher 5-year cumulative incidence of relapse ( P =0.005), when compared with IKZF1 -deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1 , did not affect the outcome of IKZF1 -deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1 -deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1 +/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1 +/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function. Copyright© Ferrata Storti Foundation.

Spin Transition in the Lower Mantle: Deep Learning and Pattern Recognition of Superplumes from the Mid-mantle and Mid-mantle Slab Stagnation

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Yuen, D. A.; Shahnas, M. H.; De Hoop, M. V.; Pysklywec, R.

2016-12-01

The broad, slow seismic anomalies under Africa and Pacific cannot be explained without ambiguity. There is no well-established theory to explain the fast structures prevalent globally in seismic tomographic images that are commonly accepted to be the remnants of fossil slabs at different depths in the mantle. The spin transition from high spin to low spin in iron in ferropericlase and perovskite, two major constituents of the lower mantle can significantly impact their physical properties. We employ high resolution 2D-axisymmetric and 3D-spherical control volume models to reconcile the influence of the spin transition-induced anomalies in density, thermal expansivity, and bulk modulus in ferropericlase and perovskite on mantle dynamics. The model results reveal that the spin transition effects increase the mixing in the lower regions of mantle. Depending on the changes of bulk modulus associated with the spin transition, these effects may also cause both stagnation of slabs and rising plumes at mid-mantle depths ( 1600 km). The stagnation may be followed by downward or upward penetration of cold or hot mantle material, respectively, through an avalanche process. The size of these mid-mantle plumes reaches 1500 km across with a radial velocity reaching 20 cm/yr near the seismic transition zone and plume heads exceeding 2500 km across. We will employ a deep-learning algorithm to formulate this challenge as a classification problem where modelling/computation aids in the learning stage for detecting the particular patterns.The parameters based on which the convection models are developed are poorly constrained. There are uncertainties in initial conditions, heterogeneities and boundary conditions in the simulations, which are nonlinear. Thus it is difficult to reconstruct the past configuration over long time scales. In order to extract information and better understand the parameters in mantle convection, we employ deep learning algorithm to search for different

The Earth's mantle and geoneutrinos

International Nuclear Information System (INIS)

Fiorentini, Giovanni; Fogli, Gian Luigi; Lisi, Eligio; Mantovani, Fabio; Rotunno, Anna Maria; Xhixha, Gerti

2013-01-01

The KamLAND and Borexino experiments have observed, each at ∼4σ level, signals of electron antineutrinos produced in the decay chains of thorium and uranium in the Earth's crust and mantle (Th and U geoneutrinos). Various pieces of geochemical and geophysical information allow an estimation of the crustal geoneutrino flux components with relatively small uncertainties. The mantle component may then be inferred by subtracting the estimated crustal flux from the measured total flux. We find that crust-subtracted signals show hints of a residual mantle component, emerging at ∼2.4σ level by combining the KamLAND and Borexino data. The inferred mantle flux, slightly favoring scenarios with relatively high Th and U abundances, within ∼1σ uncertainties is comparable to the predictions from recent mantle models

Mantle wedge serpentinization effects on slab dips

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Eh Tan

2017-01-01

Full Text Available The mechanical coupling between a subducting slab and the overlying mantle wedge is an important factor in controlling the subduction dip angle and the flow in mantel wedge. This paper investigates the role of the amount of mantle serpentinization on the subduction zone evolution. With numerical thermos-mechanical models with elasto-visco-plastic rheology, we vary the thickness and depth extent of mantle serpentinization in the mantle wedge to control the degree of coupling between the slab and mantle wedge. A thin serpentinized mantle layer is required for stable subduction. For models with stable subduction, we find that the slab dip is affected by the down-dip extent and the mantle serpentinization thickness. A critical down-dip extent exists in mantle serpentinization, determined by the thickness of the overriding lithosphere. If the down-dip extent does not exceed the critical depth, the slab is partially coupled to the overriding lithosphere and has a constant dip angle regardless of the mantle serpentinization thickness. However, if the down-dip extent exceeds the critical depth, the slab and the base of the overriding lithosphere would be separated and decoupled by a thick layer of serpentinized peridotite. This allows further slab bending and results in steeper slab dip. Increasing mantle serpentinization thickness will also result in larger slab dip. We also find that with weak mantle wedge, there is no material flowing from the asthenosphere into the serpentinized mantle wedge. All of these results indicate that serpentinization is an important ingredient when studying the subduction dynamics in the mantle wedge.

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

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Rehan Mujeeb Faridi

Full Text Available Allogeneic hematopoietic cell transplantation (HCT can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs and 'validation' (146 pairs cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD, chronic GVHD needing systemic therapy (cGVHD and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS, cGVHD & relapse free survival (cGRFS and overall survival (OS] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17 and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11. High incidence of cGVHD associated with KIR genotype mismatching was

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

Science.gov (United States)

Faridi, Rehan Mujeeb; Kemp, Taylor J; Dharmani-Khan, Poonam; Lewis, Victor; Tripathi, Gaurav; Rajalingam, Raja; Daly, Andrew; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

2016-01-01

Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT. The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable

Eutectic melting temperature of the lowermost Earth's mantle

Science.gov (United States)

Andrault, D.; Lo Nigro, G.; Bolfan-Casanova, N.; Bouhifd, M.; Garbarino, G.; Mezouar, M.

2009-12-01

Partial melting of the Earth's deep mantle probably occurred at different stages of its formation as a consequence of meteoritic impacts and seismology suggests that it even continues today at the core-mantle boundary. Melts are important because they dominate the chemical evolution of the different Earth's reservoirs and more generally the dynamics of the whole planet. Unfortunately, the most critical parameter, that is the temperature profile inside the deep Earth, remains poorly constrained accross the planet history. Experimental investigations of the melting properties of materials representative of the deep Earth at relevant P-T conditions can provide anchor points to refine past and present temperature profiles and consequently determine the degree of melting at the different geological periods. Previous works report melting relations in the uppermost lower mantle region, using the multi-anvil press [1,2]. On the other hand, the pyrolite solidus was determined up to 65 GPa using optical observations in the laser-heated diamond anvil cell (LH-DAC) [3]. Finally, the melting temperature of (Mg,Fe)2SiO4 olivine is documented at core-mantle boundary (CMB) conditions by shock wave experiments [4]. Solely based on these reports, experimental data remain too sparse to draw a definite melting curve for the lower mantle in the relevant 25-135 GPa pressure range. We reinvestigated melting properties of lower mantle materials by means of in-situ angle dispersive X-ray diffraction measurements in the LH-DAC at the ESRF [5]. Experiments were performed in an extended P-T range for two starting materials: forsterite and a glass with chondrite composition. In both cases, the aim was to determine the onset of melting, and thus the eutectic melting temperatures as a function of pressure. Melting was evidenced from drastic changes of diffraction peak shape on the image plate, major changes in diffraction intensities in the integrated pattern, disappearance of diffraction rings

Mantle Convection on Modern Supercomputers

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Weismüller, J.; Gmeiner, B.; Huber, M.; John, L.; Mohr, M.; Rüde, U.; Wohlmuth, B.; Bunge, H. P.

2015-12-01

Mantle convection is the cause for plate tectonics, the formation of mountains and oceans, and the main driving mechanism behind earthquakes. The convection process is modeled by a system of partial differential equations describing the conservation of mass, momentum and energy. Characteristic to mantle flow is the vast disparity of length scales from global to microscopic, turning mantle convection simulations into a challenging application for high-performance computing. As system size and technical complexity of the simulations continue to increase, design and implementation of simulation models for next generation large-scale architectures is handled successfully only in an interdisciplinary context. A new priority program - named SPPEXA - by the German Research Foundation (DFG) addresses this issue, and brings together computer scientists, mathematicians and application scientists around grand challenges in HPC. Here we report from the TERRA-NEO project, which is part of the high visibility SPPEXA program, and a joint effort of four research groups. TERRA-NEO develops algorithms for future HPC infrastructures, focusing on high computational efficiency and resilience in next generation mantle convection models. We present software that can resolve the Earth's mantle with up to 1012 grid points and scales efficiently to massively parallel hardware with more than 50,000 processors. We use our simulations to explore the dynamic regime of mantle convection and assess the impact of small scale processes on global mantle flow.

Discovery and characterization of a novel CCND1/MRCK gene fusion in mantle cell lymphoma

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Chioniso Patience Masamha

2016-03-01

Full Text Available Abstract The t(11;14 translocation resulting in constitutive cyclin D1 expression is an early event in mantle cell lymphoma (MCL transformation. Patients with a highly proliferative phenotype produce cyclin D1 transcripts with truncated 3′UTRs that evade miRNA regulation. Here, we report the recurrence of a novel gene fusion in MCL cell lines and MCL patient isolates that consists of the full protein coding region of cyclin D1 (CCND1 and a 3′UTR consisting of sequences from both the CCND1 3′UTR and myotonic dystrophy kinase-related Cdc42-binding kinase's (MRCK intron one. The resulting CCND1/MRCK mRNA is resistant to CCND1-targeted miRNA regulation, and targeting the MRCK region of the chimeric 3′UTR with siRNA results in decreased CCND1 levels.

Gender differences in alcohol and substance use relapse.

Science.gov (United States)

Walitzer, Kimberly S; Dearing, Ronda L

2006-03-01

This review explores gender differences in relapse and characteristics of relapse events in alcohol and substance use. For alcohol, relapse rates were similar across gender. Although negative mood, childhood sexual abuse, alcohol-related self-efficacy, and poorer coping strategies predicted alcohol relapse, gender did not moderate these effects. Gender did moderate the association between marriage and alcohol relapse. For women, marriage and marital stress were risk factors for alcohol relapse; among men, marriage lowered relapse risk. This gender difference in the role of marriage in relapse may be a result of partner differences in problem drinking. Alcoholic women are more likely to be married to heavy drinking partners than are alcoholic men; thus, alcoholic women may be put at risk of relapse by marriage and alcoholic men may be protected by marriage. There are fewer studies documenting gender differences in substance abuse relapse so conclusions are limited and tentative. In contrast to the lack of gender differences in alcohol relapse rates, women appear less likely to experience relapse to substance use, relative to men. Women relapsing to substance use appear to be more sensitive to negative affect and interpersonal problems. Men, in contrast, may be more likely to have positive experiences prior to relapse.

Conditional Risk of Relapse in Surveillance for Clinical Stage I Testicular Cancer.

Science.gov (United States)

Nayan, Madhur; Jewett, Michael A S; Hosni, Ali; Anson-Cartwright, Lynn; Bedard, Philippe L; Moore, Malcolm; Hansen, Aaron R; Chung, Peter; Warde, Padraig; Sweet, Joan; O'Malley, Martin; Atenafu, Eshetu G; Hamilton, Robert J

2017-01-01

Patients on surveillance for clinical stage I (CSI) testicular cancer are counseled regarding their baseline risk of relapse. The conditional risk of relapse (cRR), which provides prognostic information on patients who have survived for a period of time without relapse, have not been determined for CSI testicular cancer. To determine cRR in CSI testicular cancer. We reviewed 1239 patients with CSI testicular cancer managed with surveillance at a tertiary academic centre between 1980 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: cRR estimates were calculated using the Kaplan-Meier method. We stratified patients according to validated risk factors for relapse. We used linear regression to determine cRR trends over time. At orchiectomy, the risk of relapse within 5 yr was 42.4%, 17.3%, 20.3%, and 12.2% among patients with high-risk nonseminomatous germ cell tumor (NSGCT), low-risk NSGCT, seminoma with tumor size ≥3cm, and seminoma with tumor size testicular cancer is very low. Consideration should be given to adapting surveillance protocols to individualized risk of relapse based on cRR as opposed to static protocols based on baseline factors. This strategy could reduce the intensity of follow-up for the majority of patients. Our study is the first to provide data on the future risk of relapse during surveillance for clinical stage I testicular cancer, given a patient has been without relapse for a specified period of time. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Bendamustine/Mitoxantrone/Rituximab (BMR): a very effective, well tolerated outpatient chemoimmunotherapy for relapsed and refractory CD20-positive indolent malignancies. Final results of a pilot study.

Science.gov (United States)

Weide, Rudolf; Pandorf, Annette; Heymanns, Jochen; Köppler, Hubert

2004-12-01

We have developed a new chemoimmunotherapy for patients with relapsed or refractory CD20-positive indolent lymphomas and CLL by combining the chemotherapeutic agents Bendamustine (B) and Mitoxantrone (M) with the monoclonal antibody Rituximab. Treatment consisted of (B): 90 mg/m2 (80 mg/m2 in CLL) day 1 + 2, (M): 10 mg/m2 day 1 and (R): 375 mg/m2 day 8,15,22 and 29. BM was repeated 3 times starting on day 36, thereafter every 4 weeks. The maximal therapy consisted of 1 x BMR followed by 5 x BM. We have treated 54 patients with BMR. Median age was 68 years (36-82). Disease distribution was as follows: 21 B-CLL, 1 B-PLL, 8 lymphoplasmacytic, 14 follicular, 2 mantle cell, 2 marginal zone, 6 secondary high grade. Median number of previous treatments was 2 (1-7). ORR was 96% with 41% CR and 55% PR. Median time to progression is 17 months in CLL and has not been reached in indolent lymphomas with a median observation time of 27 months (3-60+). The time to next antilymphoma treatment is prolonged significantly by BMR. No therapy associated death or hospitalization occurred within the study period. BMR is a well tolerated very effective outpatient treatment for relapsed and refractory CD20-positive indolent lymphomas and CLL.

Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

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Ogura, Michinori; Tobinai, Kensei; Hatake, Kiyohiko; Uchida, Toshiki; Suzuki, Tatsuya; Kobayashi, Yukio; Mori, Masakazu; Terui, Yasuhito; Yokoyama, Masahiro; Hotta, Tomomitsu

2013-01-01

As CD20 has become an established target for treating B-cell malignancies, there is interest in developing anti-CD20 antibodies with different functional activity from rituximab that might translate into improved efficacy. Obinutuzumab (GA101) is a glycoengineered, humanized type II anti-CD20 monoclonal antibody that has demonstrated superior activity to type I antibodies in preclinical studies and is currently being investigated in phase III trials. In this phase I dose-escalating study in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the primary endpoint was to characterize the safety of GA101; secondary endpoints were efficacy, pharmacokinetics and pharmacodynamics. Patients received up to nine doses of GA101 with up to 52 weeks' follow up. Most adverse events were grade 1 or 2 infusion-related reactions, and 10 grade 3/4 adverse events occurred. No dose-limiting toxicities were observed and the maximum tolerated dose was not identified. Out of 12 patients, 7 responded (end-of-treatment response rate 58%), with 2 complete responses and 5 partial responses. Responses were observed from low to high doses, and no dose-efficacy relationship was observed. B-cell depletion occurred in all patients after the first infusion and was maintained for the duration of treatment. Serum levels of GA101 increased in a dose-dependent fashion, although there was inter-patient variability. This phase I study demonstrated that GA101 has an acceptable safety profile and offers encouraging activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. © 2012 Japanese Cancer Association.

Discordant lymphoma consisting of splenic mantle cell lymphoma and marginal zone lymphoma involving the bone marrow and peripheral blood: a case report

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Caracciolo Francesco

2011-09-01

Full Text Available Abstract Introduction Discordant lymphomas are rare entities characterized by the simultaneous presence of two distinct types of lymphomas in different anatomic sites. We describe a very rare case of simultaneous occurrence of splenic mantle cell lymphoma and marginal zone lymphoma involving the bone marrow and peripheral blood. Case presentation We report the case of a 60-year-old asymptomatic Caucasian woman in whom discordant lymphomas were discovered when a slight lymphocytosis and a conspicuous splenomegaly were observed. The different morphological, immunophenotypical and immunohistochemical features found in the different pathologic samples obtained from peripheral blood, bone marrow and spleen sections made it possible to differentiate two types of non-Hodgkin B-cell lymphomas: a mantle cell lymphoma infiltrating the spleen and a marginal zone lymphoma involving both the bone marrow and peripheral blood. Since a similar IgH gene rearrangement was found both in the bone marrow and in the spleen, the hypothesis of a common origin, followed by a different clonal selection of the neoplastic lymphocytes may be taken into consideration. Conclusion Our case emphasizes the usefulness of investigating simultaneous specimens from different anatomic sites from the same patient and the relevant diagnostic role of splenectomy.

Cytogenetic Evolution in Myeloid Neoplasms at Relapse after Allogeneic Hematopoietic Cell Transplantation: Association with Previous Chemotherapy and Effect on Survival.

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Ertz-Archambault, Natalie; Kosiorek, Heidi; Slack, James L; Lonzo, Melissa L; Greipp, Patricia T; Khera, Nandita; Kelemen, Katalin

2017-05-01

Cytogenetic evolution (CGE) in patients with myeloid neoplasms who relapsed after an allogeneic (allo) hematopoietic cell transplantation (HCT) has been evaluated by only few studies. The effect of the CGE on survival of relapsed allo-HCT recipients is not clear. The effect of previously received chemotherapy to induce CGE in this patient population has not been studied. The aims of our study are to (1) characterize the patterns of cytogenetic change in patients with myeloid neoplasms who relapsed after an allo-HCT, (2) evaluate the effect of CGE on survival, and (3) explore the association of CGE with previous chemotherapy (including the lines of salvage therapy, type of induction, and conditioning therapy). Of 49 patients with a myeloid malignancy (27 acute myeloid leukemia [AML], 19 myelodysplastic syndrome [MDS]/myeloproliferative neoplasm [MPN], and 3 chronic myelogenous leukemia) who relapsed after an allo-HCT, CGE was observed in 25 (51%), whereas 24 patients had unchanged cytogenetic findings at relapse. The CGE group carried more cytogenetic abnormalities at original diagnosis. The most frequent cytogenetic change was the acquisition of 3 or more new chromosomal abnormalities followed by acquisition of unbalanced abnormalities, aneuploidy, and emergence of apparently new clones unrelated to the original clone. The CGE cohort had higher proportion of MDS and MPN and fewer patients with de novo AML. Disease risk assessment category showed a trend to higher frequency of high-risk patients in the CGE group, though the difference was not statistically significant. Time from diagnosis to transplantation and time from transplantation to relapse were not different between the CGE and non-CGE groups. CGE and non-CGE cohorts had similar exposures to salvage therapy and to induction chemotherapy, as well as similar conditioning regimens; thus, no particular type of chemotherapy emerged as a predisposing factor to CGE. CGE was associated with significantly shortened

Metastatic Mantle Cell Lymphoma to the Pituitary Gland: Case Report and Literature Review

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Arthur Wang

2016-01-01

Full Text Available We present an unusual case of a metastatic mantle cell lymphoma (MCL to the pituitary gland. The patient had a known history of MCL for which she previously received chemotherapy. She presented with new-onset diplopia and confusion, and reported a history of progressive vision blurriness associated with headache, nausea, and vomiting. MRI of the brain showed an enhancing lesion within the sella turcica involving the cavernous sinuses bilaterally, extending into Meckel's cave on the left, and abutting the optic nerves bilaterally. Following surgical excision, histopathology revealed the tumor to be a MCL. Metastatic pituitary tumors are rare and have been estimated to make up 1% of tumors discovered in the sellar region. The two most common secondary metastatic lesions to the sella are breast and lung carcinoma followed by prostate, renal cell, and gastrointestinal carcinoma. Metastatic lymphoma to the pituitary gland is especially rare and is estimated to constitute 0.5% of all metastatic tumors to the sella turcica. To our knowledge, this is the first reported case of MCL metastasizing to the pituitary gland.

Large-scale global convection in the mantle beneath Australia from 55 Ma to now

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Zhang, M.

1999-01-01

Full text: The global-scale mantle convection cells in the asthenosphere are not geochemically homogeneous. The heterogeneity is most prominently reflected in the isotopic compositions (Pb-Sr-Nd) of the mid-ocean ridge basalts (MORB) that are direct partial melts from the underlying asthenosphere. Of particular relevance to Australia's geodynamic evolution from about 100 million years, are the distinctive geochemical signatures of the asthenosphere beneath the Pacific Ocean (Pacific MORB) and Indian Ocean (Indian MORB). Therefore, delineation of the boundary between the two distinct mantle reservoirs and any change in that boundary with time provide information about the patterns of global-scale asthenospheric mantle convection. This information has also allowed us to track large-scale mantle chemical reservoirs such as the distinctive Gondwana lithospheric mantle, and hence better understand the geodynamic evolution of the Australian continent from the time of Gondwana dispersal. Pb-Sr-Nd isotope data for Cenozoic basalts in eastern Australia (Zhang et al, 1999) indicate that Pacific-MORB type isotopic signatures characterise the lava-field basalts (55-14 Ma) in southeastern Australia, whereas Indian-MORB type isotopic signatures characterise younger basalts (6-0 Ma) from northeastern Australia. This discovery helps to constrain the changing locus of the major asthenospheric mantle convection cells represented by the Pacific and Indian MORB sources during and following the breakup of the eastern part of Gondwana, and locates, for the first time, the boundary of these convection cells beneath the Australian continent. This extends previous work in the SW Pacific back-arc basins (eg Hickey-Vargas et al., 1995) and the Southern Ocean (Lanyon et al., 1995) that indicates that the 1- and P-MORB mantle convection cells have been moving in opposite directions since the early Tertiary. These new data also indicate that the Indian-MORB source is a long-term asthenospheric

Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma

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Kahl Brad S

2008-05-01

Full Text Available Abstract Background The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL. However, NF-κB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-κB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear. Results Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-κB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA. Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231 and a breast carcinoma cell line (MDA-MB-468, the bortezomib-resistant NF-κB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10 displayed bortezomib-resistant constitutive NF-κB activity. Conclusion Our findings show that bortezomib-resistant NF-κB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.

Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma.

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Peponi, Evangelia; Drakos, Elias; Reyes, Guadalupe; Leventaki, Vasiliki; Rassidakis, George Z; Medeiros, L Jeffrey

2006-12-01

Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.

Regional nodal relapse in surgically staged Merkel cell carcinoma

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Hoeller, Ulrike; Mueller, Thomas; Schubert, Tina; Budach, Volker; Ghadjar, Pirus [Charite Universitaetsmedizin Berlin, Department of Radiation Oncology, Berlin (Germany); Brenner, Winfried [Charite Universitaetsmedizin Berlin, Department of Nuclear Medicine, Berlin (Germany); Kiecker, Felix [Charite Universitaetsmedizin Berlin, Department of Dermatology, Berlin (Germany); Schicke, Bernd [Tumor Center Berlin, Berlin (Germany); Haase, Oliver [Charite Universitaetsmedizin Berlin, Department of Surgery, Berlin (Germany)

2014-10-08

The nodal relapse pattern of surgically staged Merkel cell carcinoma (MCC) with/without elective nodal radiotherapy (RT) was studied in a single institution. A total of 51 patients with MCC, 33 % UICC stage I, 14 % II, 53 % III (4 lymph node metastases of unknown primary) were eligible. All patients had surgical staging: 23 patients sentinel node biopsy (SNB), 22 patients SNB followed by lymphadenectomy (LAD) and 6 patients LAD. In all, 94 % of the primary tumors (PT) were completely resected; 57 % of patients received RT, 51 % of known PT sites, 33 % (8/24 patients) regional RT to snN0 nodes and 68 % (17/27 patients) to pN+ nodes, mean reference dose 51.5 and 50 Gy, respectively. Mean follow-up was 6 years (range 2-14 years). A total of 22 % (11/51) patients developed regional relapses (RR); the 5-year RR rate was 27 %. In snN0 sites (stage I/II), relapse occurred in 5 of 14 nonirradiated vs. none of 8 irradiated sites (p = 0.054), resulting in a 5-year RR rate of 33 % versus 0 % (p = 0.16). The crude RR rate was lower in stage I (12 %, 2/17 patients) than for stage II (43 %, 3/7 patients). In stage III (pN+), RR appeared to be less frequent in irradiated sites (18 %, 3/14 patients) compared with nonirradiated sites (33 %, 3/10 patients, p = 0.45) with 5-year RR rates of 23 % vs. 34 %, respectively. Our data suggest that adjuvant nodal RT plays a major role even if the sentinel nodes were negative. Adjuvant RT of the lymph nodes in patients with stage IIa tumors and RT after LAD in stage III tumors is proposed and should be evaluated prospectively. (orig.) [German] Untersucht wurde das regionaere Rezidivmuster des Merkelzell-Karzinoms (MCC) nach chirurgischem Staging und stadienadaptierter Therapie. Eingeschlossen wurden 51 Patienten mit lokalisiertem MCC: 33 % hatten UICC-Stadium-I-, 14 % -II-, 53 % -III-Tumoren (davon 4 Lymphknotenmetastasen eines unbekannten Primaertumors). Alle Patienten erhielten ein chirurgisches Staging: 23 Waechterlymphknotenbiopsien (SNB

Seismic Imaging of Mantle Plumes

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Nataf, Henri-Claude

The mantle plume hypothesis was proposed thirty years ago by Jason Morgan to explain hotspot volcanoes such as Hawaii. A thermal diapir (or plume) rises from the thermal boundary layer at the base of the mantle and produces a chain of volcanoes as a plate moves on top of it. The idea is very attractive, but direct evidence for actual plumes is weak, and many questions remain unanswered. With the great improvement of seismic imagery in the past ten years, new prospects have arisen. Mantle plumes are expected to be rather narrow, and their detection by seismic techniques requires specific developments as well as dedicated field experiments. Regional travel-time tomography has provided good evidence for plumes in the upper mantle beneath a few hotspots (Yellowstone, Massif Central, Iceland). Beneath Hawaii and Iceland, the plume can be detected in the transition zone because it deflects the seismic discontinuities at 410 and 660 km depths. In the lower mantle, plumes are very difficult to detect, so specific methods have been worked out for this purpose. There are hints of a plume beneath the weak Bowie hotspot, as well as intriguing observations for Hawaii. Beneath Iceland, high-resolution tomography has just revealed a wide and meandering plume-like structure extending from the core-mantle boundary up to the surface. Among the many phenomena that seem to take place in the lowermost mantle (or D''), there are also signs there of the presence of plumes. In this article I review the main results obtained so far from these studies and discuss their implications for plume dynamics. Seismic imaging of mantle plumes is still in its infancy but should soon become a turbulent teenager.

Phase 1 study of inotuzumab ozogamicin combined with R-GDP for the treatment of patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma.

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Sangha, Randeep; Davies, Andrew; Dang, Nam H; Ogura, Michinori; MacDonald, David A; Ananthakrishnan, Revathi; Paccagnella, M Luisa; Vandendries, Erik; Boni, Joseph; Goh, Yeow Tee

2017-01-01

Objective : To evaluate safety, tolerability, and preliminary activity of inotuzumab ozogamicin (InO) plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL). Methods : Patients received InO plus R-GDP (21-day cycle; six-cycle maximum) using up-and-down dose-escalation schema for gemcitabine and cisplatin to define the highest dosage regimen(s) with acceptable toxicity (Part 1; n  = 27). Part 2 ( n  = 10) confirmed safety and tolerability; Part 3 ( n  = 18) evaluated preliminary efficacy. Results: Among 55 patients enrolled, 42% were refractory at baseline (median 2 [range, 1-6] prior therapies); 38% had diffuse large B-cell lymphoma (DLBCL). The highest dosage regimen with acceptable toxicity was InO 0.8 mg/m 2 , rituximab 375 mg/m 2 , cisplatin 50 mg/m 2 , gemcitabine 500 mg/m 2 (day 1 only) and dexamethasone 40 mg (days 1-4); this was confirmed in Part 2, in which three patients had dose-limiting toxicities (grade 4 thrombocytopenia [ n  = 2], febrile neutropenia [ n  = 2]). Most frequent treatment-related adverse events were thrombocytopenia (any grade, 85%; grade ≥3, 75%) and neutropenia (69%; 62%). Overall (objective) response rate (ORR) was 53% (11 complete, 18 partial responses); ORR was 71%, 33%, and 62% in patients with follicular lymphoma ( n  = 14), DLBCL ( n  = 21), and mantle cell lymphoma ( n  = 13), respectively. Conclusions: InO 0.8 mg/m 2 plus R-GDP was associated with manageable toxicity, although gemcitabine and cisplatin doses were lower than in the standard R-GDP regimen due to hematologic toxicity. Evidence of antitumor activity was observed; however, these exploratory data should be interpreted with caution due to the small sample size and short follow-up duration (Clinicaltrials.gov number: NCT01055496).

Elevation of CD16+CD56+ NK-cells and down-regulation of serum interleukin-21 (IL-21) and IL-1α after splenectomy in relapsed hemophagocytic lymphohistiocytosis of unknown cause.

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Wang, Jingshi; Han, Wei; Gao, Zhuo; Wang, Yini; Wu, Lin; Zhang, Jia; Lai, Wenyuan; Wang, Zhao

2017-09-01

Encouraging progress has been made in application of splenectomy in the treatment of relapsed hemophagocytic lymphohistiocytosis (HLH) of unknown cause. The aim was to determine the roles of lymphocyte subpopulations and inflammatory cytokines in splenectomy. We retrospectively analyzed changes in lymphocyte subpopulations and levels of inflammatory cytokines at different time-points before and after splenectomy in the patients with relapsed HLH of unknown cause, as well as the correlations between these changes and the disease prognosis. During the period from June 2006 to June 2016, we enrolled 107 patients with relapsed HLH of unknown cause, of whom 29 were treated with splenectomy. Among the 29 patients, 7 cases were non-Hodgkin lymphomas based on spleen pathology, 1 case withdrew and the remaining 21 non-lymphoma cases were available for analysis. Results showed a significant increase in both percentage of CD16 + CD56 + NK cells (P = 0.003) and NK cell activity (P = 0.028) at 24 wk after splenectomy compared to their baseline pre-surgery levels. We also examined seven patients for the changes in cytokine levels before and after splenectomy and found that IL-21 and IL-1α decreased at 4 wk after splenectomy (P splenectomy had significantly longer survival (P = 0.001) compared to the 24 patients with relapsed HLH of unknown cause who were also determined as NR but not treated by splenectomy. Splenectomy can improve clinical symptoms and survival of patients with relapsed HLH of unknown cause. The mechanism is likely related to the changes in percent NK cells and cytokines (IL-21 and IL-1α) after surgery.

Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse.

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Hahn, M; Böttcher, S; Dietrich, S; Hegenbart, U; Rieger, M; Stadtherr, P; Bondong, A; Schulz, R; Ritgen, M; Schmitt, T; Tran, T H; Görner, M; Herth, I; Luft, T; Schönland, S; Witzens-Harig, M; Zenz, T; Kneba, M; Ho, A D; Dreger, P

2015-10-01

To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.

Clinical factors related to schizophrenia relapse.

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Porcelli, Stefano; Bianchini, Oriana; De Girolamo, Giovanni; Aguglia, Eugenio; Crea, Luciana; Serretti, Alessandro

2016-01-01

Relapses represent one of the main problems of schizophrenia management. This article reviews the clinical factors associated with schizophrenia relapse. A research of the last 22 years of literature data was performed. Two-hundred nineteen studies have been included. Three main groups of factors are related to relapse: factors associated with pharmacological treatment, add-on psychotherapeutic treatments and general risk factors. Overall, the absence of a maintenance therapy and treatment with first generation antipsychotics has been associated with higher risk of relapse. Further, psychotherapy add-on, particularly with cognitive behaviour therapy and psycho-education for both patients and relatives, has shown a good efficacy for reducing the relapse rate. Among general risk factors, some could be modified, such as the duration of untreated psychosis or the substance misuse, while others could not be modified as male gender or low pre-morbid level of functioning. Several classes of risk factors have been proved to be relevant in the risk of relapse. Thus, a careful assessment of the risk factors here identified should be performed in daily clinical practice in order to individualise the relapse risk for each patient and to provide a targeted treatment in high-risk subjects.

Residual tumor cells that drive disease relapse after chemotherapy do not have enhanced tumor initiating capacity.

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Ganapati V Hegde

Full Text Available Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs. We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell's ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell's ability to drive disease recurrence.

Immunotoxin – a new treatment option in patients with relapsed and refractory Hodgkin lymphoma

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Novakovic Barbara Jezersek

2015-12-01

Full Text Available Background. Even though Hodgkin lymphoma is a highly curable disease, some of the patients have either a refractory disease or experience a relapse following a successful primary therapy. Durable responses and remissions in patients with relapsed or refractory disease may be achieved in approximately one-half with salvage chemotherapy followed by high dose chemotherapy (HDT and autologous hematopoietic cell rescue (SCT. On the other hand, patients who relapse after HDT and autologous SCT or those who have failed at least two prior multi-agent chemotherapy regimens and are not candidates for HDT have limited treatment options.

Jab1/Csn5-Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress.

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Zhou, Fuling; Pan, Yunbao; Wei, Yongchang; Zhang, Ronghua; Bai, Gaigai; Shen, Qiuju; Meng, Shan; Le, Xiao-Feng; Andreeff, Michael; Claret, Francois X

2017-08-01

Purpose: High levels of ROS and ineffective antioxidant systems contribute to oxidative stress, which affects the function of hematopoietic cells in acute myeloid leukemia (AML); however, the mechanisms by which ROS lead to malignant transformation in relapsed AML-M5 are not completely understood. We hypothesized that alterations in intracellular ROS would trigger AML-M5 relapse by activating the intrinsic pathway. Experimental Design: We studied ROS levels and conducted c-Jun activation domain-binding protein-1 ( JAB1/COPS5 ) and thioredoxin ( TRX ) gene expression analyses with blood samples obtained from 60 matched AML-M5 patients at diagnosis and relapse and conducted mechanism studies of Jab1's regulation of Trx in leukemia cell lines. Results: Our data showed that increased production of ROS and a low capacity of antioxidant enzymes were characteristics of AML-M5, both at diagnosis and at relapse. Consistently, increased gene expression levels of TRX and JAB1/COPS5 were associated with low overall survival rates in patients with AML-M5. In addition, stimulating AML-M5 cells with low concentrations of hydrogen peroxide led to increased Jab1 and Trx expression. Consistently, transfection of ectopic Jab1 into leukemia cells increased Trx expression, whereas silencing of Jab1 in leukemia cells reduced Trx expression. Mechanistically, Jab1 interacted with Trx and stabilized Trx protein. Moreover, Jab1 transcriptionally regulated Trx. Furthermore, depletion of Jab1 inhibited leukemia cell growth both in vitro and in vivo Conclusions: We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of AML-M5. Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5. Clin Cancer Res; 23(15); 4450-61. ©2017 AACR . ©2017 American Association for Cancer Research.

Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission

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Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Lee, Dong-Gun; Eom, Ki-Seong; Kim, Yoo-Jin; Min, Chang-Ki; Cho, Seok-Goo; Min, Woo-Sung; Lee, Jong Wook

2016-01-01

Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice cons...

Regional homogeneity changes between heroin relapse and non-relapse patients under methadone maintenance treatment: a resting-state fMRI study.

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Chang, Haifeng; Li, Wei; Li, Qiang; Chen, Jiajie; Zhu, Jia; Ye, Jianjun; Liu, Jierong; Li, Zhe; Li, Yongbin; Shi, Ming; Wang, Yarong; Wang, Wei

2016-08-18

Methadone maintenance treatment (MMT) is recognized as one of the most effective treatments for heroin addiction but its effect is dimmed by the high incidence of heroin relapse. However, underlying neurobiology mechanism of heroin relapse under MMT is still largely unknown. Here, we took advantage of a resting-state fMRI technique by analysis of regional homogeneity (ReHo), and tried to explore the difference of brain function between heroin relapsers and non-relapsers in MMT. Forty MMT patients were included and received a 12-month follow-up. All patients were given baseline resting-state fMRI scans by using a 3.0 T GE Signa Excite HD whole-body MRI system. Monthly self-report and urine test were used to assess heroin relapse or non-relapse. Subjective craving was measured with visual analog scale. The correlation between ReHo and the degree of heroin relapse was analyzed. Compared with the non-relapsers, ReHo values were increased in the bilateral medial orbitofrontal cortex, right caudate, and right cerebellum of the heroin relapsers while those in the left parahippocampal gyrus, left middle temporal gyrus, right lingual gyrus, and precuneus were decreased in heroin relapsers. Importantly, altered ReHo in the right caudate were positively correlated with heroin relapse rates or subjective craving response. Using the resting-state fMRI technique by analysis of ReHo, we provided the first resting-state fMRI evidence that right caudate may serve as a potential biomarker for heroin relapse prediction and also as a promising target for reducing relapse risk.

[Research and control of relapse tuberculosis cases].

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Yamagishi, Fumio; Toyota, Makoto

2009-12-01

With this symposium, we focused on the relapse of tuberculosis in Japan. Out of 19,893 tuberculosis patients registered in 2007 in Japan, 7.48% were classified as relapse cases. Relapse cases have the risk of acquired drug resistance. But we have few analyses of the proportion of relapse tuberculosis cases with standard short course regimens for six months, factors contributing to tuberculosis relapse and the proportion of drug resistance among relapse TB cases in Japan. Therefore we analyzed the relapse tuberculosis cases in two rural areas and three urban areas. We also analyzed the proportion of drug resistance among relapse cases with the data of drug susceptibility survey of Ryoken. 1. Research of relapse tuberculosis cases: Makoto TOYOTA (Kochi City Public Health Center). To clarify the relapse rate and factors contributing to tuberculosis relapse, we investigated the relapse tuberculosis cases in the municipality where the proportion of elderly tuberculosis patients was high. Out of 902 tuberculosis patients registered in Kochi City Public Health Center during 10 years, 20 pulmonary tuberculosis patients were confirmed relapse cases with initial registered records. Pretreatment cavitations, sputum culture positivity at 2 months, medical miss-management (e.g. number of doses, duration of therapy) and poor adherence were considered to be factors contributing to tuberculosis relapse. Out of 20 relapse cases, 12 cases were detected with symptoms, while only 3 cases were detected by examination in law. 2. A clinical study on relapse cases of pulmonary tuberculosis: Shuichi TAKIKAWA (National Hospital Organization Nishibeppu National Hospital). The relapse of pulmonary tuberculosis was investigated. In the cases with a treatment history before short course chemotherapy, drug resistance rate was high, and thus it needs to be cautious of drug resistance at the time of the retreatment. In the cases with a treatment history of short course chemotherapy, relapse cases

Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone.

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Palmerini, E; Jones, R L; Marchesi, E; Paioli, A; Cesari, M; Longhi, A; Meazza, C; Coccoli, L; Fagioli, F; Asaftei, S; Grignani, G; Tamburini, A; Pollack, S M; Picci, P; Ferrari, S

2016-04-20

Few new compounds are available for relapsed osteosarcoma. We retrospectively evaluated the activity of gemcitabine (G) plus docetaxel (D) in patients with relapsed high-grade osteosarcoma and high-grade spindle cell sarcoma of bone (HGS). Patients receiving G 900 mg/m(2) d 1, 8; D 75 mg/m(2) d 8, every 21 days were eligible. Primary end-point: progression-free survival (PFS) at 4 months; secondary end-point: overall survival (OS) and response rate. Fifty-one patients were included, with a median age of 17 years (8-71), 26 (51%) were pediatric patients. GD line of treatment: 2nd in 14 patients, ≥3rd in 37. 25 (49%) patients had metastases limited to lungs, 26 (51%) multiple sites. 40 (78%) osteosarcoma, 11 (22%) HGS. Eight (16%) patients achieved surgical complete response (sCR2) after GD. Four-month PFS rate was 46%, and significantly better for patients with ECOG 0 (ECOG 0: 54% vs ECOG 1: 43% vs ECOG 2: 0%; p = 0.003), for patients undergoing metastasectomy after GD (sCR2 75% vs no-sCR2 40 %, p = 0.02) and for osteosarcoma (osteosarcoma 56% vs HGS 18%; p = 0.05), with no differences according to age, line of treatment, and pattern of metastases. Forty-six cases had RECIST measurable disease: 6 (13%) patients had a partial response (PR), 20 (43%) had stable disease (SD) and 20 (43%) had progressive disease (PD). The 1-year OS was 30%: 67% for PR, 54% for SD and 20% for PD (p = 0.005). GD is an active treatment for relapsed high-grade osteosarcoma, especially for ECOG 0 patients, and should be included in the therapeutic armamentarium of metastatic osteosarcoma.

Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone

International Nuclear Information System (INIS)

Palmerini, E.; Jones, R. L.; Marchesi, E.; Paioli, A.; Cesari, M.; Longhi, A.; Meazza, C.; Coccoli, L.; Fagioli, F.; Asaftei, S.; Grignani, G.; Tamburini, A.; Pollack, S. M.; Picci, P.; Ferrari, S.

2016-01-01

Few new compounds are available for relapsed osteosarcoma. We retrospectively evaluated the activity of gemcitabine (G) plus docetaxel (D) in patients with relapsed high-grade osteosarcoma and high-grade spindle cell sarcoma of bone (HGS). Patients receiving G 900 mg/m 2 d 1, 8; D 75 mg/m 2 d 8, every 21 days were eligible. Primary end-point: progression-free survival (PFS) at 4 months; secondary end-point: overall survival (OS) and response rate. Fifty-one patients were included, with a median age of 17 years (8–71), 26 (51 %) were pediatric patients. GD line of treatment: 2nd in 14 patients, ≥3rd in 37. 25 (49 %) patients had metastases limited to lungs, 26 (51 %) multiple sites. Histology: 40 (78 %) osteosarcoma, 11 (22 %) HGS. Eight (16 %) patients achieved surgical complete response (sCR2) after GD. Four-month PFS rate was 46 %, and significantly better for patients with ECOG 0 (ECOG 0: 54 % vs ECOG 1: 43 % vs ECOG 2: 0 %; p = 0.003), for patients undergoing metastasectomy after GD (sCR2 75 % vs no-sCR2 40 %, p = 0.02) and for osteosarcoma (osteosarcoma 56 % vs HGS 18 %; p = 0.05), with no differences according to age, line of treatment, and pattern of metastases. Forty-six cases had RECIST measurable disease: 6 (13 %) patients had a partial response (PR), 20 (43 %) had stable disease (SD) and 20 (43 %) had progressive disease (PD). The 1-year OS was 30 %: 67 % for PR, 54 % for SD and 20 % for PD (p = 0.005). GD is an active treatment for relapsed high-grade osteosarcoma, especially for ECOG 0 patients, and should be included in the therapeutic armamentarium of metastatic osteosarcoma

Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropic hormone (ACTH

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Amy ePerrin Ross

2013-03-01

Full Text Available Relapses in multiple sclerosis (MS are disruptive and frequently disabling for patients, and their treatment is often a challenge to clinicians. Despite progress in the understanding of the pathophysiology of MS and development of new treatments for long-term management of MS, options for treating relapses have not changed substantially over the past few decades. Corticosteroids, a component of the HPA axis that modulate immune responses and reduce inflammation, are currently the mainstay of relapse treatment. Adrenocorticotropic hormone (ACTH gel is another treatment option. Although it has long been assumed that the efficacy of ACTH in treating relapses depends on the peptide’s ability to increase endogenous corticosteroid production, evidence from research on the melanocortin system suggests that steroidogenesis may only partly account for ACTH influences. Indeed, the melanocortin peptides (ACTH and α-, β-, γ-melanocyte-stimulating hormones [MSH] and their receptors (MCRs exert multiple actions, including modulation of inflammatory and immune mediator production. Melanocortin receptors are widely distributed within the central nervous system and in peripheral tissues including immune cells (eg, macrophages. This suggests that the mechanism of action of ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system. An increased understanding of the role of the melanocortin system, particularly ACTH, in the immune and inflammatory processes underlying relapses may help to improve relapse management.

Large-scale compositional heterogeneity in the Earth's mantle

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Ballmer, M.

2017-12-01

Seismic imaging of subducted Farallon and Tethys lithosphere in the lower mantle has been taken as evidence for whole-mantle convection, and efficient mantle mixing. However, cosmochemical constraints point to a lower-mantle composition that has a lower Mg/Si compared to upper-mantle pyrolite. Moreover, geochemical signatures of magmatic rocks indicate the long-term persistence of primordial reservoirs somewhere in the mantle. In this presentation, I establish geodynamic mechanisms for sustaining large-scale (primordial) heterogeneity in the Earth's mantle using numerical models. Mantle flow is controlled by rock density and viscosity. Variations in intrinsic rock density, such as due to heterogeneity in basalt or iron content, can induce layering or partial layering in the mantle. Layering can be sustained in the presence of persistent whole mantle convection due to active "unmixing" of heterogeneity in low-viscosity domains, e.g. in the transition zone or near the core-mantle boundary [1]. On the other hand, lateral variations in intrinsic rock viscosity, such as due to heterogeneity in Mg/Si, can strongly affect the mixing timescales of the mantle. In the extreme case, intrinsically strong rocks may remain unmixed through the age of the Earth, and persist as large-scale domains in the mid-mantle due to focusing of deformation along weak conveyor belts [2]. That large-scale lateral heterogeneity and/or layering can persist in the presence of whole-mantle convection can explain the stagnation of some slabs, as well as the deflection of some plumes, in the mid-mantle. These findings indeed motivate new seismic studies for rigorous testing of model predictions. [1] Ballmer, M. D., N. C. Schmerr, T. Nakagawa, and J. Ritsema (2015), Science Advances, doi:10.1126/sciadv.1500815. [2] Ballmer, M. D., C. Houser, J. W. Hernlund, R. Wentzcovitch, and K. Hirose (2017), Nature Geoscience, doi:10.1038/ngeo2898.

A >100 Ma Mantle Geochemical Record: Retiring Mantle Plumes may be Premature

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Konter, J. G.; Hanan, B. B.; Blichert-Toft, J.; Koppers, A. A.; Plank, T.; Staudigel, H.

2006-12-01

Hotspot volcanism has long been attributed to mantle plumes, but in recent years suggestions have been made that plate tectonic processes, such as extension, can account for all hotspot tracks. This explanation involves a profoundly less dynamic lower mantle, which justifies a critical evaluation before the plume model is dismissed. Such an evaluation has to involve a wide range of geochemical, geological, and geophysical techniques, broadly investigating the products of volcanism as well as the underlying lithosphere and mantle. We argue here that the combined geological record and geochemistry of intraplate volcanoes holds some important clues that help us decide between models of plume-like upwelling versus passive upwelling with lithospheric extension. The best of these integrated datasets can be obtained from the long seamount chains in the Pacific Ocean. A new combined dataset of trace element and isotopic compositions, along with modern 40Ar/39Ar ages from seamounts in the Gilbert Ridge, Tokelau chain, and West Pacific Seamount Province (WPSP) provides a record of current to Cretaceous volcanism in the South Pacific. We have reconstructed the eruptive locations of the seamounts using a range of absolute plate motion models, including some models with hotspot motion and others that use the Indo-Atlantic hotspot reference frame. Our results show that the backtracked locations consistently form clusters (300km radius) around the active ends of the Macdonald, Rurutu and Rarotonga hotspot chains, while closely matching their distinct C-HIMU and C-EM1 signatures. The oldest WPSP seamounts (older than 100 Ma) form the only exception and backtrack, with larger uncertainty, to north of Rarotonga. Therefore, the mantle currently underlying the Cook-Austral islands has produced volcanoes in three geochemically distinct areas for at least 100 m.y. Furthermore, we find the shortest mantle residence time, 0.6 Ga, for a source of mixed recycled DMM and an EM1-like

Relapse prevention and smoking cessation.

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Davis, J R; Glaros, A G

1986-01-01

A multicomponent smoking relapse prevention treatment based on Marlatt and Gordon's (1980) model of the relapse process was developed and evaluated. Behavior-analytic methods were used to develop assessment instruments, training situations, and coping responses. The prevention components were presented in the context of a basic broad-spectrum stop-smoking program, and were compared with the basic program plus discussion control, and the basic program alone. Smoking-related dependent variables generally did not differ between groups at any time from pre-treatment to 12 month follow-up. Only the subjects in the relapse prevention condition improved problem-solving and social skills needed to cope with high-risk situations. These subjects also tended to take longer to relapse and smoke fewer cigarettes at the time of relapse. Subjects above the median level of competence on measures of social skill at post-treatment remained abstinent significantly longer. Maintenance of non-smoking was found to be related to the degree of competence with which individuals deal with high-risk situations. Results are discussed in relation to models of compliance with therapeutic regimens.

Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation

NARCIS (Netherlands)

Millot, F; Guilhot, J; Nelken, B; Leblanc, T; De Bont, ES; Bekassy, AN; Gadner, H; Sufliarska, S; Stary, J; Gschaidmeier, H; Guilhot, F; Suttorp, M

A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon a-based regimen. In

LATE-BREAKING ABSTRACT: Early relapse of non-small cell lung cancer (NSCLC) found after CNS-symptoms

DEFF Research Database (Denmark)

Hansen, Niels-Chr. G.; Laursen, Christian B.; Jeppesen, Stefan S.

2016-01-01

whether the introduction in 2010 of follow-up by CT of thorax and upper abdomen every three months has reduced the incidence of relapse suspected from CNS-symptoms.Results: All 827 NSCLC patients from Funen completing curative treatment from 2005 to 2013 were included. The total number of relapses found...... or III were found.Conclusion: CT-based follow-up has not reduced the incidence of relapse suspected from CNS-symptoms in stage II-IV, and therefore we suggest routine MR of the brain before curative treatment for this group of patients.Number, fractions(%), and [95%CI]Jan. 2005 - June 2010July 2010 - Dec...... after symptoms within 24 months decreased in the 3½ years after the introduction of CT-based follow-up, p < 0,001 (table), but the total fraction presenting with CNS-symptoms did not change, p = 0.296. Relapses after stage I cancer decreased (p = 0.025), while no differences or changes for stages II...

Primary Refractory and Relapsed Classical Hodgkin Lymphoma - Significance of Differential CD15 Expression in Hodgkin-Reed-Sternberg Cells

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Daniel Benharroch, Shai Pilosof, Jacob Gopas, Itai Levi

2012-01-01

Full Text Available We recognized a few possible complications of classical Hodgkin lymphoma therapy in a cohort of 209 patients: 8 developed a primary refractory disease (primary progression, 36 showed an early relapse and 21 showed a late relapse. Sialyl-CD15 expression in Hodgkin-Reed-Sternberg cells was significantly more positive in primary refractory Hodgkin lymphoma, which confirms our previously published findings. Bcl-2 showed a significantly lower level of expression in primary refractory disease than in the other follow-up groups. This is in contrast with a previous finding of Bcl-2, associated with a poor prognosis in primary refractory illness. Another category of variables, old age and advanced stages, was significantly different in the various complications but this finding is probably to be expected. We could not demonstrate a difference between the sequels and the control group with regard to several clinical and immunohistochemical markers. Sialyl-CD15 and Bcl-2 expression, in contrast, were confirmed as prognostic factors, mainly of tumor progression into primary refractory disease.

Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.

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Byrd, John C; Furman, Richard R; Coutre, Steven E; Flinn, Ian W; Burger, Jan A; Blum, Kristie A; Grant, Barbara; Sharman, Jeff P; Coleman, Morton; Wierda, William G; Jones, Jeffrey A; Zhao, Weiqiang; Heerema, Nyla A; Johnson, Amy J; Sukbuntherng, Juthamas; Chang, Betty Y; Clow, Fong; Hedrick, Eric; Buggy, Joseph J; James, Danelle F; O'Brien, Susan

2013-07-04

The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).

Relapsing polychondritis: commentary

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R.D. Altman

2011-09-01

Full Text Available Relapsing Polychondritis (RP is a multisystem disease of unknown etiology characterized by episodic inflammation of cartilage and potentially progressive degeneration of cartilaginous tissue, such as auricular, nasal and laryngotracheobronchial cartilage. However, many other proteoglycan- rich structures may be involved, such as inner ear, eyes, blood vessels, heart and kidneys (1- 4. RP was first described by Jacksh-Wartenhorst in 1923, who named it “polychondropathia” (5. Pearson et al. (6 introduced the term “relapsing polychondritis” in 1960...

Asymmetric three-dimensional topography over mantle plumes.

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Burov, Evgueni; Gerya, Taras

2014-09-04

The role of mantle-lithosphere interactions in shaping surface topography has long been debated. In general, it is supposed that mantle plumes and vertical mantle flows result in axisymmetric, long-wavelength topography, which strongly differs from the generally asymmetric short-wavelength topography created by intraplate tectonic forces. However, identification of mantle-induced topography is difficult, especially in the continents. It can be argued therefore that complex brittle-ductile rheology and stratification of the continental lithosphere result in short-wavelength modulation and localization of deformation induced by mantle flow. This deformation should also be affected by far-field stresses and, hence, interplay with the 'tectonic' topography (for example, in the 'active/passive' rifting scenario). Testing these ideas requires fully coupled three-dimensional numerical modelling of mantle-lithosphere interactions, which so far has not been possible owing to the conceptual and technical limitations of earlier approaches. Here we present new, ultra-high-resolution, three-dimensional numerical experiments on topography over mantle plumes, incorporating a weakly pre-stressed (ultra-slow spreading), rheologically realistic lithosphere. The results show complex surface evolution, which is very different from the smooth, radially symmetric patterns usually assumed as the canonical surface signature of mantle upwellings. In particular, the topography exhibits strongly asymmetric, small-scale, three-dimensional features, which include narrow and wide rifts, flexural flank uplifts and fault structures. This suggests a dominant role for continental rheological structure and intra-plate stresses in controlling dynamic topography, mantle-lithosphere interactions, and continental break-up processes above mantle plumes.

Water in Earth's mantle: Hydrogen analysis of mantle olivine, pyroxenes and garnet using the SIMS

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Kurosawa, Masanori; Yurimoto, Hisayoshi; Sueno, Shigeho

1993-01-01

Hydrogen (or water) in the Earth's interior plays a key role in the evolution and dynamics of the planet. However, the abundance and the existence form of the hydrogen have scarcely been clear in practice. Hydrogen in the mantle was incorporated in the interior during the formation of the Earth. The incorporated hydrogen was hardly possible to concentrate locally inside the Earth considering its high mobility and high reactivity. The hydrogen, preferably, could be distributed homogeneously over the mantle and the core by the subsequent physical and chemical processes. Therefore, hydrogen in the mantle could be present in the form of trace hydrogen in nominally anhydrous mantle minerals. The hydrogen and the other trace elements in mantle olivines, orthopyroxenes, clinopyroxenes, and garnets were determined using secondary ion mass spectrometry (SIMS) for elucidating (1) the exact hydrogen contents, (2) the correlation between the hydrogen and the other trace elements, (3) the dependence of the hydrogen contents on the depth, and (4) the dependence of the whole rock water contents on the depth.

Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.

Science.gov (United States)

Casanova, Bonaventura; Jarque, Isidro; Gascón, Francisco; Hernández-Boluda, Juan Carlos; Pérez-Miralles, Francisco; de la Rubia, Javier; Alcalá, Carmen; Sanz, Jaime; Mallada, Javier; Cervelló, Angeles; Navarré, Arantxa; Carcelén-Gadea, María; Boscá, Isabel; Gil-Perotin, Sara; Solano, Carlos; Sanz, Miguel Angel; Coret, Francisco

2017-07-01

The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

Thermal Stratification in Vertical Mantle Tanks

DEFF Research Database (Denmark)

Knudsen, Søren; Furbo, Simon

2001-01-01

It is well known that it is important to have a high degree of thermal stratification in the hot water storage tank to achieve a high thermal performance of SDHW systems. This study is concentrated on thermal stratification in vertical mantle tanks. Experiments based on typical operation conditions...... are carried out to investigate how the thermal stratification is affected by different placements of the mantle inlet. The heat transfer between the solar collector fluid in the mantle and the domestic water in the inner tank is analysed by CFD-simulations. Furthermore, the flow pattern in the vertical mantle...

Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies.

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Liu, Jun; Zhong, Jiang F; Zhang, Xi; Zhang, Cheng

2017-01-31

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the cornerstone in treatment of hematological malignancies. However, relapse of the hematological disease after allo-HSCT remains a challenge and is associated with poor long-term survival. Chimeric antigen receptor redirected T cells (CAR-T cells) can lead to disease remission in patients with relapsed/refractory hematological malignancies. However, the therapeutic window for infusion of CAR-T cells post allo-HSCT and its efficacy are debatable. In this review, we first discuss the use of CAR-T cells for relapsed cases after allo-HSCT. We then review the toxicities and the occurrence of graft-versus-host disease in relapsed patients who received CAR-T cells post allo-HSCT. Finally, we review clinical trial registrations and the therapeutic time window for infusion of CAR-T cells post allo-HSCT. The treatment of allogeneic CAR-T cells is beneficial for patients with relapsed B cell malignancies after allo-HSCT with low toxicities and complications. However, multicenter clinical trials with larger sample sizes should be performed to select the optimal therapeutic window and confirm its efficacy.

Archean crust-mantle geochemical differentiation

Science.gov (United States)

Tilton, G. R.

Isotope measurements on carbonatite complexes and komatiites can provide information on the geochemical character and geochemical evolution of the mantle, including the sub-continental mantle. Measurements on young samples establish the validity of the method. These are based on Sr, Nd and Pb data from the Tertiary-Mesozoic Gorgona komatiite and Sr and Pb data from the Cretaceous Oka carbonatite complex. In both cases the data describe a LIL element-depleted source similar to that observed presently in MORB. Carbonatite data have been used to study the mantle beneath the Superior Province of the Canadian Shield one billion years (1 AE) ago. The framework for this investigation was established by Bell et al., who showed that large areas of the province appear to be underlain by LIL element-depleted mantle (Sr-85/Sr-86=0.7028) at 1 AE ago. Additionally Bell et al. found four complexes to have higher initial Sr ratios (Sr-87/Sr-86=0.7038), which they correlated with less depleted (bulk earth?) mantle sources, or possibly crustal contamination. Pb isotope relationships in four of the complexes have been studied by Bell et al.

Archean crust-mantle geochemical differentiation

Science.gov (United States)

Tilton, G. R.

1983-01-01

Isotope measurements on carbonatite complexes and komatiites can provide information on the geochemical character and geochemical evolution of the mantle, including the sub-continental mantle. Measurements on young samples establish the validity of the method. These are based on Sr, Nd and Pb data from the Tertiary-Mesozoic Gorgona komatiite and Sr and Pb data from the Cretaceous Oka carbonatite complex. In both cases the data describe a LIL element-depleted source similar to that observed presently in MORB. Carbonatite data have been used to study the mantle beneath the Superior Province of the Canadian Shield one billion years (1 AE) ago. The framework for this investigation was established by Bell et al., who showed that large areas of the province appear to be underlain by LIL element-depleted mantle (Sr-85/Sr-86=0.7028) at 1 AE ago. Additionally Bell et al. found four complexes to have higher initial Sr ratios (Sr-87/Sr-86=0.7038), which they correlated with less depleted (bulk earth?) mantle sources, or possibly crustal contamination. Pb isotope relationships in four of the complexes have been studied by Bell et al.

Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis.

Science.gov (United States)

Kalinina Ayuso, Viera; van de Winkel, Evelyne Leonce; Rothova, Aniki; de Boer, Joke Helena

2011-02-01

To evaluate the efficacy of methotrexate (MTX) and the effect of its withdrawal on relapse rate of uveitis associated with juvenile idiopathic arthritis (JIA). Retrospective case series. Data of 22 pediatric JIA patients who were being treated with MTX for active uveitis were studied retrospectively. Relapse rate after the withdrawal of MTX was established. Anterior chamber (AC) inflammation, topical steroid use during the first year of MTX treatment, and associations of relapses after the withdrawal were evaluated statistically. Duration of MTX treatment and its withdrawal was determined individually in collaboration with a rheumatologist with an intention to continue the treatment for at least 1 year and to withdraw in case of inactivity of uveitis and arthritis. Inactivity of uveitis was defined as the presence of ≤0.5+ cells in the AC. Eighteen patients (18/22; 82%) showed improvement of their uveitis with a significant decrease in activity of AC inflammation after a minimal period of 3 months of MTX treatment. A topical steroid-sparing effect was observed when MTX was administered for a period of 3 to 9 months. MTX was discontinued because of inactive uveitis in 13 patients. In 9 patients (8/13; 69%) a relapse of uveitis was observed after a mean time of 7.5 months (± SD 7.3). Six patients (6/13; 46%) had a relapse within the first year after the withdrawal. Relapse-free survival after withdrawal of MTX was significantly longer in patients who had been treated with MTX for more than 3 years (P = .009), children who were older than 8 years at the moment of withdrawal (P = .003), and patients who had an inactivity of uveitis of longer than 2 years before withdrawal of MTX (P = .033). Longer inactivity under MTX therapy was independently protective for relapses after the withdrawal (hazard ratio = 0.07; 95% confidence interval 0.01-0.86; P = .038), which means that 1-year increase of duration of inactive uveitis before the withdrawal of MTX results in a

The Role of Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) Gene, Thyroid Stimulating Hormone Receptor (TSHR) Gene and Regulatory T-cells as Risk Factors for Relapse in Patients with Graves Disease.

Science.gov (United States)

Eliana, Fatimah; Suwondo, Pradana; Asmarinah, Asmarinah; Harahap, Alida; Djauzi, Samsuridjal; Prihartono, Joedo; Pemayun, Tjokorda Gde Dalem

2017-07-01

graves' disease (GD) is the most common condition of thyrotoxicosis. The management of GD is initiated with the administration of antithyroid drugs; however, it requires a long time to achieve remission. In reality more than 50% of patients who had remission may be at risk for relapse after the drug is stopped. This study aimed to evaluate the role of clinical factors such as smoking habit, degree of ophtalmopathy, degree of thyroid enlargement; genetic factors such as CTLA-4 gene on nucleotide 49 at codon 17 of exon 1, CTLA-4 gene of promotor -318, TSHR gene polymorphism rs2268458 of intron 1; and immunological factors such as regulatory T cells (Treg) and thyroid receptor antibody (TRAb); that affecting the relapse of patients with Graves' disease in Indonesia. this was a case-control study, that compared 72 subjects who had relapse and 72 subjects without relapse at 12 months after cessation of antithyroid treatment, who met the inclusion criteria. Genetic polymorphism examination was performed using PCR-RFLP. The number of regulatory T cells was counted using flow cytometry analysis and ELISA was used to measure TRAb. The logistic regression was used since the dependent variables were categorical variables. the analysis of this study demonstrated that there was a correlation between relapse of disease and family factors (p=0.008), age at diagnosis (p=0.021), 2nd degree of Graves' ophthalmopathy (p=0.001), enlarged thyroid gland, which exceeded the lateral edge of the sternocleidomastoid muscles (p=0.040), duration of remission period (p=0.029), GG genotype of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1 (p=0.016), CC genotype of TSHR gene on the rs2268458 of intron 1 (p=0.003), the number of regulatory T cells (p=0.001) and TRAb levels (p=0.002). genetic polymorphisms of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1, TSHR gene SNP rs2268458 of intron 1, number of regulatory T cells and TRAb levels play a role as risk factors for relapse in

The Role of Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4 Gene, Thyroid Stimulating Hormone Receptor (TSHR Gene and Regulatory T-cells as Risk Factors for Relapse in Patients with Graves Disease

Directory of Open Access Journals (Sweden)

Fatimah Eliana

2017-11-01

Full Text Available Background: graves’ disease (GD is the most common condition of thyrotoxicosis. The management of GD is initiated with the administration of antithyroid drugs; however, it requires a long time to achieve remission. In reality more than 50% of patients who had remission may be at risk for relapse after the drug is stopped. This study aimed to evaluate the role of clinical factors such as smoking habit, degree of ophtalmopathy, degree of thyroid enlargement; genetic factors such as CTLA-4 gene on nucleotide 49 at codon 17 of exon 1, CTLA-4 gene of promotor -318, TSHR gene polymorphism rs2268458 of intron 1; and immunological factors such as regulatory T cells (Treg and thyroid receptor antibody (TRAb; that affecting the relapse of patients with Graves’ disease in Indonesia. Methods: this was a case-control study, that compared 72 subjects who had relapse and 72 subjects without relapse at 12 months after cessation of antithyroid treatment, who met the inclusion criteria. Genetic polymorphism examination was performed using PCR-RFLP. The number of regulatory T cells was counted using flow cytometry analysis and ELISA was used to measure TRAb. The logistic regression was used since the dependent variables were categorical variables. Results: the analysis of this study demonstrated that there was a correlation between relapse of disease and family factors (p=0.008, age at diagnosis (p=0.021, 2nd degree of Graves’ ophthalmopathy (p=0.001, enlarged thyroid gland, which exceeded the lateral edge of the sternocleidomastoid muscles (p=0.040, duration of remission period (p=0.029, GG genotype of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1 (p=0.016, CC genotype of TSHR gene on the rs2268458 of intron 1 (p=0.003, the number of regulatory T cells (p=0.001 and TRAb levels (p=0.002. Conclusion: genetic polymorphisms of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1, TSHR gene SNP rs2268458 of intron 1, number of regulatory T cells and

The role of plumes in mantle helium fluxes

International Nuclear Information System (INIS)

Kellogg, L.H.; Wasserburg, G.J.

1990-01-01

We present a simple model of 3 He and 4 He transport in the mantle using the appropriate rates of mass and species transfer and 4 He production. Previous workers have shown the presence of excess 3 He in hotspots such as Hawaii and Iceland and inferred that these hotspots tap a source with a higher 3 He/ 4 He ratio than the source region of mid-ocean ridge basalts (MORB). Hotspot ocean islands probably originate over upwelling plumes which carry material from the lower mantle to the upper mantle. Melting at hotspots and at mid-ocean ridges degasses the mantle of volatiles such as helium. The upper mantle is outgassed largely of helium due to melting at mid-ocean ridges and hotspots. We postulate that the excess 3 He seen in MORB originates in material that was carried from the lower mantle in plumes but not completely outgassed at hotspots. This helium is incoporated into the depleted upper mantle. Assuming that the upper mantle is in a quasi-steady-state with respect to helium, a simple model balancing 3 He and 4 He fluxes in the upper mantle indicates that the hotspots significantly outgas the lower mantle of 3 He. The concentration of 4 He in the plume source reservoir is 2-3 orders of magnitude lower than the concentration in carbonaceous chondrites. The residence time of helium in the upper mantle depends on the outgassing efficiency at hotspots, since the hotspots may outgas some upper mantle material which has been entrained in the plumes. The residence time of He in the upper mantle is about 1.4x10 9 yr. We conclude that the efficiency of outgassing of He from plumes is high and that the plumes dominate the present 3 He loss to the atmosphere. The 4 He in the less depleted layer of the mantle is not trapped ''primordial'' but is predominantly from in situ decay of U and Th in the depleted layer over ≅ 1.4x10 9 yr. The 4 He in the lower mantle is dominantly from in situ decay of U and Th over 4.4x10 9 yr. (orig./WL)

Nd-isotopes in selected mantle-derived rocks and minerals and their implications for mantle evolution

Science.gov (United States)

Basu, A.R.; Tatsumoto, M.

1980-01-01

The Sm-Nd systematics in a variety of mantle-derived samples including kimberlites, alnoite, carbonatite, pyroxene and amphibole inclusions in alkali basalts and xenolithic eclogites, granulites and a pyroxene megacryst in kimberlites are reported. The additional data on kimberlites strengthen our earlier conclusion that kimberlites are derived from a relatively undifferentiated chondritic mantle source. This conclusion is based on the observation that the e{open}Nd values of most of the kimberlites are near zero. In contrast with the kimberlites, their garnet lherzolite inclusions show both time-averaged Nd enrichment and depletion with respect to Sm. Separated clinopyroxenes in eclogite xenoliths from the Roberts Victor kimberlite pipe show both positive and negative e{open}Nd values suggesting different genetic history. A whole rock lower crustal scapolite granulite xenolith from the Matsoku kimberlite pipe shows a negative e{open}Nd value of -4.2, possibly representative of the base of the crust in Lesotho. It appears that all inclusions, mafic and ultramafic, in kimberlites are unrelated to their kimberlite host. The above data and additional Sm-Nd data on xenoliths in alkali basalts, alpine peridotite and alnoite-carbonatites are used to construct a model for the upper 200 km of the earth's mantle - both oceanic and continental. The essential feature of this model is the increasing degree of fertility of the mantle with depth. The kimberlite's source at depths below 200 km in the subcontinental mantle is the most primitive in this model, and this primitive layer is also extended to the suboceanic mantle. However, it is clear from the Nd-isotopic data in the xenoliths of the continental kimberlites that above 200 km the continental mantle is distinctly different from their suboceanic counterpart. ?? 1980 Springer-Verlag.

Numerical simulations of the mantle lithosphere delamination

Science.gov (United States)

Morency, C.; Doin, M.-P.

2004-03-01

Sudden uplift, extension, and increased igneous activity are often explained by rapid mechanical thinning of the lithospheric mantle. Two main thinning mechanisms have been proposed, convective removal of a thickened lithospheric root and delamination of the mantle lithosphere along the Moho. In the latter case, the whole mantle lithosphere peels away from the crust by the propagation of a localized shear zone and sinks into the mantle. To study this mechanism, we perform two-dimensional (2-D) numerical simulations of convection using a viscoplastic rheology with an effective viscosity depending strongly on temperature, depth, composition (crust/mantle), and stress. The simulations develop in four steps. (1) We first obtain "classical" sublithospheric convection for a long time period (˜300 Myr), yielding a slightly heterogeneous lithospheric temperature structure. (2) At some time, in some simulations, a strong thinning of the mantle occurs progressively in a small area (˜100 km wide). This process puts the asthenosphere in direct contact with the lower crust. (3) Large pieces of mantle lithosphere then quickly sink into the mantle by the horizontal propagation of a detachment level away from the "asthenospheric conduit" or by progressive erosion on the flanks of the delaminated area. (4) Delamination pauses or stops when the lithospheric mantle part detaches or when small-scale convection on the flanks of the delaminated area is counterbalanced by heat diffusion. We determine the parameters (crustal thicknesses, activation energies, and friction coefficients) leading to delamination initiation (step 2). We find that delamination initiates where the Moho temperature is the highest, as soon as the crust and mantle viscosities are sufficiently low. Delamination should occur on Earth when the Moho temperature exceeds ˜800°C. This condition can be reached by thermal relaxation in a thickened crust in orogenic setting or by corner flow lithospheric erosion in the

Gemcitabine and treatment of diffuse large B-cell lymphoma in relapsed or refractory elderly patients: A prospective randomized trial in Algeria

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Aribi Mourad

2010-01-01

Full Text Available Context: Support for non-Hodgkin′s lymphoma (NHL with large cells that is refractory or relapsed after first-line chemotherapy poses a greater therapeutic problem with bone marrow transplant therapy or when old age is a contra-indication for high-dose chemotherapy, especially among developing countries such as Algeria. Aim: To show that the regimen, including gemcitabine, could be more effective in treating elderly patients with diffuse large B-cell lymphoma (DLBCL in relapse / refractory, without complete remission, when compared with the ESHAP (etoposide, cisplatine, solumedrol, aracytine regimen. Materials and Methods: Ninety-six patients in the age group of 60-70 years were volunteers for a prospective randomized single-blind study, carried out for three years. Patients were divided into two groups by the drawing of lots. The first group (GA, n = 48, relapse; n = 27 [56.3%], refractory; n = 21 [43.7%] received treatment with ESHAP protocol and the second one (GB, n = 48, relapse; n = 28 [58%], refractory; n = 20 [42%] with GPD (gemcitabine, dexamethasone, cisplatine protocol. Results: The overall response rates and mean survival at three years were significantly higher among patients subjected to GPD treatment compared with those subjected to ESHAP treatment (63% vs. 55%, P = 0.01 and 20.5% [95% CI 16.5-24.5] vs. 11.8% [8.9-14.6], respectively. Additionally, three-year progression-free and event-free survival rates were 20.5% (16.3-24 and 19.7% (15.9-23.5, respectively, for the GPD regimen and 10.9% (8.2-13.7 and 11.1% (95% CI 8.5-13.7, respectively, for the ESHAP regimen. Moreover, the GPD regimen was associated with improving overall survival (RR=2.02, 95% CI 1.59-2.56; P = 0.000, event-free survival (2.03, 1.64-2.52; P < 0.001 and progression-free survival (1.86, 1.46-2.37; P < 0.001. Conclusion: In cases of contra-indication for high-dose chemotherapy for elderly patients with DLBCL, without complete remission, the Gemcitabine

Clinicopathological Features of Ocular Adnexal Mantle-Cell Lymphoma in an International Multicenter Cohort

DEFF Research Database (Denmark)

Knudsen, Marina K H; Rasmussen, Peter K; Coupland, Sarah E

2017-01-01

Importance: To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort. Objective: To characterize the clinical features of OA-MCL. Design, Setting, and Participants: This retrospective multicenter study...... included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months. Main Outcomes and Measures: Overall survival, disease-specific survival....... Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease-specific survival adjusted by eye cancer center was better in patients who had...

In search of the optimal platform for Post-Allogeneic SCT immunotherapy in relapsed multiple myeloma: a systematic review.

Science.gov (United States)

Oostvogels, R; Uniken Venema, S M; de Witte, M; Raymakers, R; Kuball, J; Kröger, N; Minnema, M C

2017-09-01

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce sustained remissions in patients with multiple myeloma (MM). Currently, allo-SCT is primarily performed in high-risk MM patients, most often in the setting of early relapse after first-line therapy with autologous SCT. However, the implementation of allo-SCT for MM is jeopardized by high treatment-related mortality (TRM) rates as well as high relapse rates. In this systematic review, we aimed to identify a safe allo-SCT strategy that has optimal 1-year results regarding mortality, relapse and severe GvHD, creating opportunities for post-transplantation strategies to maintain remissions in the high-risk group of relapsed MM patients. Eleven studies were included. Median PFS ranged from 5.2 to 36.8 months and OS was 13.0 to 63.0 months. The relapse related mortality at 1 year varied between 0 and 50% and TRM between 8 and 40%. Lowest GvHD incidences were reported for conditioning regimens with T-cell depletion using ATG or graft CD34+ selection. Similar strategies could lay the foundation for a post-transplant immune platform, this should be further evaluated in prospective clinical trials.

Traveltime dispersion in an isotropic elastic mantle: strong lower-mantle signal in differential-frequency residuals

Science.gov (United States)

Schuberth, Bernhard S. A.; Zaroli, Christophe; Nolet, Guust

2015-12-01

We study wavefield effects of direct P- and S-waves in elastic and isotropic 3-D seismic structures derived from the temperature field of a high-resolution mantle circulation model. More specifically, we quantify the dispersion of traveltime residuals caused by diffraction in structures with dynamically constrained length scales and magnitudes of the lateral variations in seismic velocities and density. 3-D global wave propagation is simulated using a spectral element method. Intrinsic attenuation (i.e. dissipation of seismic energy) is deliberately neglected, so that any variation of traveltimes with frequency can be attributed to structural effects. Traveltime residuals are measured at 15, 22.5, 34 and 51 s dominant periods by cross-correlation of 3-D and 1-D synthetic waveforms. Additional simulations are performed for a model in which 3-D structure is removed in the upper 800 km to isolate the dispersion signal of the lower mantle. We find that the structural length scales inherent to a vigorously convecting mantle give rise to significant diffraction-induced body-wave traveltime dispersion. For both P- and S-waves, the difference between long-period and short-period residuals for a given source-receiver pair can reach up to several seconds for the period bands considered here. In general, these `differential-frequency' residuals tend to increase in magnitude with increasing short-period delay. Furthermore, the long-period signal typically is smaller in magnitude than the short-period one; that is, wave-front healing is efficient independent of the sign of the residuals. Unlike the single-frequency residuals, the differential-frequency residuals are surprisingly similar between the `lower-mantle' and the `whole-mantle' model for corresponding source-receiver pairs. The similarity is more pronounced in case of S-waves and varies between different combinations of period bands. The traveltime delay acquired in the upper mantle seems to cancel in these differential

Mantle flow influence on subduction evolution

Science.gov (United States)

Chertova, Maria V.; Spakman, Wim; Steinberger, Bernhard

2018-05-01

The impact of remotely forced mantle flow on regional subduction evolution is largely unexplored. Here we investigate this by means of 3D thermo-mechanical numerical modeling using a regional modeling domain. We start with simplified models consisting of a 600 km (or 1400 km) wide subducting plate surrounded by other plates. Mantle inflow of ∼3 cm/yr is prescribed during 25 Myr of slab evolution on a subset of the domain boundaries while the other side boundaries are open. Our experiments show that the influence of imposed mantle flow on subduction evolution is the least for trench-perpendicular mantle inflow from either the back or front of the slab leading to 10-50 km changes in slab morphology and trench position while no strong slab dip changes were observed, as compared to a reference model with no imposed mantle inflow. In experiments with trench-oblique mantle inflow we notice larger effects of slab bending and slab translation of the order of 100-200 km. Lastly, we investigate how subduction in the western Mediterranean region is influenced by remotely excited mantle flow that is computed by back-advection of a temperature and density model scaled from a global seismic tomography model. After 35 Myr of subduction evolution we find 10-50 km changes in slab position and slab morphology and a slight change in overall slab tilt. Our study shows that remotely forced mantle flow leads to secondary effects on slab evolution as compared to slab buoyancy and plate motion. Still these secondary effects occur on scales, 10-50 km, typical for the large-scale deformation of the overlying crust and thus may still be of large importance for understanding geological evolution.

Treatment of refractory/relapsed adult acute lymphoblastic leukemia with bortezomib- based chemotherapy

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Zhao J

2015-06-01

Full Text Available Junmei Zhao,* Chao Wang,* Yongping Song, Yuzhang Liu, Baijun FangHenan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital, Zhengzhou University, Zhengzhou, People’s Republic of China  *These authors contributed equally to this work Abstract: Nine pretreated patients aged >19 years with relapsed/refractory acute lymphoblastic leukemia (ALL were treated with a combination of bortezomib plus chemotherapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT. Eight (88.9% patients, including two Philadelphia chromosome-positive ALL patients, achieved a complete remission. Furthermore, the evaluable patients have benefited from allo-HSCT after response to this reinduction treatment. We conclude that bortezomib-based chemotherapy was highly effective for adults with refractory/relapsed ALL before allo-HSCT. Therefore, this regimen deserves a larger series within prospective trials to confirm these results. Keywords: acute lymphoblastic leukemia, refractory, relapsed, bortezomib

Survival of the primitive mantle reservoir?

Science.gov (United States)

Huang, S.; Jacobsen, S. B.; Mukhopadhyay, S.

2010-12-01

The high-3He lavas are thought to originate from a deep primitive mantle source that has not been much modified since the formation of Earth’s core. Comparison of 4He/3He in MORBs and plume lavas indicate that the plume sources must be a lower mantle feature, in agreement with most geophysical inferences. However, the lithophile element isotope systems of plume lavas are not primitive. The idea that the high-3He source is significantly less processed and more primitive than MORB source is clearly supported by mixing trends in plots of 4He/3He versus Sr, Nd and Pb isotope ratios, which have been extrapolated to an inferred 4He/3He of ~17,000 (~43x the atmospheric ratio), a mantle reservoir named PHEM (Primitive HElium Mantle). Slightly lower 4He/3He, ~15,000, were reported for Baffin Island picrites. Recently, Jackson et al. (2010) claimed that some Baffin Island and Greenland picrites with single-stage Pb model ages of ~4.5 Ga have low 4He/3He, and argued that “their source is the most ancient accessible reservoir in the Earth’s mantle, and it may be parental to all mantle reservoirs”. However, the available data are insufficient to make such a claim, and we suggest an alternative interpretation. Specially: 1. Four out of ten Baffin Island and Greenland picrites used by Jackson et al. (2010) have 4He/3He higher than average MORB value and all are far removed from the lowest measured value of 15,000. 2. Five Greenland picrites which cluster around the 4.50 Gyr geochron (Jackson et al., 2010) form a curved 207Pb*/206Pb*-4He/3He trend. This trend is best explained as a mixing line, implying that the single-stage Pb ages of these lavas are meaningless. 3. In a 207Pb*/206Pb*-4He/3He plot, Koolau lavas from Hawaii overlap with Baffin Island and Greenland picrites. If Baffin Island and Greenland picrites represent melts from the primitive mantle based on their Pb and He isotopes (Jackson et al., 2010), a similar argument can be applied to Koolau lavas. However, it

Stagnant lids and mantle overturns: Implications for Archaean tectonics, magmagenesis, crustal growth, mantle evolution, and the start of plate tectonics

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Jean H. Bédard

2018-01-01

Full Text Available The lower plate is the dominant agent in modern convergent margins characterized by active subduction, as negatively buoyant oceanic lithosphere sinks into the asthenosphere under its own weight. This is a strong plate-driving force because the slab-pull force is transmitted through the stiff sub-oceanic lithospheric mantle. As geological and geochemical data seem inconsistent with the existence of modern-style ridges and arcs in the Archaean, a periodically-destabilized stagnant-lid crust system is proposed instead. Stagnant-lid intervals may correspond to periods of layered mantle convection where efficient cooling was restricted to the upper mantle, perturbing Earth's heat generation/loss balance, eventually triggering mantle overturns. Archaean basalts were derived from fertile mantle in overturn upwelling zones (OUZOs, which were larger and longer-lived than post-Archaean plumes. Early cratons/continents probably formed above OUZOs as large volumes of basalt and komatiite were delivered for protracted periods, allowing basal crustal cannibalism, garnetiferous crustal restite delamination, and coupled development of continental crust and sub-continental lithospheric mantle. Periodic mixing and rehomogenization during overturns retarded development of isotopically depleted MORB (mid-ocean ridge basalt mantle. Only after the start of true subduction did sequestration of subducted slabs at the core-mantle boundary lead to the development of the depleted MORB mantle source. During Archaean mantle overturns, pre-existing continents located above OUZOs would be strongly reworked; whereas OUZO-distal continents would drift in response to mantle currents. The leading edge of drifting Archaean continents would be convergent margins characterized by terrane accretion, imbrication, subcretion and anatexis of unsubductable oceanic lithosphere. As Earth cooled and the background oceanic lithosphere became denser and stiffer, there would be an increasing

Mantle strength of the San Andreas fault system and the role of mantle-crust feedbacks

NARCIS (Netherlands)

Chatzaras, V.; Tikoff, B.; Newman, J.; Withers, A.C.; Drury, M.R.

2015-01-01

In lithospheric-scale strike-slip fault zones, upper crustal strength is well constrained from borehole observations and fault rock deformation experiments, but mantle strength is less well known. Using peridotite xenoliths, we show that the upper mantle below the San Andreas fault system

The mantle-plume model, its feasibility and consequences

NARCIS (Netherlands)

Calsteren, van P.W.C.

1981-01-01

High beat-flow foci on the Earth have been named ‘hot-spots’ and are commonly correlated with ‘mantle-plumes’ in the deep. A mantle plume may be described as a portion of mantle material with a higher heat content than its surroundings. The intrusion of a mantle-plume is inferred to be similar to

Mantle geofluid and uranium ore-formation model

International Nuclear Information System (INIS)

Wu Jianhua; Liu Shuai; Yu Dagan; Zhang Bangtong

2005-01-01

Results of the recent research show that volcanic-type and granite-type uranium deposits have both early and late phases of uranium mineralization, and the early phase uranium mineralization is characterized by metallogenetic features of mantle fluids. This paper discusses the geofluids and related metallogenesis, as well as characteristics of early phase uranium mineralisation, and emphasizes, that the ΣCO 2 , U and H 2 O, that comprise the bulk of the ore-forming hot fluids, are originated from different sources, namely CO 2 comes from mantle fluids, U comes from country rocks the mantle fluids have passed during their ascending way, and H 2 O comes from mantle fluids and country rocks the mantle fluids have passed during their ascending way. (authors)

Identification of methylated genes associated with aggressive clinicopathological features in mantle cell lymphoma.

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Anna Enjuanes

Full Text Available BACKGROUND: Mantle cell lymphoma (MCL is genetically characterized by the t(11;14(q13;q32 translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. METHODOLOGY/PRINCIPAL FINDINGS: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n = 38. After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n = 25 in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9, HOXA9, AHR, NR2F2, and ROBO1 frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. CONCLUSIONS: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP that may influence the behaviour of the tumours.

Patterns of failure following high-dose chemotherapy and stem cell rescue for relapsed/refractory non-Hodgkin's lymphoma: implications for the use of adjuvant involved field radiotherapy

International Nuclear Information System (INIS)

Mundt, Arno J.; Williams, Stephanie F.; Hallahan, Dennis; Weichselbaum, Ralph R.

1996-01-01

Purpose: Recent data have suggested a benefit to involved-field radiotherapy (IFRT) in conjunction with high-dose chemotherapy (HDCT) and autologous stem cell rescue (SCR) in patients with metastatic breast cancer, advanced neuroblastoma and relapsed/refractory Hodgkin's disease. The purpose of this study is to determine whether a similar role exists for IFRT in patients with relapsed/refractory Non-Hodgkin's Lymphoma (NHL) undergoing HDCT. Methods/Materials: Forty-nine adult patients with refractory (17) or relapsed (32) NHL underwent HDCT with SCR between 9/90 and 9/95. The most common histology was diffuse large cell (42.8%). Initial stages were I (3), II (23), III (5) and IV (18). All patients had a history of conventional chemotherapy (median regimens 2, range 1-3), 17 (34.7%) had previous RT. Treatment consisted of conventional dose induction chemotherapy followed by high-dose intensification with cytoxan, busulfan and either ara-C or VP-16. Seven patients (14.3%) received IFRT (median dose 34.5 Gy, range 20-45 Gy) to eleven sites of persistent disease following HDCT (HDCT+IFRT). Patients treated with RT to sites of progressive disease following HDCT (salvage RT) were not included in the HDCT+IFRT group. No patient received total body irradiation (TBI). One hundred sixty four sites were identified. Sites were designated as amenable or not to IFRT and divided into those achieving a complete response to induction (IndCR) and those which did not (non-IndCR). An amenable site is defined as disease localized to either an organ or nodal chain and encompassable within a standard RT portal. Relapse sites were designated as in previous (involved) sites (present prior to HDCT) or in new (uninvolved) sites. Median followup was 19.7 months (range, 1-57.3 months). Results: The 4-year actuarial progression-free (PFS), cause-specific (CSS) and overall (OS) survivals of the entire group were 36.4%, 45.9% and 34.9%, respectively. Excluding toxic deaths, 20 (47.6%) patients

Sub-Moho Reflectors, Mantle Faults and Lithospheric Rheology

Science.gov (United States)

Brown, L. D.

2013-12-01

One of the most unexpected and dramatic observations from the early years of deep reflection profiling of the continents using multichannel CMP techniques was the existing of prominent reflections from the upper mantle. The first of these, the Flannan thrust/fault/feature, was traced by marine profiling of the continental margin offshore Britain by the BIRPS program, which soon found them to be but one of several clear sub-crustal discontinuities in that area. Subsequently, similar mantle reflectors have been observed in many areas around the world, most commonly beneath Precambrian cratonic areas. Many, but not all, of these mantle reflections appear to arise from near the overlying Moho or within the lower crust before dipping well into the mantle. Others occur as subhorizontal events at various depths with the mantle, with one suite seeming to cluster at a depth of about 75 km. The dipping events have been variously interpreted as mantle roots of crustal normal faults or the deep extension of crustal thrust faults. The most common interpretation, however, is that these dipping events are the relicts of ancient subduction zones, the stumps of now detached Benioff zones long since reclaimed by the deeper mantle. In addition to the BIRPS reflectors, the best known examples include those beneath Fennoscandia in northern Europe, the Abitibi-Grenville of eastern Canada, and the Slave Province of northwestern Canada (e.g. on the SNORCLE profile). The most recently reported example is from beneath the Sichuan Basin of central China. The preservation of these coherent, and relatively delicate appearing, features beneath older continental crust and presumably within equally old (of not older) mantle lithosphere, has profound implications for the history and rheology of the lithosphere in these areas. If they represent, as widely believe, some form of faulting with the lithosphere, they provide corollary constraints on the nature of faulting in both the lower crust and

Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML.

Science.gov (United States)

Zampini, Matteo; Tregnago, Claudia; Bisio, Valeria; Simula, Luca; Borella, Giulia; Manara, Elena; Zanon, Carlo; Zonta, Francesca; Serafin, Valentina; Accordi, Benedetta; Campello, Silvia; Buldini, Barbara; Pession, Andrea; Locatelli, Franco; Basso, Giuseppe; Pigazzi, Martina

2018-02-02

The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission. The epigenetic signature, made up of 337 differentially methylated regions, was then integrated with gene and protein expression profiles, leading to a network, where cell-to-cell adhesion and cell-motility pathways were found to be aberrantly activated in relapsed patients. We identified most of these factors as RUNX1-RUNX1T1 targets, with Ras Homolog Family Member (RHOB) overexpression being the core of this network. We documented how RHOB re-organized the actin cytoskeleton through its downstream ROCK-LIMK-COFILIN axis: this increases blast adhesion by stress fiber formation, and reduces mitochondrial apoptotic cell death after chemotherapy treatment. Altogether, our data show an epigenetic heterogeneity within t(8;21)-rearranged AML patients at diagnosis able to influence the program of the chimeric transcript, promoting blast re-emergence and progression to relapse.

Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study.

Science.gov (United States)

Cruz, Conrad Russell Y; Micklethwaite, Kenneth P; Savoldo, Barbara; Ramos, Carlos A; Lam, Sharon; Ku, Stephanie; Diouf, Oumar; Liu, Enli; Barrett, A John; Ito, Sawa; Shpall, Elizabeth J; Krance, Robert A; Kamble, Rammurti T; Carrum, George; Hosing, Chitra M; Gee, Adrian P; Mei, Zhuyong; Grilley, Bambi J; Heslop, Helen E; Rooney, Cliona M; Brenner, Malcolm K; Bollard, Catherine M; Dotti, Gianpietro

2013-10-24

Autologous T cells expressing a CD19-specific chimeric antigen receptor (CD19.CAR) are active against B-cell malignancies, but it is unknown whether allogeneic CD19.CAR T cells are safe or effective. After allogeneic hematopoietic stem cell transplantation (HSCT), infused donor-derived virus-specific T cells (VSTs) expand in vivo, persist long term, and display antiviral activity without inducing graft-vs-host disease; therefore, we determined whether donor VSTs, engineered to express CD19.CAR, retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity. We treated 8 patients with allogeneic (donor-derived) CD19.CAR-VSTs 3 months to 13 years after HSCT. There were no infusion-related toxicities. VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites. Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence, whereas 2 patients who received cells while in remission remain disease free. In 2 of 3 patients with viral reactivation, donor CD19.CAR-VSTs expanded concomitantly with VSTs. Hence CD19.CAR-VSTs display antitumor activity and, because their number may be increased in the presence of viral stimuli, earlier treatment post-HSCT (when lymphodepletion is greater and the incidence of viral infection is higher) or planned vaccination with viral antigens may enhance disease control.

Thermoconvective waves in the earth's mantle

Science.gov (United States)

Birger, B. I.

1980-06-01

The thermoconvective instability of the Earth's mantle is analysed. The mantle is modelled as an infinite horizontal layer with a free upper surface, heated from below. The creep in the mantle is supposed to be transient when strains are small. This transient creep is described by Lomnitz's law modified by Jeffreys (1958a). It is shown that disturbances, in the form of thermoconvective waves with a period of 10 8 - 10 9y and wavelength of the order 10 3 km, can propagate through the mantle without attenuation. These waves induce oscillations of the Earth's surface. The pattern of flows differs greatly from that suggested by plate tectonics. An attempt is made to give a new explanation for the linear magnetic anomalies over oceanic ridges.

Recent advances in post autologous transplantation maintenance therapies in B-cell non-Hodgkin lymphomas

Science.gov (United States)

Epperla, Narendranath; Fenske, Timothy S; Hari, Parameswaran N; Hamadani, Mehdi

2015-01-01

Lymphomas constitute the second most common indication for high dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT). The intent of administering HDT in these heterogeneous disorders varies from cure (e.g., in relapsed aggressive lymphomas) to disease control (e.g., most indolent lymphomas). Regardless of the underlying histology or remission status at transplantation, disease relapse remains the number one cause of post auto-HCT therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at prevention of post auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. In relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL), although post auto-HCT maintenance rituximab seems to be safe and feasible, it does not provide improved survival outcomes and is not recommended. The preliminary results with anti- programmed death -1 (PD-1) antibody therapy as post auto-HCT maintenance in DLBCL is promising but requires randomized validation. Similarly in follicular lymphoma, maintenance therapies including rituximab following auto-HCT should be considered investigational and offered only on a clinical trial. Rituximab maintenance results in improved progression-free survival but has not yet shown to improve overall survival in mantle cell lymphoma (MCL), but given the poor prognosis with post auto-HCT failure in MCL, maintenance rituximab can be considered on a case-by-case basis. Ongoing trials evaluating the efficacy of post auto-HCT maintenance with novel compounds (e.g., immunomodulators, PD-1 inhibitors, proteasome inhibitors and bruton’s tyrosine kinase inhibitors) will likely change the practice landscape in the near future for B cell non-Hodgkin lymphomas patients following HDT and auto-HCT. PMID:26421260

Does cement mantle thickness really matter?

OpenAIRE

Caruana, J.

2008-01-01

The thickness of the cement mantle around the femoral component of total hip replacements is a contributing factor to aseptic loosening and revision. Nevertheless, various designs of stems and surgical tooling lead to cement mantles of differing thicknesses. This thesis is concerned with variability in cement thickness around the Stanmore Hip, due to surgical approach, broach size and stem orientation, and its effects on stress and cracking in the cement. The extent to which cement mantle thi...

Relapses in Multiple Sclerosis: Definition, Pathophysiology, Features, Imitators, and Treatment

Directory of Open Access Journals (Sweden)

Serhan Sevim

2016-09-01

Full Text Available Relapse in multiple sclerosis (MS is defined as a neurologic deficit associated with an acute inflammatory demyelinating event that lasts at least 24 hours in the absence of fever and infection. Myelinoclasis and axonal transection occur in relapses. Diagnosis, prognosis, treatment, and many other features of the disease are directly related to the relapses. MS starts as the relapsing-remitting (RRMS form in 85% of patients. A large number of relapses in the first years, polysymptomatic relapses, and pyramidal system, brain stem, and spinal cord involvement are signs of a poor outcome. The average frequency of relapses is approximately one per year during the first years of RRMS. The frequency of relapses increases during systemic infections, psychological stress, and in the postpartum first 3 months. Seventy-five percent of relapses are monosymptomatic. Pseudo-relapses and paroxysmal symptoms are distinguished from relapses by their sudden onset, sudden termination, and shorter duration. Contrast enhancement is valuable in imaging, but undetectable in most relapses. The regression in the first few weeks of relapses is explained by reduction of the edema, and by remyelination in the following months. Relapses and their features are also among the main determinants of treatment. High-dose methylprednisolone and early treatment with adrenocorticotropic hormone reduce post-relapse disability and shorten the duration of relapses. Plasmapheresis is a good option for patients who do not respond to steroid treatment. Identification of relapses by patients and physicians, distinguishing them from imitators, proper evaluation, treatment when necessary, and monitoring the results are of great importance for patients with MS. The educational levels of patients and physicians regarding these parameters should be increased. Well-designed studies that evaluate the long-term effect of relapse treatment on disability are needed.

Formation and modification of chromitites in the mantle

Science.gov (United States)

Arai, Shoji; Miura, Makoto

2016-11-01

Podiform chromitites have long supplied us with unrivaled information on various mantle processes, including the peridotite-magma reaction, deep-seated magmatic evolution, and mantle dynamics. The recent discovery of ultrahigh-pressure (UHP) chromitites not only sheds light on a different aspect of podiform chromitites, but also changes our understanding of the whole picture of podiform chromitite genesis. In addition, new evidence was recently presented for hydrothermal modification/formation chromite/chromitite in the mantle, which is a classical but innovative issue. In this context, we present here an urgently needed comprehensive review of podiform chromitites in the upper mantle. Wall-rock control on podiform chromitite genesis demonstrates that the peridotite-magma reaction at the upper mantle condition is an indispensable process. We may need a large system in the mantle, far larger than the size of outcrops or mining areas, to fulfill the Cr budget requirement for podiform chromitite genesis. The peridotite-magma reaction over a large area may form a melt enriched with Na and other incompatible elements, which mixes with a less evolved magma supplied from the depth to create chromite-oversaturated magma. The incompatible-element-rich magma trapped by the chromite mainly precipitates pargasite and aspidolite (Na analogue of phlogopite), which are stable under upper mantle conditions. Moderately depleted harzburgites, which contain chromite with a moderate Cr# (0.4-0.6) and a small amount of clinopyroxene, are the best reactants for the chromitite-forming reaction, and are the best hosts for podiform chromitites. Arc-type chromitites are dominant in ophiolites, but some are of the mid-ocean ridge type; chromitites may be common beneath the ocean floor, although it has not yet been explored for chromitite. The low-pressure (upper mantle) igneous chromitites were conveyed through mantle convection or subduction down to the mantle transition zone to form

Sublithospheric flows in the mantle

Science.gov (United States)

Trifonov, V. G.; Sokolov, S. Yu.

2017-11-01

The estimated rates of upper mantle sublithospheric flows in the Hawaii-Emperor Range and Ethiopia-Arabia-Caucasus systems are reported. In the Hawaii-Emperor Range system, calculation is based on motion of the asthenospheric flow and the plate moved by it over the branch of the Central Pacific plume. The travel rate has been determined based on the position of variably aged volcanoes (up to 76 Ma) with respect to the active Kilauea Volcano. As for the Ethiopia-Arabia-Caucasus system, the age of volcanic eruptions (55-2.8 Ma) has been used to estimate the asthenospheric flow from the Ethiopian-Afar superplume in the northern bearing lines. Both systems are characterized by variations in a rate of the upper mantle flows in different epochs from 4 to 12 cm/yr, about 8 cm/yr on average. Analysis of the global seismic tomographic data has made it possible to reveal rock volumes with higher seismic wave velocities under ancient cratons; rocks reach a depth of more than 2000 km and are interpreted as detached fragments of the thickened continental lithosphere. Such volumes on both sides of the Atlantic Ocean were submerged at an average velocity of 0.9-1.0 cm/yr along with its opening. The estimated rates of the mantle flows clarify the deformation properties of the mantle and regulate the numerical models of mantle convection.

Regional homogeneity changes between heroin relapse and non-relapse patients under methadone maintenance treatment: a resting-state fMRI study

OpenAIRE

Chang, Haifeng; Li, Wei; Li, Qiang; Chen, Jiajie; Zhu, Jia; Ye, Jianjun; Liu, Jierong; Li, Zhe; Li, Yongbin; Shi, Ming; Wang, Yarong; Wang, Wei

2016-01-01

Background Methadone maintenance treatment (MMT) is recognized as one of the most effective treatments for heroin addiction but its effect is dimmed by the high incidence of heroin relapse. However, underlying neurobiology mechanism of heroin relapse under MMT is still largely unknown. Here, we took advantage of a resting-state fMRI technique by analysis of regional homogeneity (ReHo), and tried to explore the difference of brain function between heroin relapsers and non-relapsers in MMT. Met...

The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking.

Science.gov (United States)

Nair, Sunila G; Adams-Deutsch, Tristan; Epstein, David H; Shaham, Yavin

2009-09-01

Relapse to old, unhealthy eating habits is a major problem in human dietary treatments. The mechanisms underlying this relapse are unknown. Surprisingly, until recently this clinical problem has not been systematically studied in animal models. Here, we review results from recent studies in which a reinstatement model (commonly used to study relapse to abused drugs) was employed to characterize the effect of pharmacological agents on relapse to food seeking induced by either food priming (non-contingent exposure to small amounts of food), cues previously associated with food, or injections of the pharmacological stressor yohimbine. We also address methodological issues related to the use of the reinstatement model to study relapse to food seeking, similarities and differences in mechanisms underlying reinstatement of food seeking versus drug seeking, and the degree to which the reinstatement procedure provides a suitable model for studying relapse in humans. We conclude by discussing implications for medication development and future research. We offer three tentative conclusions: (1)The neuronal mechanisms of food-priming- and cue-induced reinstatement are likely different from those of reinstatement induced by the pharmacological stressor yohimbine. (2)The neuronal mechanisms of reinstatement of food seeking are possibly different from those of ongoing food-reinforced operant responding. (3)The neuronal mechanisms underlying reinstatement of food seeking overlap to some degree with those of reinstatement of drug seeking.

Characteristics of Vertical Mantle Heat Exchangers for Solar Water Heaters

DEFF Research Database (Denmark)

Shah, Louise Jivan; Morrison, G.L.; Behnia, M.

1999-01-01

- The flow structure in vertical mantle heat exchangers was investigated using a full-scale tank designed to facilitate flow visualisation. The flow structure and velocities in the mantle were measured using a particle Image Velocimetry (PIV) system. A CFD simulation model of vertical mantle heat...... exchangers was also developed for detailed evaluation of the heat flux distribution over the mantle surface. Both the experimental and simulation results indicate that distribution of the flow around the mantle gap is governed by buoyancy driven recirculation in the mantle. The operation of the mantle...

MODELLING MANTLE TANKS FOR SDHW SYSTEMS USING PIV AND CFD

DEFF Research Database (Denmark)

Shah, Louise Jivan; Morrison, G.L.; Behnia, Masud

1999-01-01

Characteristics of vertical mantle heat exchanger tanks for SDHW systems have been investigated experimentally and theoretically using particle image velocimetry (PIV) and CFD modelling. A glass model of a mantle heat exchanger tank was constructed so that the flow distribution in the mantle could...... be studied using the PIV test facility. Two transient three-dimensional CFD-models of the glass model mantle tank were developed using the CFD-programmes CFX and FLUENT.The experimental results illustrate that the mantle flow structure in the mantle is complicated and the distribution of flow in the mantle...

Clinical Options in Relapsed or Refractory Hodgkin Lymphoma: An Updated Review

Directory of Open Access Journals (Sweden)

Roberta Fedele

2015-01-01

Full Text Available Hodgkin lymphoma (HL is a potentially curable lymphoma, and modern therapy is expected to successfully cure more than 80% of the patients. Second-line salvage high-dose chemotherapy and autologous stem cell transplantation (auto-SCT have an established role in the management of refractory and relapsed HL, leading to long-lasting responses in approximately 50% of relapsed patients and a minority of refractory patients. Patients progressing after intensive treatments, such as auto-SCT, have a very poor outcome. Allogeneic SCT represents the only strategy with a curative potential for these patients; however, its role is controversial. Based on recent knowledge of HL pathology, biology, and immunology, antibody-drug conjugates targeting CD30, small molecule inhibitors of cell signaling, and antibodies that inhibit immune checkpoints are currently explored. This review will discuss the clinical results regarding auto-SCT and allo-SCT as well as the current role of emerging new treatment strategies.

Relapsing Polychondritis Following Alopecia Areata

Directory of Open Access Journals (Sweden)

John C. Starr

2010-01-01

Full Text Available A case of alopecia areata followed by relapsing polychondritis is presented. Similar cases from the literature are reviewed and speculation about the relationship of these diseases is offered. Although the occurrence of these diseases together could be coincidental, an association seems immunologically plausible. Thus, relapsing polychondritis might be an unusual systemic manifestation of alopecia areata.

Plerixafor and Filgrastim For Mobilization of Donor Peripheral Blood Stem Cells Before A Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

Science.gov (United States)

2017-06-26

Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

Salvage chemotherapy of gemcitabine, dexamethasone, and cisplatin (GDP) for patients with relapsed or refractory peripheral T-cell lymphomas: a consortium for improving survival of lymphoma (CISL) trial.

Science.gov (United States)

Park, Byeong-Bae; Kim, Won Seog; Suh, Cheolwon; Shin, Dong-Yeop; Kim, Jeong-A; Kim, Hoon-Gu; Lee, Won Sik

2015-11-01

There is no standard salvage chemotherapy for relapsed or refractory peripheral T-cell lymphomas (PTCLs). Gemcitabine combined with cisplatin has been known as an effective regimen for lymphoma treatment in the salvage setting. We investigated the efficacy and toxicity of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory PTCLs in search of a more effective and less toxic therapy. Patients with relapsed or refractory PTCLs with more than one previous regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4, and cisplatin 70 mg/m(2) i.v. on day 1, and then every 21 days. Patients could proceed to autologous stem cell transplantation (ASCT) after four cycles of GDP or receive up to six treatment cycles. Twenty-five eligible patients were evaluated for toxicity and response. The diagnoses of participants included 14 cases of PTCL-not otherwise specified (NOS) (56 %) and four cases of angioimmunoblastic T-cell lymphoma (16 %) among others. The median age of the patients was 59 years (range 20-75 years). After treatments with GDP, which delivered a median of four GDP cycles, there were 12 patients with complete responses (CR; 48 %) and six with partial responses (PR; 24 %). The overall response rate (RR) was 72 %. Four patients preceded to ASCT, and three patients finally achieved CR. The median progression free survival was 9.3 months (95 % confidence interval (CI); 4.1-14.6) with a median follow-up duration of 27.1 months. In a total of 86 cycles of GDP, grade 3 or 4 neutropenia and thrombocytopenia occurred in 16.3 and 12.8 % of cycles, respectively. Three patients (3.3 %) experienced febrile neutropenia. GDP is a highly effective and optimal salvage regimen for relapsed or refractory PTCLs and can be administered with acceptable toxicity.

Second allogeneic hematopoietic SCT for relapsed ALL in children.

Science.gov (United States)

Kato, M; Horikoshi, Y; Okamoto, Y; Takahashi, Y; Hasegawa, D; Koh, K; Takita, J; Inoue, M; Kigasawa, H; Ogawa, A; Sasahara, Y; Kawa, K; Yabe, H; Sakamaki, H; Suzuki, R; Kato, K

2012-10-01

A second SCT is generally accepted as the only potentially curative approach for ALL patients that relapse after SCT, but the role of second SCT for pediatric ALL is not fully understood. We performed a retrospective analysis of 171 pediatric patients who received a second allo-SCT for relapsed ALL after allo-SCT. OS at 2 years was 29.4 ± 3.7%, the cumulative incidence of relapse was 44.1 ± 4.0% and non-relapse mortality was 18.8 ± 3.5%. Relapse occurred faster after the second SCT than after the first SCT (117 days vs 164 days, P=0.04). Younger age (9 years or less), late relapse (180 days or more after first SCT), CR at the second SCT, and myeloablative conditioning were found to be related to longer survival. Neither acute GVHD nor the type of donor influenced the outcome of second SCT. Multivariate analysis showed that younger age and late relapse were associated with better outcomes. Our analysis suggests that second SCT for relapsed pediatric ALL is an appropriate treatment option for patients that have achieved CR, which is associated with late relapse after the first SCT.

The ruthenium isotopic composition of the oceanic mantle

Science.gov (United States)

Bermingham, K. R.; Walker, R. J.

2017-09-01

The approximately chondritic relative, and comparatively high absolute mantle abundances of the highly siderophile elements (HSE), suggest that their concentrations in the bulk silicate Earth were primarily established during a final ∼0.5 to 1% of ;late accretion; to the mantle, following the cessation of core segregation. Consequently, the isotopic composition of the HSE Ru in the mantle reflects an amalgamation of the isotopic compositions of late accretionary contributions to the silicate portion of the Earth. Among cosmochemical materials, Ru is characterized by considerable mass-independent isotopic variability, making it a powerful genetic tracer of Earth's late accretionary building blocks. To define the Ru isotopic composition of the oceanic mantle, the largest portion of the accessible mantle, we report Ru isotopic data for materials from one Archean and seven Phanerozoic oceanic mantle domains. A sample from a continental lithospheric mantle domain is also examined. All samples have identical Ru isotopic compositions, within analytical uncertainties, indicating that Ru isotopes are well mixed in the oceanic mantle, defining a μ100Ru value of 1.2 ± 7.2 (2SD). The only known meteorites with the same Ru isotopic composition are enstatite chondrites and, when corrected for the effects of cosmic ray exposure, members of the Main Group and sLL subgroup of the IAB iron meteorite complex which have a collective CRE corrected μ100Ru value of 0.9 ± 3.0. This suggests that materials from the region(s) of the solar nebula sampled by these meteorites likely contributed the dominant portion of late accreted materials to Earth's mantle.

Mantle Circulation Models with variational data assimilation: Inferring past mantle flow and structure from plate motion histories and seismic tomography

Science.gov (United States)

Bunge, H.; Hagelberg, C.; Travis, B.

2002-12-01

EarthScope will deliver data on structure and dynamics of continental North America and the underlying mantle on an unprecedented scale. Indeed, the scope of EarthScope makes its mission comparable to the large remote sensing efforts that are transforming the oceanographic and atmospheric sciences today. Arguably the main impact of new solid Earth observing systems is to transform our use of geodynamic models increasingly from conditions that are data poor to an environment that is data rich. Oceanographers and meteorologists already have made substantial progress in adapting to this environment, by developing new approaches of interpreting oceanographic and atmospheric data objectively through data assimilation methods in their models. However, a similarly rigorous theoretical framework for merging EarthScope derived solid Earth data with geodynamic models has yet to be devised. Here we explore the feasibility of data assimilation in mantle convection studies in an attempt to fit global geodynamic model calculations explicitly to tomographic and tectonic constraints. This is an inverse problem not quite unlike the inverse problem of finding optimal seismic velocity structures faced by seismologists. We derive the generalized inverse of mantle convection from a variational approach and present the adjoint equations of mantle flow. The substantial computational burden associated with solutions to the generalized inverse problem of mantle convection is made feasible using a highly efficient finite element approach based on the 3-D spherical fully parallelized mantle dynamics code TERRA, implemented on a cost-effective topical PC-cluster (geowulf) dedicated specifically to large-scale geophysical simulations. This dedicated geophysical modeling computer allows us to investigate global inverse convection problems having a spatial discretization of less than 50 km throughout the mantle. We present a synthetic high-resolution modeling experiment to demonstrate that mid

A cytogenetic model predicts relapse risk and survival in patients with acute myeloid leukemia undergoing hematopoietic stem cell transplantation in morphologic complete remission.

Science.gov (United States)

Rashidi, Armin; Cashen, Amanda F

2015-01-01

Up to 30% of patients with acute myeloid leukemia (AML) and abnormal cytogenetics have persistent cytogenetic abnormalities (pCytAbnl) at morphologic complete remission (mCR). We hypothesized that the prognostic significance of pCytAbnl in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in mCR varies with cytogenetic risk group. We analyzed the data on 118 patients with AML and abnormal cytogenetics who underwent HSCT in mCR, and developed a risk stratification model based on pCytAbnl and cytogenetic risk group. The model distinguished three groups of patients (Pcytogenetics (n=25) had the shortest median time to relapse (TTR; 5 months), relapse-free survival (RFS; 3 months), and overall survival (OS; 7 months). The group with favorable/intermediate risk cytogenetics and without pCytAbnl (n=43) had the longest median TTR (not reached), RFS (57 months), and OS (57 months). The group with pCytAbnl and favorable/intermediate risk cytogenetics, or, without pCytAbnl but with unfavorable risk cytogenetics (n=50) experienced intermediate TTR (18 months), RFS (9 months), and OS (18 months). In conclusion, a cytogenetic risk model identifies patients with AML in mCR with distinct rates of relapse and survival following HSCT. Copyright © 2014 Elsevier Ltd. All rights reserved.

The basal part of the Oman ophiolitic mantle: a fossil Mantle Wedge?

Science.gov (United States)

Prigent, Cécile; Guillot, Stéphane; Agard, Philippe; Godard, Marguerite; Chauvet, Alain; Dubacq, Benoit; Monié, Patrick; Yamato, Philippe

2014-05-01

Although the Oman ophiolite is classically regarded as being the direct analog of oceanic lithosphere created at fast spreading ridges, the geodynamic context of its formation is still highly debated. The other alternative end-member model suggests that this ophiolite entirely formed in a supra-subduction zone setting. Fluids involved in the hydration of the oceanic lithosphere and in the presence of a secondary boninitic and andesitic volcanism may provide a way to discriminate between these two interpretations: are they descending near-axis hydrothermal fluxes (first model) or ascending from a subducting slab (second model)? We herein focus on the base of the ophiolitic mantle in order to characterize the origin of fluids and decipher hydration processes. Samples were taken along hecto- to kilometre-long sections across the basal banded unit directly overlying the amphibolitic/granulitic metamorphic sole. We carried out a petrological, structural and geochemical study on these rocks and their constitutive minerals. Our results show that, unlike the generally refractory character of Oman harzburgites, all the basal mantle rocks display secondary crystallization of clinopyroxene and amphibole through metasomatic processes. The microstructures and the chronology of these secondary mineralizations (clinopyroxene, pargasitic amphibole, antigorite and then lizardite/chrysotile) suggest that these basal rocks have been affected by cooling from mantle temperatures (serpentines (B, Sr, Rb, Ba, As), are consistent with amphibolite-derived fluids (Ishikawa et al., 2005) and cannot be easily explained by other sources. Based on these observations, we propose a geodynamic model in which intense and continuous metasomatism of the cooling base of the ophiolitic mantle is due to the release of fluids coming from the progressive dehydration of underlying amphibolitic rocks. This process is compatible with the progressive subduction of the Arabian margin during the Upper

Atlas of the underworld: Slab remnants in the mantle, their sinking history, and a new outlook on lower mantle viscosity

Science.gov (United States)

van der Meer, Douwe G.; van Hinsbergen, Douwe J. J.; Spakman, Wim

2018-01-01

Across the entire mantle we interpret 94 positive seismic wave-speed anomalies as subducted lithosphere and associate these slabs with their geological record. We document this as the Atlas of the Underworld, also accessible online at www.atlas-of-the-underworld.org, a compilation comprising subduction systems active in the past 300 Myr. Deeper slabs are correlated to older geological records, assuming no relative horizontal motions between adjacent slabs following break-off, using knowledge of global plate circuits, but without assuming a mantle reference frame. The longest actively subducting slabs identified reach the depth of 2500 km and some slabs have impinged on Large Low Shear Velocity Provinces in the deepest mantle. Anomously fast sinking of some slabs occurs in regions affected by long-term plume rising. We conclude that slab remnants eventually sink from the upper mantle to the core-mantle boundary. The range in subduction-age versus - depth in the lower mantle is largely inherited from the upper mantle history of subduction. We find a significant depth variation in average sinking speed of slabs. At the top of the lower mantle average slab sinking speeds are between 10 and 40 mm/yr, followed by a deceleration to 10-15 mm/yr down to depths around 1600-1700 km. In this interval, in situ time-stationary sinking rates suggest deceleration from 20 to 30 mm/yr to 4-8 mm/yr, increasing to 12-15 mm/yr below 2000 km. This corroborates the existence of a slab deceleration zone but we do not observe long-term (> 60 My) slab stagnation, excluding long-term stagnation due to compositional effects. Conversion of slab sinking profiles to viscosity profiles shows the general trend that mantle viscosity increases in the slab deceleration zone below which viscosity slowly decreases in the deep mantle. This is at variance with most published viscosity profiles that are derived from different observations, but agrees qualitatively with recent viscosity profiles suggested

Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome.

Science.gov (United States)

Scheer, Carina; Kratz, Christian; Witt, Olaf; Creutzig, Ursula; Reinhardt, Dirk; Klusmann, Jan-Henning

2016-09-01

Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS. © 2016 Wiley Periodicals, Inc.

A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma – the STORM trial

International Nuclear Information System (INIS)

Witzens-Harig, Mathias; Memmer, Marie Luise; Dreyling, Martin; Hess, Georg

2013-01-01

The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the rituximab era however, this treatment approach has shown only limited benefit. In particular, patients relapsing after rituximab-containing primary treatment have an adverse prognosis, especially if this occurs within the first year after therapy or if the disease is primarily refractory. Therefore there is an ultimate need for improved salvage treatment approaches. The STORM study is a prospective, multicentre phase I/II study to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to the standard therapy rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. The primary objective of the phase I of the trial is to establish the maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP. The secondary objective is to demonstrate that stem cells can be mobilized during this regimen in patients scheduled to proceed to high dose therapy. In phase II, the previously established maximum tolerated dose of temsirolimus will be used. The primary objective is to evaluate the overall response rate (ORR) in patients with relapsed DLBCL. The secondary objective is to evaluate progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by an analysis of lymphoma subtypes determined by gene expression analysis (GEP). The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. It also might identify predictive markers for this treatment modality. ClinicalTrials.gov http

Lapse and relapse following inpatient treatment of opiate dependence.

LENUS (Irish Health Repository)

Smyth, B P

2010-06-01

We conducted a prospective follow-up study of consecutive opiate dependent patients admitted to a residential addiction treatment service for detoxification. We measured the rate of relapse following discharge, and sought to identify factors that were associated with early relapse (i.e., a return to daily opiate use). Follow-up interviews were conducted with 109 patients, of whom, 99 (91%) reported a relapse. The initial relapse occurred within one week in 64 (59%) cases. Multivariate survival analysis revealed that earlier relapse was significantly predicted by younger age, greater heroin use prior to treatment, history of injecting, and a failure to enter aftercare. Unexpectedly, those who were in a relationship with an opiate user had significantly delayed relapse. Those who completed the entire six-week inpatient treatment programme also had a significantly delayed relapse. In order to reduce relapse and the associated increased risk of fatal overdose, services providing residential opiate detoxification should prepare people for admission, strive to retain them in treatment for the full admission period and actively support their entry into planned aftercare in order to improve outcome.

Multiple Sclerosis Relapses: Epidemiology, Outcomes and Management. A Systematic Review.

Science.gov (United States)

Kalincik, Tomas

2015-01-01

Relapses (episodic exacerbations of neurological signs or symptoms) are a defining feature of relapsing-remitting multiple sclerosis (MS), the most prevalent MS phenotype. While their diagnostic value relates predominantly to the definition of clinically definite MS, their prognostic value is determined by their relatively high associated risk of incomplete remission resulting in residual disability. The mechanisms governing a relapse incidence are unknown, but numerous modifiers of relapse risk have been described, including demographic and clinical characteristics, many of which represent opportunities for improved disease management. Also relapse phenotypes have been associated with patient and disease characteristics and an individual predisposition to certain phenotypic presentations may imply individual neuroanatomical disease patterns. While immunomodulatory therapies and corticosteroids represent the mainstay of relapse prevention and acute management, respectively, their effect has only been partial and further search for more efficient relapse therapies is warranted. Other areas of research include pathophysiology and determinants of relapse incidence, recurrence and phenotypes, including the characteristics of the relapsing and non-relapsing multiple sclerosis variants and their responsiveness to therapies. © 2015 S. Karger AG, Basel.

Preoperative [18F]-fluorodeoxyglucose positron emission tomography standardized uptake value of neck lymph nodes may aid in selecting patients with oral cavity squamous cell carcinoma for salvage therapy after relapse

International Nuclear Information System (INIS)

Liao, Chun-Ta; Huang, Shiang-Fu; Chen, I. How; Chang, Joseph Tung-Chieh; Wang, Hung-Ming; Ng, Shu-Hang; Hsueh, Chuen; Lee, Li-Yu.; Lin, Chih-Hung; Cheng, Ann-Joy; Yen, Tzu-Chen

2009-01-01

Relapse of tumours in patients with oral cavity squamous cell carcinoma (OSCC) is associated with a dismal outcome. In this prospective study, we sought to investigate the clinical significance of the preoperative maximal standardized uptake value (SUVmax) at the neck lymph nodes in selecting patients with OSCC for salvage therapy after relapse. Between 2002 and 2007, 108 patients with early relapse of OSCC (n=75) or late relapse of OSCC (n=33) were identified. Salvage therapy was performed in 47 patients. All patients underwent 2-deoxy-2[ 18 F]-fluoro-d-glucose positron emission tomography during the 2 weeks before surgery and neck dissection. All patients were followed for 12 months or more after surgery or until death. The optimal cut-off value for the neck lymph node SUVmax (SUVnodal-max) was selected according to the 5-year disease-specific survival (DSS) rate. Independent risk factors were identified by Cox regression analysis. The mean follow-up for all patients was 20.3 months (41.1 months for surviving patients). In the early relapse group, several prognostic factors were identified in univariate and multivariate analyses, including a SUVnodal-max value of ≥4.2. A scoring system based on univariate analysis was formulated. Patients with a score of 0 had a better 5-year DSS than those with scores of 1 or higher (58% vs. 5%, p=0.0003). In patients with late relapse, a SUVnodal-max value of ≥4.2 had the highest prognostic value for predicting the 5-year DSS (45% vs. 0%, p=0.0005). Among patients with relapsed OSCC, the SUVnodal-max value may aid in selecting patients for salvage therapy. (orig.)

A classification framework for drug relapse prediction | Salleh ...

African Journals Online (AJOL)

mining algorithms, Artificial Intelligence Neural Network (ANN) is one of the best algorithms to predict relapse among drug addicts. This may help the rehabilitation center to predict relapse individually and the prediction result is hoped to prevent drug addicts from relapse. Keywords: classification; artificial neural network; ...

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries

DEFF Research Database (Denmark)

Oskarsson, Trausti; Söderhäll, Stefan; Arvidson, Johan

2016-01-01

Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic...... leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were...

Temperature Profile of the Upper Mantle

International Nuclear Information System (INIS)

Anderson, O.L.

1980-01-01

Following the procedure outlined by Magnitsky [1971], thermal profiles of the upper mantle are computed by deriving the thermal gradient from the seismic data given as dv/sub s//drho used along with the values of (dv/sub s//dT9/sub p/ and (dv/sub s//dP)/sub T/ of selected minerals, measured at high temperature. The resulting values of dT/dZ are integrated from 380 km upward toward the surface, where the integrating constant is taken from Akagi and Akimoto's work, T=1400 0 C at 380 km. The resulting geotherms for minerals are used to derive geotherms for an eclogite mantle and a lherzolite mantle, with and without partial melting in the low-velocity zone. The geotherms are all subadiabatic, and some are virtually isothermal in the upper mantle. Some are characterized by a large thermal hump at the lithosphere boundary

Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.

Science.gov (United States)

Paroni, Moira; Maltese, Virginia; De Simone, Marco; Ranzani, Valeria; Larghi, Paola; Fenoglio, Chiara; Pietroboni, Anna M; De Riz, Milena A; Crosti, Maria C; Maglie, Stefano; Moro, Monica; Caprioli, Flavio; Rossi, Riccardo; Rossetti, Grazisa; Galimberti, Daniela; Pagani, Massimiliano; Scarpini, Elio; Abrignani, Sergio; Geginat, Jens

2017-09-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is caused by autoreactive T cells and associated with viral infections. However, the phenotype of pathogenic T cells in peripheral blood remains to be defined, and how viruses promote MS is debated. We aimed to identify and characterize potentially pathogenic autoreactive T cells, as well as protective antiviral T cells, in patients with MS. We analyzed CD4 + helper T-cell subsets from peripheral blood or cerebrospinal fluid for cytokine production, gene expression, plasticity, homing potentials, and their reactivity to self-antigens and viral antigens in healthy subjects and patients with MS. Moreover, we monitored their frequencies in untreated and fingolimod- or natalizumab-treated patients with MS. T H 1/T H 17 central memory (T H 1/T H 17 CM ) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. T H 1/T H 17 CM cells were closely related to conventional T H 17 cells but had more pathogenic features. In particular, they could shuttle between lymph nodes and the CNS and produced encephalitogenic cytokines. The cerebrospinal fluid of patients with active MS was enriched for CXCL10 and contained mainly CXCR3-expressing T H 1 and T H 1/T H 17 subsets. However, while T H 1 cells responded consistently to viruses, T H 1/T H 17 CM cells reacted strongly with John Cunningham virus in healthy subjects but responded instead to myelin-derived self-antigens in patients with MS. Fingolimod and natalizumab therapies efficiently targeted autoreactive T H 1/T H 17 CM cells but also blocked virus-specific T H 1 cells. We propose that autoreactive T H 1/T H 17 CM cells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas T H 1 cells perform immune surveillance. Thus the selective targeting of T H 1/T H 17 cells could inhibit relapses without causing John

Tomography of core-mantle boundary and lowermost mantle coupled by geodynamics: joint models of shear and compressional velocity

Directory of Open Access Journals (Sweden)

Gaia Soldati

2015-03-01

Full Text Available We conduct joint tomographic inversions of P and S travel time observations to obtain models of delta v_P  and delta v_S in the entire mantle. We adopt a recently published method which takes into account the geodynamic coupling between mantle heterogeneity and core-mantle boundary (CMB topography by viscous flow, where sensitivity of the seismic travel times to the CMB is accounted for implicitly in the inversion (i.e. the CMB topography is not explicitly inverted for. The seismic maps of the Earth's mantle and CMB topography that we derive can explain the inverted seismic data while being physically consistent with each other. The approach involved scaling P-wave velocity (more sensitive to the CMB to density anomalies, in the assumption that mantle heterogeneity has a purely thermal origin, so that velocity and density heterogeneity are proportional to one another. On the other hand, it has sometimes been suggested that S-wave velocity might be more directly sensitive to temperature, while P heterogeneity is more strongly influenced by chemical composition. In the present study, we use only S-, and not P-velocity, to estimate density heterogeneity through linear scaling, and hence the sensitivity of core-reflected P phases to mantle structure. Regardless of whether density is more closely related to P- or S-velocity, we think it is worthwhile to explore both scaling approaches in our efforts to explain seismic data. The similarity of the results presented in this study to those obtained by scaling P-velocity to density suggests that compositional anomaly has a limited impact on viscous flow in the deep mantle.

OPTIMISATION OF MANTLE TANKS FOR LOW FLOW SOLAR HEATING SYSTEMS

DEFF Research Database (Denmark)

Shah, Louise Jivan; Furbo, Simon

1996-01-01

A model, describing the heat transfer coefficients in the mantle of a mantle tank has been developed. The model is validated by means of measurements with varying operational conditions for different designed mantle tanks. The model has been implemented in an existing detailed mathematical...... with the programme and by means of tests of three SDHW systems with different designed mantle tanks. Based on the investigations design rules for mantle tanks are proposed. The model, describing the heat transfer coefficients in the mantle is approximate. In addition, the measurements have revealed...... that a temperature stratification in the hot water tank, above the mantle is built up. This phenomenon may be important, but it is not taken into calculation in the programme. Therefore, theoretical and practical work is continuing in order to make a more precise model for the whole mantle tank....

Mantle structure and tectonic history of SE Asia

Science.gov (United States)

Hall, Robert; Spakman, Wim

2015-09-01

Seismic travel-time tomography of the mantle under SE Asia reveals patterns of subduction-related seismic P-wave velocity anomalies that are of great value in helping to understand the region's tectonic development. We discuss tomography and tectonic interpretations of an area centred on Indonesia and including Malaysia, parts of the Philippines, New Guinea and northern Australia. We begin with an explanation of seismic tomography and causes of velocity anomalies in the mantle, and discuss assessment of model quality for tomographic models created from P-wave travel times. We then introduce the global P-wave velocity anomaly model UU-P07 and the tectonic model used in this paper and give an overview of previous interpretations of mantle structure. The slab-related velocity anomalies we identify in the upper and lower mantle based on the UU-P07 model are interpreted in terms of the tectonic model and illustrated with figures and movies. Finally, we discuss where tomographic and tectonic models for SE Asia converge or diverge, and identify the most important conclusions concerning the history of the region. The tomographic images of the mantle record subduction beneath the SE Asian region to depths of approximately 1600 km. In the upper mantle anomalies mainly record subduction during the last 10 to 25 Ma, depending on the region considered. We interpret a vertical slab tear crossing the entire upper mantle north of west Sumatra where there is a strong lateral kink in slab morphology, slab holes between c.200-400 km below East Java and Sumbawa, and offer a new three-slab explanation for subduction in the North Sulawesi region. There is a different structure in the lower mantle compared to the upper mantle and the deep structure changes from west to east. What was imaged in earlier models as a broad and deep anomaly below SE Asia has a clear internal structure and we argue that many features can be identified as older subduction zones. We identify remnants of slabs

Role of mantle flow in Nubia-Somalia plate divergence

Science.gov (United States)

Stamps, D. S.; Iaffaldano, G.; Calais, E.

2015-01-01

Present-day continental extension along the East African Rift System (EARS) has often been attributed to diverging sublithospheric mantle flow associated with the African Superplume. This implies a degree of viscous coupling between mantle and lithosphere that remains poorly constrained. Recent advances in estimating present-day opening rates along the EARS from geodesy offer an opportunity to address this issue with geodynamic modeling of the mantle-lithosphere system. Here we use numerical models of the global mantle-plates coupled system to test the role of present-day mantle flow in Nubia-Somalia plate divergence across the EARS. The scenario yielding the best fit to geodetic observations is one where torques associated with gradients of gravitational potential energy stored in the African highlands are resisted by weak continental faults and mantle basal drag. These results suggest that shear tractions from diverging mantle flow play a minor role in present-day Nubia-Somalia divergence.

Hf isotope evidence for a hidden mantle reservoir

DEFF Research Database (Denmark)

Bizzarro, Martin; Simonetti, A.; Stevenson, R.K.

2002-01-01

High-precision Hf isotopic analyses and U-Pb ages of carbonatites and kimberlites from Greenland and eastern North America, including Earth's oldest known carbonatite (3 Ga), indicate derivation from an enriched mantle source. This previously unidentified mantle reservoir-marked by an unradiogenic...... Hf isotopic composition and preserved in the deep mantle for at least 3 b.y.-may account for the mass imbalance in Earth's Hf-Nd budget. The Hf isotopic data presented here support a common mantle source region and genetic link between carbonatite and some oceanic-island basalt volcanoes....

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

Science.gov (United States)

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

2013-01-01

Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19+CD5+ cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738. PMID:23940282

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

Science.gov (United States)

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

2013-10-03

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

The Earth's heterogeneous mantle a geophysical, geodynamical, and geochemical perspective

CERN Document Server

Khan, Amir

2015-01-01

This book highlights and discusses recent developments that have contributed to an improved understanding of observed mantle heterogeneities and their relation to the thermo-chemical state of Earth's mantle, which ultimately holds the key to unlocking the secrets of the evolution of our planet. This series of topical reviews and original contributions address 4 themes. Theme 1 covers topics in geophysics, including global and regional seismic tomography, electrical conductivity and seismic imaging of mantle discontinuities and heterogeneities in the upper mantle, transition zone and lower mantle. Theme 2 addresses geochemical views of the mantle including lithospheric evolution from analysis of mantle xenoliths, composition of the deep Earth and the effect of water on subduction-zone processes. Theme 3 discusses geodynamical perspectives on the global thermo-chemical structure of the deep mantle. Theme 4 covers application of mineral physics data and phase equilibrium computations to infer the regional-scale ...

SEM investigation of incandescent lamp mantle structure on durability

International Nuclear Information System (INIS)

Gerneke, D.; Lang, C.

2002-01-01

Full text: The incandescent mantle as used on pressure and non-pressure liquid fuel lamps has been in use for over 100 years. What remains unexplained is the way in which the resistance to mechanical shock and the decline in tensile strength with usage is experienced. It has been suggested that to improve durability it is necessary to continuously burn a new mantle for the first two to three hours. The known factors in mantle durability and mechanical strength are chemical composition and fabric weave. This study was undertaken to investigate the effects of burning time and temperature on thorium oxide mantles. The operating temperature of mantles on a range of kerosene pressure lamps was measured and found to be between 800 and 1100 deg C. Heat treatments of thorium based Coleman mantles were carried out in a laboratory furnace within these ranges of temperatures for periods ranging from 2 minutes to 2 hours. The mantles were then viewed in a LEO S440 analytical SEM. Results at 800 deg C show a distinct change in surface morphology with increasing exposure time. At the shorter times (2-5 minutes) the surface was relatively smooth. With increased time periods (15 - 120 minutes) the surface was observed to have a large lumpy structure. At 1100 deg C the difference in surface morphology was not apparent between the shortest and longest times. The surface appears much smoother and no lumpy structure was observed. This suggests that when a mantle is operated at the higher temperature of 1100 deg C the structure of the Thorium oxide is quickly transformed into the known stronger amorphous form. This is taken as the observed smooth structure seen in the SEM images of the 1100 deg C samples. Thus the mantle is expected to be more resistant to mechanical shock and have increased durability. Practical field test results confirm these observations. The mantle on a lamp that is operating efficiently, burns brightly, will far outlast a mantle on an inefficient lamp which bums

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.

Science.gov (United States)

Ryan, Christine E; Sahaf, Bita; Logan, Aaron C; O'Brien, Susan; Byrd, John C; Hillmen, Peter; Brown, Jennifer R; Dyer, Martin J S; Mato, Anthony R; Keating, Michael J; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R; Styles, Lori; Coutre, Steven E; Miklos, David B

2016-12-22

Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. © 2016 by The American Society of Hematology.

Rapid Treatment of Leukostasis in Leukemic Mantle Cell Lymphoma Using Therapeutic Leukapheresis: A Case Report

Directory of Open Access Journals (Sweden)

Xuan Duc Nguyen

2011-01-01

Full Text Available We describe a case of severe leukocytosis caused by leukemic mantle cell lymphoma (MCL, complicated by leukostasis with myocardial infarction in which leukapheresis was used in the initial management. A 73-year-old male presented to the emergency department because of fatigue and thoracic pain. Blood count revealed 630 × 109/L WBC (white blood cells. The electrocardiogram showed ST-elevation with an increase of troponin and creatinine kinase. The diagnosis was ST-elevation myocardial infarction (STEMI induced and complicated by leukostasis. Immunophenotyping, morphology, cytogenetic and fluorescence-in-situ-hybridization analysis revealed the diagnosis of a blastoid variant of MCL. To remove leukocytes rapidly, leukapheresis was performed in the intensive care unit. Based on the differential blood count with 95% blasts, which were assigned to the lymphocyte population by the automatic hematology analyzer, leukapheresis procedures were then performed with the mononuclear cell standard program on the Spectra cell separator. The patient was treated with daily leukapheresis for 3 days. The WBC count decreased to 174 × 109/L after the third leukapheresis, with a 72% reduction. After the second apheresis, treatment with vincristine, cyclophosphamide, and prednisolone was started. The patient fully recovered in the further course of the treatment. To the best of our knowledge, this is the first report on blastoid MCL with leukostasis associated with a STEMI that was successfully treated by leukapheresis. Effective harvest of circulating lymphoma cells by leukapheresis requires adaptation of instrument settings based on the results of the differential blood count prior to apheresis.

Radiation doses from radioactivity in incandescent mantles

International Nuclear Information System (INIS)

1985-01-01

Thorium nitrate is used in the production of incandescent mantles for gas lanterns. In this report dose estimates are given for internal and external exposure that result from the use of the incandescent mantles for gas lanterns. The collective, effective dose equivalent for all users of gas mantles is estimated to be about 100 Sv per annum in the Netherlands. For the population involved (ca. 700,000 persons) this is roughly equivalent to 5% to 10% of the collective dose equivalent associated with exposure to radiation from natural sources. The major contribution to dose estimates comes from inhalation of radium during burning of the mantles. A pessimistic approach results in individual dose estimates for inhalation of up to 0.2 mSv. Consideration of dose consequences in case of a fire in a storage department learns that it is necessary for emergency personnel to wear respirators. It is concluded that the uncontrolled removal of used gas mantles to the environment (soil) does not result in a significant contribution to environmental radiation exposure. (Auth.)

European Lithospheric Mantle; geochemical, petrological and geophysical processes

Science.gov (United States)

Ntaflos, Th.; Puziewicz, J.; Downes, H.; Matusiak-Małek, M.

2017-04-01

The second European Mantle Workshop occurred at the end of August 2015, in Wroclaw, Poland, attended by leading scientists in the study the lithospheric mantle from around the world. It built upon the results of the first European Mantle Workshop (held in 2007, in Ferrara, Italy) published in the Geological Society of London Special Publication 293 (Coltorti & Gregoire, 2008).

A mantle plume model for the Equatorial Highlands of Venus

Science.gov (United States)

Kiefer, Walter S.; Hager, Bradford H.

1991-01-01

The possibility that the Equatorial Highlands are the surface expressions of hot upwelling mantle plumes is considered via a series of mantle plume models developed using a cylindrical axisymmetric finite element code and depth-dependent Newtonian rheology. The results are scaled by assuming whole mantle convection and that Venus and the earth have similar mantle heat flows. The best model fits are for Beta and Atla. The common feature of the allowed viscosity models is that they lack a pronounced low-viscosity zone in the upper mantle. The shape of Venus's long-wavelength admittance spectrum and the slope of its geoid spectrum are also consistent with the lack of a low-viscosity zone. It is argued that the lack of an asthenosphere on Venus is due to the mantle of Venus being drier than the earth's mantle. Mantle plumes may also have contributed to the formation of some smaller highland swells, such as the Bell and Eistla regions and the Hathor/Innini/Ushas region.

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

Science.gov (United States)

2018-02-07

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

Prefrontal gamma-aminobutyric acid type A receptor insertion controls cue-induced relapse to nicotine seeking.

Science.gov (United States)

Lubbers, Bart R; van Mourik, Yvar; Schetters, Dustin; Smit, August B; De Vries, Taco J; Spijker, Sabine

2014-11-01

Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling relapse to nicotine seeking. Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein-interacting domain of GABA type A (GABAA) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABAA receptor agonist. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABAA receptor subunits α1 and γ2 were upregulated, and interference with GABAA receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABAA transmission with muscimol in the dorsal and ventral mPFC attenuated relapse. These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

The value of nodal information in predicting lung cancer relapse using 4DPET/4DCT

Energy Technology Data Exchange (ETDEWEB)

Li, Heyse, E-mail: heyse.li@mail.utoronto.ca [Department of Mechanical and Industrial Engineering, University of Toronto, 5 King’s College Road, Toronto, Ontario M5S 3G8 (Canada); Becker, Nathan; Raman, Srinivas [Radiation Oncology, UHN Princess Margaret Cancer Centre, 610 University of Avenue, Toronto, Ontario M5T 2M9 (Canada); Chan, Timothy C. Y. [Department of Mechanical and Industrial Engineering, University of Toronto, 5 King’s College Road, Toronto, Ontario M5S 3G8, Canada and Techna Institute for the Advancement of Technology for Health, 124 - 100 College Street, Toronto, Ontario M5G 1P5 (Canada); Bissonnette, Jean-Pierre [Radiation Oncology, UHN Princess Margaret Cancer Centre, 610 University of Avenue, Toronto, Ontario M5T 2M9, Canada and Techna Institute for the Advancement of Technology for Health, 124 - 100 College Street, Toronto, Ontario M5G 1P5 (Canada)

2015-08-15

Purpose: There is evidence that computed tomography (CT) and positron emission tomography (PET) imaging metrics are prognostic and predictive in nonsmall cell lung cancer (NSCLC) treatment outcomes. However, few studies have explored the use of standardized uptake value (SUV)-based image features of nodal regions as predictive features. The authors investigated and compared the use of tumor and node image features extracted from the radiotherapy target volumes to predict relapse in a cohort of NSCLC patients undergoing chemoradiation treatment. Methods: A prospective cohort of 25 patients with locally advanced NSCLC underwent 4DPET/4DCT imaging for radiation planning. Thirty-seven image features were derived from the CT-defined volumes and SUVs of the PET image from both the tumor and nodal target regions. The machine learning methods of logistic regression and repeated stratified five-fold cross-validation (CV) were used to predict local and overall relapses in 2 yr. The authors used well-known feature selection methods (Spearman’s rank correlation, recursive feature elimination) within each fold of CV. Classifiers were ranked on their Matthew’s correlation coefficient (MCC) after CV. Area under the curve, sensitivity, and specificity values are also presented. Results: For predicting local relapse, the best classifier found had a mean MCC of 0.07 and was composed of eight tumor features. For predicting overall relapse, the best classifier found had a mean MCC of 0.29 and was composed of a single feature: the volume greater than 0.5 times the maximum SUV (N). Conclusions: The best classifier for predicting local relapse had only tumor features. In contrast, the best classifier for predicting overall relapse included a node feature. Overall, the methods showed that nodes add value in predicting overall relapse but not local relapse.

Pillars of the Mantle

KAUST Repository

Pugmire, David

2017-07-05

In this work, we investigate global seismic tomographic models obtained by spectral-element simulations of seismic wave propagation and adjoint methods. Global crustal and mantle models are obtained based on an iterative conjugate-gradient type of optimization scheme. Forward and adjoint seismic wave propagation simulations, which result in synthetic seismic data to make measurements and data sensitivity kernels to compute gradient for model updates, respectively, are performed by the SPECFEM3D-GLOBE package [1] [2] at the Oak Ridge Leadership Computing Facility (OLCF) to study the structure of the Earth at unprecedented levels. Using advances in solver techniques that run on the GPUs on Titan at the OLCF, scientists are able to perform large-scale seismic inverse modeling and imaging. Using seismic data from global and regional networks from global CMT earthquakes, scientists are using SPECFEM3D-GLOBE to understand the structure of the mantle layer of the Earth. Visualization of the generated data sets provide an effective way to understand the computed wave perturbations which define the structure of mantle in the Earth.

Low-dose total body irradiation and G-CSF without hematopoietic stem cell support in the treatment of relapsed or refractory acute myelogenous leukemia (AML), or AML in second or subsequent remission

International Nuclear Information System (INIS)

Shulman, Lawrence N.; Tarbell, Nancy J.; Storen, Elizabeth; Marcus, Karen; Mauch, Peter M.

1998-01-01

Purpose: Patients with relapsed acute myelogenous leukemia (AML), who are not eligible for bone marrow transplantation, have a poor prognosis when treated with chemotherapy alone. Total body irradiation (TBI) is an effective modality against AML when used in doses of 1000-1400 cGy with hematopoietic stem cell support. We undertook a phase I study of TBI with granulocyte-colony-stimulating factor (G-CSF) support, without stem cell support in patients with AML either in relapse or second or subsequent remission. Methods and Materials: Patients with relapsed AML, or AML in second or subsequent remission were treated in a phase I study of TBI followed by G-CSF. The first dose level was 200 cGy. After the initial cohort of patients it was clear that patients with overt leukemia did not benefit from this treatment, and subsequent patients were required to be in remission at the time of TBI. Results: Eleven patients were treated, 4 in overt relapse, and 7 in remission. 200 cGy was used in all, and dose escalation was not possible due to prolonged thrombocytopenia in all patients but one. Neutrophil recovery was adequate in those patients who remained in remission after TBI. Patients with overt leukemia had transient reduction in blast counts, but rapid recurrence of their leukemia. Patients treated in remission had short remissions, with the exception of one patient who is in remission 32 months after treatment. Conclusion: There is some antileukemic effect of TBI even at 200 cGy, though this dose appears to be too low to help a significant number of patients. If TBI is to be escalated without stem cell support, then a thrombopoietic agent will need to be used

Second auto-SCT for treatment of relapsed multiple myeloma.

Science.gov (United States)

Gonsalves, W I; Gertz, M A; Lacy, M Q; Dispenzieri, A; Hayman, S R; Buadi, F K; Dingli, D; Hogan, W J; Kumar, S K

2013-04-01

High-dose therapy and auto-SCT remain integral in the initial treatment of multiple myeloma (MM), and are increasingly being applied for management of relapsed disease. We examined the outcomes in 98 patients undergoing salvage auto-SCT (auto-SCT2) for relapsed MM after receiving an initial transplant (auto-SCT1) between 1994 and 2009. The median age at auto-SCT2 was 60 years (range: 35-74). The median time between auto-SCT1 and auto-SCT2 was 46 months (range: 10-130). Treatment-related mortality was seen in 4%. The median PFS from auto-SCT2 was 10.3 (95% confidence interval (CI): 7-14) months and the median OS from auto-SCT2 was 33 months (95% CI: 28-51). In a multivariable analysis, shorter time to progression (TTP) after auto-SCT1, not achieving a CR after auto-SCT2, higher number of treatment regimens before auto-SCT2 and a higher plasma cell labeling index at auto-SCT2 predicted for shorter PFS. However, only a shorter TTP after auto-SCT1 predicted for a shorter OS post auto-SCT2. Hence, auto-SCT2 is an effective and feasible therapeutic option for MM patients relapsing after other treatments, especially in patients who had a TTP of at least 12 months after their auto-SCT1.

Can Lower Mantle Slab-like Seismic Anomalies be Explained by Thermal Coupling Between the Upper and Lower Mantles?

NARCIS (Netherlands)

Cízková, H. (Hana); Cadek, O.; Berg, A.P. van den; Vlaar, N.J.

1999-01-01

Below subduction zones, high resolution seismic tomographic models resolve fast anomalies that often extend into the deep lower mantle. These anomalies are generally interpreted as slabs penetrating through the 660-km seismic discontinuity, evidence in support of whole-mantle convection. However,

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence.

Science.gov (United States)

Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

2016-07-02

Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.

Mantle superplumes induce geomagnetic superchrons

Directory of Open Access Journals (Sweden)

Peter eOlson

2015-07-01

Full Text Available We use polarity reversal systematics from numerical dynamos to quantify the hypothesis that the modulation of geomagnetic reversal frequency, including geomagnetic superchrons, results from changes in core heat flux related to growth and collapse of lower mantle superplumes. We parameterize the reversal frequency sensitivity from numerical dynamos in terms of average core heat flux normalized by the difference between the present-day core heat flux and the core heat flux at geomagnetic superchron onset. A low-order polynomial fit to the 0-300 Ma Geomagnetic Polarity Time Scale (GPTS reveals that a decrease in core heat flux relative to present-day of approximately 30% can account for the Cretaceous Normal Polarity and Kiaman Reverse Polarity Superchrons, whereas the hyper-reversing periods in the Jurassic require a core heat flux equal to or higher than present-day. Possible links between GPTS transitions, large igneous provinces (LIPs, and the two lower mantle superplumes are explored. Lower mantle superplume growth and collapse induce GPTS transitions by increasing and decreasing core heat flux, respectively. Age clusters of major LIPs postdate transitions from hyper-reversing to superchron geodynamo states by 30-60 Myr, suggesting that superchron onset may be contemporaneous with LIP-forming instabilities produced during collapses of lower mantle superplumes.

The origin of volatiles in the Earth's mantle

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Hier-Majumder, Saswata; Hirschmann, Marc M.

2017-08-01

The Earth's deep interior contains significant reservoirs of volatiles such as H, C, and N. Due to the incompatible nature of these volatile species, it has been difficult to reconcile their storage in the residual mantle immediately following crystallization of the terrestrial magma ocean (MO). As the magma ocean freezes, it is commonly assumed that very small amounts of melt are retained in the residual mantle, limiting the trapped volatile concentration in the primordial mantle. In this article, we show that inefficient melt drainage out of the freezing front can retain large amounts of volatiles hosted in the trapped melt in the residual mantle while creating a thick early atmosphere. Using a two-phase flow model, we demonstrate that compaction within the moving freezing front is inefficient over time scales characteristic of magma ocean solidification. We employ a scaling relation between the trapped melt fraction, the rate of compaction, and the rate of freezing in our magma ocean evolution model. For cosmochemically plausible fractions of volatiles delivered during the later stages of accretion, our calculations suggest that up to 77% of total H2O and 12% of CO2 could have been trapped in the mantle during magma ocean crystallization. The assumption of a constant trapped melt fraction underestimates the mass of volatiles in the residual mantle by more than an order of magnitude.Plain Language SummaryThe Earth's deep interior contains substantial amounts of volatile elements like C, H, and N. How these elements got sequestered in the Earth's interior has long been a topic of debate. It is generally assumed that most of these elements escaped the interior of the Earth during the first few hundred thousand years to create a primitive atmosphere, leaving the mantle reservoir nearly empty. In this work, we show that the key to this paradox involves the very early stages of crystallization of the mantle from a global magma ocean. Using numerical models, we show

Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation

Science.gov (United States)

Merz, Maximilian; Jauch, Anna; Hielscher, Thomas; Mai, Elias K.; Seckinger, Anja; Hose, Dirk; Bertsch, Uta; Neben, Kai; Raab, Marc S.; Salwender, Hans; Blau, Igor W.; Lindemann, Hans-Walter; Schmidt-Wolf, Ingo; Scheid, Christof; Haenel, Mathias; Weisel, Katja; Goldschmidt, Hartmut; Hillengass, Jens

2017-01-01

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86–33.42; P<0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65–127.66; P=0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53–8.14; P=0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09–8.59; P=0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26). PMID:28495913

Expression changes in the stroma of prostate cancer predict subsequent relapse.

Directory of Open Access Journals (Sweden)

Zhenyu Jia

Full Text Available Biomarkers are needed to address overtreatment that occurs for the majority of prostate cancer patients that would not die of the disease but receive radical treatment. A possible barrier to biomarker discovery may be the polyclonal/multifocal nature of prostate tumors as well as cell-type heterogeneity between patient samples. Tumor-adjacent stroma (tumor microenvironment is less affected by genetic alteration and might therefore yield more consistent biomarkers in response to tumor aggressiveness. To this end we compared Affymetrix gene expression profiles in stroma near tumor and identified a set of 115 probe sets for which the expression levels were significantly correlated with time-to-relapse. We also compared patients that chemically relapsed shortly after prostatectomy (<1 year, and patients that did not relapse in the first four years after prostatectomy. We identified 131 differentially expressed microarray probe sets between these two categories. 19 probe sets (15 genes overlapped between the two gene lists with p<0.0001. We developed a PAM-based classifier by training on samples containing stroma near tumor: 9 rapid relapse patient samples and 9 indolent patient samples. We then tested the classifier on 47 different samples, containing 90% or more stroma. The classifier predicted the risk status of patients with an average accuracy of 87%. This is the first general tumor microenvironment-based prognostic classifier. These results indicate that the prostate cancer microenvironment exhibits reproducible changes useful for predicting outcomes for patients.

Preventing Relapse to Cigarette Smoking by Behavioral Skill Training.

Science.gov (United States)

Hall, Sharon M.; And Others

1984-01-01

Crossed two relapse prevention conditions (skills training-vs-discussion control) with two levels of aversive smoking in volunteer subjects (N=123). Results indicated that relapse-prevention skill training did prevent relapse among cigarette smokers. Lighter smokers were more favorably influenced. (LLL)

Traveltime Dispersion in an Isotropic Elastic Mantle: Dominance of the Lower Mantle Signal in Differential-frequency Time Residuals

Science.gov (United States)

Schuberth, B. S. A.; Zaroli, C.; Nolet, G.

2014-12-01

We study wavefield effects in elastic isotropic 3-D seismic structures derived from the temperature field of a high resolution mantle circulation model. More specifically, we quantify the structural dispersion of traveltime residuals of direct P- and S-waves in a model with realistic length-scales and magnitudes of the variations in seismic velocities and density. 3-D global wave propagation is simulated using a spectral element method, and traveltime residuals are measured in four different frequency bands by cross-correlation of 3-D and 1-D synthetic waveforms. Intrinsic (dissipative) attenuation is deliberately neglected, so that any variation of traveltimes with frequency can be attributed to structural effects. Additional simulations are performed for a model in which 3-D structure is removed in the upper 800 km to isolate the dispersion signal of the lower mantle. One question that we address is whether the structural length-scales inherent to a vigorously convecting mantle give rise to significant body-wave dispersion. In our synthetic dataset, the difference between long-period and short-period traveltime residuals generally increases with increasing short-period residual. However, we do not find an exact linear dependence, and in case of P-waves even non-monotonic behaviour. At largest short-period residuals, average dispersion is on the order of 2 s for both P- and S-waves and even larger when structure is confined to the lower mantle. Dispersion also appears to be asymmetric; that is, larger for negative than for positive residuals. The standard deviations of both P- and S-wave residuals also increase with increasing period and we discuss possible explanations for this behaviour. Overall, wavefield effects in both models are generally stronger for P-waves than for S-waves at the same frequencies. We also find that for certain combinations of periods, the difference between the respective residuals is very similar between the "whole mantle" and the "lower

Metaplastic carcinoma. Breast. Relapse. Chemotherapy and Radiotherapy

International Nuclear Information System (INIS)

Marquez, A.; Terrasa, J.; Garcia, J.M.; Rifa, J.

1996-01-01

Metaplastic carcinoma of the breast is a rare tumor. The appearance of unexpected mesenchymal elements within the epithelial tumors is the squamous metaplasia. These tumors have a different clinical behaviour that classical breast carcinoma. We present a case of metaplastic mammary carcinoma with multiple relapses treated with a combination of chemotherapy and radiotherapy. The use of chemotherapy after local treatment has enhanced the relapse-free survival. The combined treatment modality seems to produce some benefit in the management of the local relapses of this neoplasms

Deep mantle seismic heterogeneities in Western Pacific subduction zones

Science.gov (United States)

Bentham, H. L. M.; Rost, S.

2012-04-01

In recent years array seismology has been used extensively to image the small scale (~10 km) structure of the Earth. In the mantle, small scale structure likely represents chemical heterogeneity and is essential in our understanding of mantle convection and especially mantle mixing. As subduction is the main source of introducing crustal material into the Earth's mantle, it is of particular interest to track the transport of subducted crust through the mantle to resolve details of composition and deformation of the crust during the subduction process. Improved knowledge of subduction can help provide constraints on the mechanical mixing process of crustal material into the ambient mantle, as well as constraining mantle composition and convection. This study uses seismic array techniques to map seismic heterogeneities associated with Western Pacific subduction zones, where a variety of slab geometries have been previously observed. We use seismic energy arriving prior to PP, a P-wave underside reflection off the Earth's surface halfway between source and receiver, to probe the mantle for small-scale heterogeneities. PP precursors were analysed at Eielson Array (ILAR), Alaska using the recently developed Toolkit for Out-of-Plane Coherent Arrival Tracking (TOPCAT) algorithm. The approach combines the calculated optimal beampower and an independent semblance (coherency) measure, to improve the signal-to-noise ratio of coherent arrivals. 94 earthquakes with sufficient coherent precursory energy were selected and directivity information of the arrivals (i.e. slowness and backazimuth) was extracted from the data. The scattering locations for 311 out-of-plane precursors were determined by ray-tracing and minimising the slowness, backazimuth and differential travel time misfit. Initial analyses show that deep scattering (>1000 km) occurs beneath the Izu-Bonin subduction zone, suggesting that subducted crust does continue into the lower mantle in this location. Other

The Total Body Irradiation Schedule Affects Acute Leukemia Relapse After Matched T Cell–Depleted Hematopoietic Stem Cell Transplantation

International Nuclear Information System (INIS)

Aristei, Cynthia; Carotti, Alessandra; Palazzari, Elisa; Amico, Lucia; Ruggeri, Loredana; Perrucci, Elisabetta; Falcinelli, Lorenzo; Lancellotta, Valentina; Palumbo, Isabella; Falzetti, Franca; Aversa, Franco; Merluzzi, Mara; Velardi, Andrea; Martelli, Massimo Fabrizio

2016-01-01

Purpose: We sought to determine whether the total body irradiation (TBI) schedule affected outcome in patients with acute leukemia in complete remission who received T cell–depleted allogeneic hematopoietic stem cell transplantation from HLA identical siblings. Methods and Materials: The study recruited 55 patients (median age, 48 years; age range, 20-66 years; 30 men and 25 women; 34 with acute myeloid leukemia and 21 with acute lymphoid leukemia). Hyperfractionated TBI (HTBI) (1.2 Gy thrice daily for 4 days [for a total dose of 14.4 Gy] from day −12 to day −9) was administered to 29 patients. Single-dose TBI (STBI) (8 Gy, at a median dose rate of 10.7 cGy/min on day −9) was given to 26 patients. Results: All patients achieved primary, sustained engraftment with full donor-type chimerism. At 10 years, the overall cumulative incidence of transplant-related mortality was 11% (SE, ±0.1%). It was 7% (SE, ±0.2%) after HTBI and 15% (SE, ±0.5%) after STBI (P=.3). The overall cumulative incidence of relapse was 33% (SE, ±0.5). It was 13% (SE, ±0.5%) after HTBI and 46% (SE, ±1%) after STBI (P=.02). The overall probability of disease-free survival (DFS) was 59% (SE, ±7%). It was 67% (SE, ±0.84%) after HTBI and 37% (SE, ±1.4%) after STBI (P=.01). Multivariate analyses showed the TBI schedule was the only risk factor that significantly affected relapse and DFS (P=.01 and P=.03, respectively). Conclusions: In patients with acute leukemia, HTBI is more efficacious than STBI in eradicating minimal residual disease after HLA-matched T cell–depleted hematopoietic stem cell transplantation, thus affecting DFS.

The Total Body Irradiation Schedule Affects Acute Leukemia Relapse After Matched T Cell–Depleted Hematopoietic Stem Cell Transplantation

Energy Technology Data Exchange (ETDEWEB)

Aristei, Cynthia, E-mail: cynthia.aristei@unipg.it [Radiation Oncology Section, Department of Surgery and Biomedical Sciences, University of Perugia and Perugia General Hospital, Perugia (Italy); Carotti, Alessandra [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Palazzari, Elisa [Radiation Oncology Section, University of Perugia, Perugia (Italy); Amico, Lucia; Ruggeri, Loredana [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Perrucci, Elisabetta; Falcinelli, Lorenzo [Radiation Oncology Division, Perugia General Hospital, Perugia (Italy); Lancellotta, Valentina [Radiation Oncology Section, University of Perugia, Perugia (Italy); Palumbo, Isabella [Radiation Oncology Section, Department of Surgery and Biomedical Sciences, University of Perugia and Perugia General Hospital, Perugia (Italy); Falzetti, Franca [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Aversa, Franco [Hematology and Bone Marrow Transplant Unit, Department of Clinical and Experimental Medicine, Parma General Hospital and University, Parma (Italy); Merluzzi, Mara; Velardi, Andrea; Martelli, Massimo Fabrizio [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy)

2016-11-15

Purpose: We sought to determine whether the total body irradiation (TBI) schedule affected outcome in patients with acute leukemia in complete remission who received T cell–depleted allogeneic hematopoietic stem cell transplantation from HLA identical siblings. Methods and Materials: The study recruited 55 patients (median age, 48 years; age range, 20-66 years; 30 men and 25 women; 34 with acute myeloid leukemia and 21 with acute lymphoid leukemia). Hyperfractionated TBI (HTBI) (1.2 Gy thrice daily for 4 days [for a total dose of 14.4 Gy] from day −12 to day −9) was administered to 29 patients. Single-dose TBI (STBI) (8 Gy, at a median dose rate of 10.7 cGy/min on day −9) was given to 26 patients. Results: All patients achieved primary, sustained engraftment with full donor-type chimerism. At 10 years, the overall cumulative incidence of transplant-related mortality was 11% (SE, ±0.1%). It was 7% (SE, ±0.2%) after HTBI and 15% (SE, ±0.5%) after STBI (P=.3). The overall cumulative incidence of relapse was 33% (SE, ±0.5). It was 13% (SE, ±0.5%) after HTBI and 46% (SE, ±1%) after STBI (P=.02). The overall probability of disease-free survival (DFS) was 59% (SE, ±7%). It was 67% (SE, ±0.84%) after HTBI and 37% (SE, ±1.4%) after STBI (P=.01). Multivariate analyses showed the TBI schedule was the only risk factor that significantly affected relapse and DFS (P=.01 and P=.03, respectively). Conclusions: In patients with acute leukemia, HTBI is more efficacious than STBI in eradicating minimal residual disease after HLA-matched T cell–depleted hematopoietic stem cell transplantation, thus affecting DFS.

Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia

DEFF Research Database (Denmark)

Schmiegelow, Kjeld; Björk, Olle; Glomstein, Anders

2003-01-01

by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E......-MTX (pharmacology group), or by WBC only (control group). RESULTS: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high...

Dynamics of upper mantle rocks decompression melting above hot spots under continental plates

Science.gov (United States)

Perepechko, Yury; Sorokin, Konstantin; Sharapov, Victor

2014-05-01

Numeric 2D simulation of the decompression melting above the hot spots (HS) was accomplished under the following conditions: initial temperature within crust mantle section was postulated; thickness of the metasomatized lithospheric mantle is determined by the mantle rheology and position of upper asthenosphere boundary; upper and lower boundaries were postulated to be not permeable and the condition for adhesion and the distribution of temperature (1400-2050°C); lateral boundaries imitated infinity of layer. Sizes and distribution of lateral points, their symmetry, and maximum temperature varied between the thermodynamic condition for existences of perovskite - majorite transition and its excess above transition temperature. Problem was solved numerically a cell-vertex finite volume method for thermo hydrodynamic problems. For increasing convergence of iterative process the method of lower relaxation with different value of relaxation parameter for each equation was used. The method of through calculation was used for the increase in the computing rate for the two-layered upper mantle - lithosphere system. Calculated region was selected as 700 x (2100-4900) km. The time step for the study of the asthenosphere dynamics composed 0.15-0.65 Ma. The following factors controlling the sizes and melting degree of the convective upper mantle, are shown: a) the initial temperature distribution along the section of upper mantleb) sizes and the symmetry of HS, c) temperature excess within the HS above the temperature on the upper and lower mantle border TB=1500-2000oC with 5-15% deviation but not exceed 2350oC. It is found, that appearance of decompression melting with HS presence initiate primitive mantle melting at TB > of 1600oC. Initial upper mantle heating influence on asthenolens dimensions with a constant HS size is controlled mainly by decompression melting degree. Thus, with lateral sizes of HS = 400 km the decompression melting appears at TB > 1600oC and HS

Rituximab in the treatment of refractory or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

Science.gov (United States)

Thiel, Jens; Hässler, Fabian; Salzer, Ulrich; Voll, Reinhard E; Venhoff, Nils

2013-09-24

Eosinophilic granulomatosis with polyangiitis (EGPA) is part of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitides. In EGPA small-vessel vasculitis is associated with eosinophilia and asthma. About 40% of EGPA patients are ANCA-positive, suggesting a role for B cells in the pathogenesis of EGPA. B cell-depleting therapy with rituximab (RTX) can be effective in ANCA-positive EGPA, but very few patients have been published to date. The role of RTX in the treatment of ANCA-negative EGPA is unclear. We report a single-center cohort of patients with eosinophilic granulomatosis with polyangiitis. Of these patients, nine (six ANCA-positive, three ANCA-negative) had been treated with RTX for relapsing or refractory disease on standard immunosuppressive treatment. In a retrospective analysis, data on treatment response, frequency of relapses, adverse events, and peripheral B-cell reconstitution were evaluated. Furthermore, serum immunoglobulin concentrations, ANCA status, and peripheral B cell subpopulations were assessed after RTX treatment. All patients had high disease activity before RTX treatment. At presentation 3 months after RTX therapy, all ANCA-positive and ANCA-negative patients had responded to RTX, with one patient being in complete remission, and eight patients being in partial remission. After a mean follow-up of 9 months, C-reactive protein concentrations had normalized, eosinophils had significantly decreased, and prednisone had been tapered in all patients. In all patients, RTX therapy was combined with a standard immunosuppressive therapy. Within the 9-month observation period, no relapse was recorded. Three patients were preemptively retreated with RTX, and during the median follow-up time of 3 years, no relapse occurred in these patients. During the follow-up of 13 patient-years, five minor but no major infections were recorded. In our analysis on nine patients with EGPA resistant to standard therapy, rituximab proved to be an

Mantle contamination and the Izu-Bonin-Mariana (IBM) 'high-tide mark': evidence for mantle extrusion caused by Tethyan closure

Science.gov (United States)

Flower, M. F. J.; Russo, R. M.; Tamaki, K.; Hoang, N.

2001-04-01

Western Pacific basins are characterized by three remarkable attributes: (1) complex kinematic histories linked to global-scale plate interactions; (2) DUPAL-like contaminated mantle; and (3) rapid post-Mesozoic rollback of the confining arc-trench systems. The coincidence of slab steepening, extreme arc curvature, and vigorous basin opening associated with the Mariana convergent margin suggests that rollback continues in response to an east-directed mantle 'wind'. Against a backdrop of conflicting kinematic and genetic interpretations we explore the notion that eastward asthenospheric flow driven by diachronous Tethyan closure caused stretching of eastern Eurasia and concomitant opening of western Pacific basins. Marking the eastern boundary of the latter, the Izu-Bonin-Mariana forearc may be regarded as a litho-tectonic 'high-tide mark' comprising igneous and metamorphic products from successive episodes (since ca. 45 Ma.) of arc sundering and backarc basin opening. The forearc also forms an isotopic boundary separating contaminated western Pacific mantle from the N-MORB Pacific Ocean reservoir. While the isotopic composition of western Pacific mantle resembles that feeding Indian Ocean hotspot and spreading systems, its spatial-temporal variation and the presence of subduction barriers to the south appear to preclude northward flow of Indian Ocean mantle and require an endogenous origin for sub-Eurasian contaminated mantle. It is concluded that the extrusion of Tethyan asthenosphere, contaminated by sub-Asian cratonic lithosphere, was a major cause of western Pacific arc rollback and basin opening. The model is consistent with paleomagnetic and geologic evidence supporting independent kinematic histories for constituent parts of the Philippine Sea and Sunda plates although interpretation of these is speculative. Compounded by effects of the Australia-Indonesia collision, late-Tethyan mantle extrusion appears to have produced the largest DUPAL domain in the

A Chinese patient with relapsed and refractory Hodgkin lymphoma treated with brentuximab vedotin

Institute of Scientific and Technical Information of China (English)

Zhi-Gang Cao; Hong-Wei Zhou; Chao-Jin Peng; Mo Liu; Yu Du; Qing-Ming Yang

2013-01-01

At present, approximately 20% of Hodgkin lymphomas (HL) are relapsed and refractory, and therapeutic methods including chemotherapy, radiotherapy, and even stem cell transplantation are unsatisfactory. Brentuximab vedotin, composed of CD30 antibody and a chemotherapeutic agent, is a new targeted drug that eradicates tumor cel s by binding to the CD30 antigen on their surface. In clinical trials, the response rate and complete remission rate of this drug were 73% and 40%, respectively, for relapsed and refractory HL. Here we report a case of CD30-positive relapsed and refractory HL that was treated with brentuximab. Before the treatment with brentuximab, the patient underwent chemotherapy, radiotherapy, and autologous stem cell transplantation. However, the disease continued to progress, affecting multiple organs and prompting symptoms such as persistent fever. After the treatment with brentuximab, the patient′s condition improved. Body temperature returned to normal after 4 days. Lung nodules were reduced in size and number after a single course of treatment, and PET/CT showed partial remission and complete remission after 3 and 6 courses of treatment, respectively. The entire treatment process progressed smoothly, though the patient experienced some symptoms due to chemotherapy, including peripheral neuritis of the limbs, irritating dry cough, and mild increase in aminotransferase. No serious adverse effects were observed. The current general condition of the patient is good;the continuous complete remission has amounted to 6 months.

Preface: Deep Slab and Mantle Dynamics

Science.gov (United States)

Suetsugu, Daisuke; Bina, Craig R.; Inoue, Toru; Wiens, Douglas A.

2010-11-01

We are pleased to publish this special issue of the journal Physics of the Earth and Planetary Interiors entitled "Deep Slab and Mantle Dynamics". This issue is an outgrowth of the international symposium "Deep Slab and Mantle Dynamics", which was held on February 25-27, 2009, in Kyoto, Japan. This symposium was organized by the "Stagnant Slab Project" (SSP) research group to present the results of the 5-year project and to facilitate intensive discussion with well-known international researchers in related fields. The SSP and the symposium were supported by a Grant-in-Aid for Scientific Research (16075101) from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government. In the symposium, key issues discussed by participants included: transportation of water into the deep mantle and its role in slab-related dynamics; observational and experimental constraints on deep slab properties and the slab environment; modeling of slab stagnation to constrain its mechanisms in comparison with observational and experimental data; observational, experimental and modeling constraints on the fate of stagnant slabs; eventual accumulation of stagnant slabs on the core-mantle boundary and its geodynamic implications. This special issue is a collection of papers presented in the symposium and other papers related to the subject of the symposium. The collected papers provide an overview of the wide range of multidisciplinary studies of mantle dynamics, particularly in the context of subduction, stagnation, and the fate of deep slabs.

Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial.

Science.gov (United States)

Kuhlen, Michaela; Willasch, Andre M; Dalle, Jean-Hugues; Wachowiak, Jacek; Yaniv, Isaac; Ifversen, Marianne; Sedlacek, Petr; Guengoer, Tayfun; Lang, Peter; Bader, Peter; Sufliarska, Sabina; Balduzzi, Adriana; Strahm, Brigitte; von Luettichau, Irene; Hoell, Jessica I; Borkhardt, Arndt; Klingebiel, Thomas; Schrappe, Martin; von Stackelberg, Arend; Glogova, Evgenia; Poetschger, Ulrike; Meisel, Roland; Peters, Christina

2018-01-01

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse. © 2017 John Wiley & Sons Ltd.

A new conceptual model for whole mantle convection and the origin of hotspot plumes

Science.gov (United States)

Yoshida, Masaki

2014-08-01

A new conceptual model of mantle convection is constructed for consideration of the origin of hotspot plumes, using recent evidence from seismology, high-pressure experiments, geodynamic modeling, geoid inversion studies, and post-glacial rebound analyses. This conceptual model delivers several key points. Firstly, some of the small-scale mantle upwellings observed as hotspots on the Earth's surface originate at the base of the mantle transition zone (MTZ), in which the Archean granitic continental material crust (TTG; tonalite-trondhjemite-granodiorite) with abundant radiogenic elements is accumulated. Secondly, the TTG crust and the subducted oceanic crust that have accumulated at the base of MTZ could act as thermal or mechanical insulators, leading to the formation of a hot and less viscous layer just beneath the MTZ; which may enhance the instability of plume generation at the base of the MTZ. Thirdly, the origin of some hotspot plumes is isolated from the large low shear-wave velocity provinces (LLSVPs) under Africa and the South Pacific. I consider that the conceptual model explains why almost all the hotspots around Africa are located above the margins of the African LLSVP. Because a planetary-scale trench system surrounding a “Pangean cell” has been spatially stable throughout the Phanerozoic, a large amount of the oceanic crustal layer is likely to be trapped in the MTZ under the Pangean cell. Therefore, under Africa, almost all of the hotspot plumes originate from the base of the MTZ, where a large amount of TTG and/or oceanic crusts has accumulated. This conceptual model may explain the fact that almost all the hotspots around Africa are located on margins above the African LLSVP. It is also considered that some of the hotspot plumes under the South Pacific thread through the TTG/oceanic crusts accumulated around the bottom of the MTZ, and some have their roots in the South Pacific LLSVP while others originate from the MTZ. The numerical simulations

Burden of a multiple sclerosis relapse: the patient's perspective.

Science.gov (United States)

Oleen-Burkey, Merrikay; Castelli-Haley, Jane; Lage, Maureen J; Johnson, Kenneth P

2012-01-01

Relapses are a common feature of relapsing-remitting multiple sclerosis (RRMS) and increasing severity has been shown to be associated with higher healthcare costs, and to result in transient increases in disability. Increasing disability likely impacts work and leisure productivity, and lowers quality of life. The objective of this study was to characterize from the patient's perspective the impact of a multiple sclerosis (MS) relapse in terms of the economic cost, work and leisure productivity, functional ability, and health-related quality of life (HR-QOL), for a sample of patients with RRMS in the US treated with immunomodulatory agents. A cross-sectional, web-based, self-report survey was conducted among members of MSWatch.com, a patient support website now known as Copaxone.com. Qualified respondents in the US had been diagnosed with RRMS and were using an immunomodulatory agent. The survey captured costs of RRMS with questions about healthcare resource utilization, use of community services, and purchased alterations and assistive items related to MS. The Work and Leisure Impairment instrument and the EQ-5D were used to measure productivity losses and HR-QOL (health utility), respectively. The Goodin MS neurological impairment questionnaire was used to measure functional disability; questions were added about relapses in the past year. Of 711 qualified respondents, 67% reported having at least one relapse during the last year, with a mean of 2.2 ± 2.3 relapses/year. Respondents who experienced at least one relapse had significantly higher mean annual direct and indirect costs compared with those who did not experience a relapse ($US38 458 vs $US28 669; p = 0.0004) [year 2009 values]. Direct health-related costs accounted for the majority of the increased cost ($US5201; 53%) and were mainly due to increases in hospitalizations, medications, and ambulatory care. Indirect costs, including informal care and productivity loss, accounted for the

Whole-mantle P-wave velocity structure and azimuthal anisotropy

Science.gov (United States)

Yamamoto, Y.; Zhao, D.

2009-12-01

There are some hotspot volcanoes on Earth, such as Hawaii and Iceland. The mantle plume hypothesis was proposed forty years ago to explain hotspot volcanoes (e.g., Wilson, 1963; Morgan, 1971). Seismic tomography is a powerful technique to detect mantle plumes and determine their detailed structures. We determined a new whole-mantle 3-D P-wave velocity model (Tohoku model) using a global tomography method (Zhao, 2004, 2009). A flexible-grid approach with a grid interval of ~200 km is adopted to conduct the tomographic inversion. Our model shows that low-velocity (low-V) anomalies with diameters of several hundreds of kilometers are visible from the core-mantle boundary (CMB) to the surface under the major hotspot regions. Under South Pacific where several hotspots including Tahiti exist, there is a huge low-V anomaly from the CMB to the surface. This feature is consistent with the previous models. We conducted extensive resolution tests in order to understand whether this low-V anomaly shows a single superplume or a plume cluster. Unfortunately this problem is still not resolved because the ray path coverage in the mantle under South Pacific is not good enough. A network of ocean bottom seismometers is necessary to solve this problem. To better understand the whole-mantle structure and dynamics, we also conducted P-wave tomographic inversions for the 3-D velocity structure and azimuthal anisotropy. At each grid node there are three unknown parameters: one represents the isotropic velocity, the other two represent the azimuthal anisotropy. Our results show that in the shallow part of the mantle (Japan trench axis. In the Tonga subduction zone, the FVD is also perpendicular to the trench axis. Under the Tibetan region the FVD is NE-SW, which is parallel to the direction of the India-Asia collision. In the deeper part of the upper mantle and in the lower mantle, the amplitude of anisotropy is reduced. One interesting feature is that the FVD aligns in a radiated fashion

Circulation of carbon dioxide in the mantle: multiscale modeling

Science.gov (United States)

Morra, G.; Yuen, D. A.; Lee, S.

2012-12-01

Much speculation has been put forward on the quantity and nature of carbon reservoirs in the deep Earth, because of its involvement in the evolution of life at the surface and inside planetary interiors. Carbon penetrates into the Earth's mantle mostly during subduction of oceanic crust, which contains carbonate deposits [1], however the form that it assumes at lower mantle depths is scarcely understood [2], hampering our ability to estimate the amount of carbon in the entire mantle by orders of magnitude. We present simulations of spontaneous degassing of supercritical CO2 using in-house developed novel implementations of the Fast-Multipole Boundary Element Method suitable for modeling two-phase flow (here mantle mineral and free CO2 fluid) through disordered materials such as porous rocks. Because the mutual interaction of droplets immersed either in a fluid or a solid matrix and their weakening effect to the host rock alters the strength of the mantle rocks, at the large scale the fluid phases in the mantle may control the creeping of mantle rocks [3]. In particular our study focuses on the percolation of supercritical CO2, estimated through the solution of the Laplace equation in a porous system, stochastically generated through a series of random Karhunen-Loeve decomposition. The model outcome is employed to extract the transmissivity of supercritical fluids in the mantle from the lowest scale up to the mantle scale and in combination with the creeping flow of the convecting mantle. The emerging scenarios on the global carbon cycle are finally discussed. [1] Boulard, E., et al., New host for carbon in the deep Earth. Proceedings of the National Academy of Sciences, 2011. 108(13): p. 5184-5187. [2] Walter, M.J., et al., Deep Mantle Cycling of Oceanic Crust: Evidence from Diamonds and Their Mineral Inclusions. Science, 2011. 334(6052): p. 54-57. [3] Morra, G., et al., Ascent of Bubbles in Magma Conduits Using Boundary Elements and Particles. Procedia Computer

Irradiation in the treatment of Hodgkin disease: a follow-up report

International Nuclear Information System (INIS)

Kim, Y.H.; Fayos, J.V.

1981-01-01

From 1971 through 1976, 167 patients with Hodgkin disease received radiation therapy. In 132, staging was determined upon laparotomy; the others had clinical staging. Most patients with stage I or II disease received either mantle or para-aortic-iliac irradiation, while the others received more extensive irradiation with or without chemotherapy. Overall five-year actuarial survival rate was 87%; Stage I, 97%; Stage II, 85%; and Stage III, 82%. Fifty-nine of the 167 patients had relapse of disease, and most relapses were seen in Stage II, located in the nodal sites on the opposite side of the diaphragm. Overall five-year relapse-free survival was 58%; Stage I, 94%; Stage II, 43%; and Stage III, 59%. Survival after the first relapse was 69%. Based on their results, the authors feel that Stage I disease of supradiaphragmatic presentation can be treated effectively with mantle field irradiation alone. In treating Stage II disease, mantle field irradiation alone was not optimal, and the authors recommend subtotal nodal irradiation

Relapse and craving in alcohol-dependent individuals

NARCIS (Netherlands)

van de Mheen, H,; Snelleman, M.; Schoenmakers, T.M.

2018-01-01

Background: Negative affective states and alcohol-related stimuli increase risk of relapse in alcohol dependence. In research and in clinical practice, craving is often used as another important indicator of relapse, but this lacks a firm empirical foundation. Objectives: The goal of the present

Water Distribution in the Continental and Oceanic Upper Mantle

Science.gov (United States)

Peslier, Anne H.

2015-01-01

Nominally anhydrous minerals such as olivine, pyroxene and garnet can accommodate tens to hundreds of ppm H2O in the form of hydrogen bonded to structural oxygen in lattice defects. Although in seemingly small amounts, this water can significantly alter chemical and physical properties of the minerals and rocks. Water in particular can modify their rheological properties and its distribution in the mantle derives from melting and metasomatic processes and lithology repartition (pyroxenite vs peridotite). These effects will be examined here using Fourier transform infrared spectrometry (FTIR) water analyses on minerals from mantle xenoliths from cratons, plume-influenced cratons and oceanic settings. In particular, our results on xenoliths from three different cratons will be compared. Each craton has a different water distribution and only the mantle root of Kaapvaal has evidence for dry olivine at its base. This challenges the link between olivine water content and survival of Archean cratonic mantle, and questions whether xenoliths are representative of the whole cratonic mantle. We will also present our latest data on Hawaii and Tanzanian craton xenoliths which both suggest the intriguing result that mantle lithosphere is not enriched in water when it interacts with melts from deep mantle upwellings (plumes).

Mantle mixing and thermal evolution during Pangaea assembly and breakup

Science.gov (United States)

Rudolph, M. L.; Li, M.; Zhong, S.; Manga, M.

2016-12-01

Continents insulate the underlying mantle, and it has been suggested that the arrangement of the continents can have a significant effect on sub-continental mantle temperatures. Additionally, the dispersal or agglomeration of continents may affect the efficacy of continental insulation, with some studies suggesting warming of 100K beneath supercontinents. During the most recent supercontinent cycle, Pangaea was encircled by subduction, potentially creating a `curtain' of subducted material that may have prevented mixing of the sub-Pangaea mantle with the sub-Panthalassa mantle. Using 3D spherical shell geometry mantle convection simulations, we quantify the effect of insulation by continents and supercontinents. We explore the differences in model predictions for purely thermal vs. thermochemical convection, and we use tracers to quantify the exchange of material between the sub-oceanic to the sub-continental mantle.

Reconstructing mantle heterogeneity with data assimilation based on the back-and-forth nudging method: Implications for mantle-dynamic fitting of past plate motions

Science.gov (United States)

Glišović, Petar; Forte, Alessandro

2016-04-01

The paleo-distribution of density variations throughout the mantle is unknown. To address this question, we reconstruct 3-D mantle structure over the Cenozoic era using a data assimilation method that implements a new back-and-forth nudging algorithm. For this purpose, we employ convection models for a compressible and self-gravitating mantle that employ 3-D mantle structure derived from joint seismic-geodynamic tomography as a starting condition. These convection models are then integrated backwards in time and are required to match geologic estimates of past plate motions derived from marine magnetic data. Our implementation of the nudging algorithm limits the difference between a reconstruction (backward-in-time solution) and a prediction (forward-in-time solution) on over a sequence of 5-million-year time windows that span the Cenozoic. We find that forward integration of reconstructed mantle heterogeneity that is constrained to match past plate motions delivers relatively poor fits to the seismic-tomographic inference of present-day mantle heterogeneity in the upper mantle. We suggest that uncertainties in the past plate motions, related for example to plate reorganization episodes, could partly contribute to the poor match between predicted and observed present-day heterogeneity. We propose that convection models that allow tectonic plates to evolve freely in accord with the buoyancy forces and rheological structure in the mantle could provide additional constraints on geologic estimates of paleo-configurations of the major tectonic plates.

Is there an increased rate of additional malignancies in patients with mantle cell lymphoma?

Science.gov (United States)

Barista, I; Cabanillas, F; Romaguera, J E; Khouri, I F; Yang, Y; Smith, T L; Strom, S S; Medeiros, L J; Hagemeister, F B

2002-02-01

To examine the frequency of additional neoplasms preceding and following the diagnosis of mantle cell lymphoma (MCL). A total of 156 patients with MCL treated on the hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternated with methotrexate and cytosine arabinoside (Hyper-CVAD/M-A) program with or without rituximab from 1994 to 2000 were the subjects of this report. These patients were followed for a median time of 26 months, and a total of 32 (21%) additional neoplasms were diagnosed, 21 preceding the diagnosis of MCL and 11 following MCL. After excluding certain types of non-invasive neoplasms, including basal cell carcinoma, meningioma and cervical intraepithelial neoplasia, we observed seven second malignancies after the diagnosis of MCL, and the 5-year cumulative incidence rate of second malignancy was 11%. The observed-to-expected (O/E) ratio was 7/0.07 = 100 [95% confidence interval (CI) 49.3 to 186.6; P <0.0001]. Of the 21 malignancies diagnosed prior to MCL, 16 were invasive and five non-invasive. There were a total of 10 urologic malignancies occurring before or after the diagnosis of MCL was established. Our findings suggest that there is an increased incidence of second malignancies in patients with MCL. In addition, the high number of cases with urinary tract cancer in our series may substantiate prior reports describing a possible association between lymphoma and urologic malignancies.

Tracing Mantle Plumes: Quantifying their Morphology and Behavior from Seismic Tomography

Science.gov (United States)

O'Farrell, K. A.; Eakin, C. M.; Jones, T. D.; Garcia, E.; Robson, A.; Mittal, T.; Lithgow-Bertelloni, C. R.; Jackson, M. G.; Lekic, V.; Rudolph, M. L.

2016-12-01

Hotspot volcanism provides a direct link between the deep mantle and the surface, but the location, depth and source of the mantle plumes that feed hotspots are highly controversial. In order to address this issue it is important to understand the journey along which plumes have travelled through the mantle. The general behavior of plumes in the mantle also has the potential to tell us about the vigor of mantle convection, net rotation of the mantle, the role of thermal versus chemical anomalies, and important bulk physical properties of the mantle such as the viscosity profile. To address these questions we developed an algorithm to trace plume-like features in shear-wave (Vs) seismic tomographic models based on picking local minima in velocity and searching for continuous features with depth. We apply this method to several of the latest tomographic models and can recover 30 or more continuous plume conduits that are >750 km long. Around half of these can be associated with a known hotspot at the surface. We study the morphology of these plume chains and find that the largest lateral deflections occur near the base of the lower mantle and in the upper mantle. We analyze the preferred orientation of the plume deflections and their gradient to infer large scale mantle flow patterns and the depth of viscosity contrasts in the mantle respectively. We also retrieve Vs profiles for our traced plumes and compare with velocity profiles predicted for different mantle adiabat temperatures. We use this to constrain the thermal anomaly associated with these plumes. This thermal anomaly is then converted to a density anomaly and an upwelling velocity is derived. We compare this to buoyancy fluxes calculated at the surface and use this in conjunction with our measured plume tilts/deflections to estimate the strength of the "mantle wind".

Chemotherapy versus Hypomethylating Agents for the Treatment of Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndrome after Allogeneic Stem Cell Transplant.

Science.gov (United States)

Motabi, Ibraheem H; Ghobadi, Armin; Liu, Jingxia; Schroeder, Mark; Abboud, Camille N; Cashen, Amanda F; Stockler-Goldstein, Keith E; Uy, Geoffrey L; Vij, Ravi; Westervelt, Peter; DiPersio, John F

2016-07-01

Allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients with relapsed disease after transplantation, intensive chemotherapy followed by donor lymphocyte infusion (DLI) or a second allo-SCT may result in a durable response in some patients. High-intensity chemotherapy and less aggressive therapy with hypomethylating agents (HAs) with and without DLI are often used for relapse after allo-SCT. Here we compared the treatment outcomes of intensive chemotherapy with that of HAs in relapsed AML and MDS after allo-SCT. Patients who had received a second SCT within 90 days of the relapse date were excluded. The primary endpoints were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression-free survival (PFS). One hundred patients were included: 73 patients received chemotherapy and 27 patients received an HA. Fifty-six percent of patients in the chemotherapy group and 33% of patients in the HA group received at least 1 DLI after treatment. Treatment with chemotherapy resulted in a higher ORR (51% versus 19%, P = .004) and a higher CR rate (40% versus 7%, P = .002). The median OS (6 versus 3.9 months, P = .01) and PFS (4.9 versus 3.8 months, P = .02) were longer in the chemotherapy group. Similar benefit of chemotherapy over HAs was maintained in all treatment outcomes after controlling for the use of DLI. The use of chemotherapy followed by DLI offered the greatest benefit (ORR, 68%; CR, 59%, 1-year OS, 44%; and median OS, 9.8 months). In conclusion, in our hands, with limited numbers, the use of more conventional salvage chemotherapy, with DLI when possible, for the treatment of relapsed AML and MDS after allo-SCT is associated with better outcomes than nonchemotherapy (HA) options. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier

Imaging the Mediterranean upper mantle by p- wave travel time tomography

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A. Morelli

1997-06-01

Full Text Available Travel times of P-waves in the Euro-Mediterranean region show strong and consistent lateral variations, which can be associated to structural heterogeneity in the underlying crust and mantle. We analyze regional and tele- seismic data from the International Seismological Centre data base to construct a three-dimensional velocity model of the upper mantle. We parameterize the model by a 3D grid of nodes -with approximately 50 km spacing -with a linear interpolation law, which constitutes a three-dimensional continuous representation of P-wave velocity. We construct summary travel time residuals between pairs of cells of the Earth's surface, both inside our study area and -with a broader spacing -on the whole globe. We account for lower mantle heterogeneity outside the modeled region by using empirical corrections to teleseismic travel times. The tomo- graphic images show generai agreement with other seismological studies of this area, with apparently higher detail attained in some locations. The signature of past and present lithospheric subduction, connected to Euro- African convergence, is a prominent feature. Active subduction under the Tyrrhenian and Hellenic arcs is clearly imaged as high-velocity bodies spanning the whole upper mantle. A clear variation of the lithospheric structure beneath the Northem and Southern Apennines is observed, with the boundary running in correspon- dence of the Ortona-Roccamonfina tectonic lineament. The western section of the Alps appears to have better developed roots than the eastern, possibly reflecting à difference in past subduction of the Tethyan lithosphere and subsequent continental collision.

Geodynamo Modeling of Core-Mantle Interactions

Science.gov (United States)

Kuang, Wei-Jia; Chao, Benjamin F.; Smith, David E. (Technical Monitor)

2001-01-01

Angular momentum exchange between the Earth's mantle and core influences the Earth's rotation on time scales of decades and longer, in particular in the length of day (LOD) which have been measured with progressively increasing accuracy for the last two centuries. There are four possible coupling mechanisms for transferring the axial angular momentum across the core-mantle boundary (CMB): viscous, magnetic, topography, and gravitational torques. Here we use our scalable, modularized, fully dynamic geodynamo model for the core to assess the importance of these torques. This numerical model, as an extension of the Kuang-Bloxham model that has successfully simulated the generation of the Earth's magnetic field, is used to obtain numerical results in various physical conditions in terms of specific parameterization consistent with the dynamical processes in the fluid outer core. The results show that depending on the electrical conductivity of the lower mantle and the amplitude of the boundary topography at CMB, both magnetic and topographic couplings can contribute significantly to the angular momentum exchange. This implies that the core-mantle interactions are far more complex than has been assumed and that there is unlikely a single dominant coupling mechanism for the observed decadal LOD variation.

Moho vs crust-mantle boundary: Evolution of an idea

Science.gov (United States)

O'Reilly, Suzanne Y.; Griffin, W. L.

2013-12-01

The concept that the Mohorovicic Discontinuity (Moho) does not necessarily coincide with the base of the continental crust as defined by rock-type compositions was introduced in the early 1980s. This had an important impact on understanding the nature of the crust-mantle boundary using information from seismology and from deep-seated samples brought to the surface as xenoliths in magmas, or as tectonic terranes. The use of empirically-constrained P-T estimates to plot the locus of temperature vs depth for xenoliths defined a variety of geotherms depending on tectonic environment. The xenolith geotherms provided a framework for constructing lithological sections through the deep lithosphere, and revealed that the crust-mantle boundary in off-craton regions commonly is transitional over a depth range of about 5-20 km. Early seismic-reflection data showed common layering near the Moho, correlating with the petrological observation of multiple episodes of basaltic intrusion around the crust-mantle boundary. Developments in seismology, petrophysics and experimental petrology have refined interpretation of lithospheric domains. The expansion of in situ geochronology (especially zircon U-Pb ages and Hf-isotopes; Os isotopes of mantle sulfides) has defined tectonic events that affected whole crust-mantle sections, and revealed that the crust-mantle boundary can change in depth through time. However, the nature of the crust-mantle boundary in cratonic regions remains enigmatic, mainly due to lack of key xenoliths or exposed sections. The observation that the Moho may lie significantly deeper than the crust-mantle boundary has important implications for modeling the volume of the crust. Mapping the crust using seismic techniques alone, without consideration of the petrological problems, may lead to an overestimation of crustal thickness by 15-30%. This will propagate to large uncertainties in the calculation of elemental mass balances relevant to crust-formation processes

Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a case report of improvement in relapsing auto-immune optic neuropathy.

Science.gov (United States)

Weiss, Jeffrey N; Levy, Steven; Benes, Susan C

2015-09-01

We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date (www.clinicaltrials.gov Identifier NCT 01920867). SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs) for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient's previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and intravitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient's visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up.

Clustering of arc volcanoes caused by temperature perturbations in the back-arc mantle.

Science.gov (United States)

Lee, Changyeol; Wada, Ikuko

2017-06-29

Clustering of arc volcanoes in subduction zones indicates along-arc variation in the physical condition of the underlying mantle where majority of arc magmas are generated. The sub-arc mantle is brought in from the back-arc largely by slab-driven mantle wedge flow. Dynamic processes in the back-arc, such as small-scale mantle convection, are likely to cause lateral variations in the back-arc mantle temperature. Here we use a simple three-dimensional numerical model to quantify the effects of back-arc temperature perturbations on the mantle wedge flow pattern and sub-arc mantle temperature. Our model calculations show that relatively small temperature perturbations in the back-arc result in vigorous inflow of hotter mantle and subdued inflow of colder mantle beneath the arc due to the temperature dependence of the mantle viscosity. This causes a three-dimensional mantle flow pattern that amplifies the along-arc variations in the sub-arc mantle temperature, providing a simple mechanism for volcano clustering.

Prediction of Central Nervous System Relapse of Diffuse Large B-Cell Lymphoma Using Pretherapeutic [18F]2-Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography/Computed Tomography.

Science.gov (United States)

Song, Yoo Sung; Lee, Won Woo; Lee, Jong Seok; Kim, Sang Eun

2015-11-01

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare complication, but has a poor prognosis with unknown pathophysiology. Recent trials of CNS prophylaxis have shown to be ineffective, despite patient's selection using several known clinical risk factors. In this study, the authors evaluated the value of pretreatment [F]2-Fluoro-2-deoxyglucose positron emission tomography in predicting CNS relapse in DLBCL patients.The authors analyzed 180 pathologically confirmed DLBCL patients, retrospectively. Patients underwent [F]2-Fluoro-2-deoxyglucose positron emission tomography/computed tomography before first line rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. Clinical characteristics were evaluated and total lesion glycolysis (TLG) with a threshold margin of 50% was calculated.Among age, sex, Ann Arbor stage, International Prognostic Index, revised International Prognostic Index, high serum lactate dehydrogenase level, presence of B symptoms, bulky disease (≥10 cm), extranodal lesion involvement, bone marrow involvement, high metabolic tumor volume ( >450 mL), and high TLG50 (>2000), the high TLG50 was the only significant prognostic factor for predicting CNS relapse in a multivariate analysis (P = 0.04). Kaplan-Meir survival analysis between high TLG50 (>2000) and low TLG50 (≤2000) groups revealed significantly different mean progression free survival (PFS) of 1317.2 ± 134.3 days and 1968.6 ± 18.3 days, respectively (P positron emission tomography/computed tomography is the most significant predictor of CNS relapse in un-treated DLBCL patients.

The Alcohol Relapse Risk Assessment: a scoring system to predict the risk of relapse to any alcohol use after liver transplant.

Science.gov (United States)

Rodrigue, James R; Hanto, Douglas W; Curry, Michael P

2013-12-01

Alcohol relapse after liver transplant heightens concern about recurrent disease, nonadherence to the immunosuppression regimen, and death. To develop a scoring system to stratify risk of alcohol relapse after liver transplant. Retrospective medical record review. All adult liver transplants performed from May 2002 to February 2011 at a single center in the United States. The incidence of return to any alcohol consumption after liver transplant. Thirty-four percent (40/118) of patients with a history of alcohol abuse/dependency relapsed to use of any alcohol after liver transplant. Nine of 25 hypothesized risk factors were predictive of alcohol relapse after liver transplant: absence of hepatocellular carcinoma, tobacco dependence, continued alcohol use after liver disease diagnosis, low motivation for alcohol treatment, poor stress management skills, no rehabilitation relationship, limited social support, lack of nonmedical behavioral consequences, and continued engagement in social activities with alcohol present. Each independent predictor was assigned an Alcohol Relapse Risk Assessment (ARRA) risk value of 1 point, and patients were classified into 1 of 4 groups by ARRA score: ARRA I = 0, ARRA II = 1 to 3, ARRA III = 4 to 6, and ARRA IV = 7 to 9. Patients in the 2 higher ARRA classifications had significantly higher rates of alcohol relapse and were more likely to return to pretransplant levels of drinking. Alcohol relapse rates are moderately high after liver transplant. The ARRA is a valid and practical tool for identifying pretransplant patients with alcohol abuse or dependency at elevated risk of any alcohol use after liver transplant.

Smoking relapse situations among a community-recruited sample of Spanish daily smokers.

Science.gov (United States)

Piñeiro, Bárbara; López-Durán, Ana; Martínez-Vispo, Carmela; Fernández Del Río, Elena; Martínez, Úrsula; Rodríguez-Cano, Rubén; Míguez, M Carmen; Becoña, Elisardo

2017-12-01

Relapse is a common factor within the behavior change process. However, there is scarce and limited knowledge of smoking relapse situations in population-based samples. The aim of this study was to identify smoking relapse situations among a sample of Spanish relapsers from the general population. A sample of 775 relapsers was recruited among the general population using a snowball method. Participants completed a survey including sociodemographic, smoking-related and psychopathology variables. Smoking relapse situations were identified through specific questions assessing different aspects related to the last relapse episode. The majority of smoking relapse situations were attributed to positive affect (36.6%) and negative affect (34.3%), followed by lack of control (10.1%), smoking habit (6.7%), craving or nicotine withdrawal (6.3%), and social pressure (5.9%). Being unemployed and having a mental disorder in the past increased the likelihood of relapse in situations of negative affect. Being single and having quit smoking to save money were associated with an increased likelihood of relapse in situations of positive affect. Affect plays a significant role in smoking relapse among a community sample of unassisted Spanish smokers. Relapse may be much more of an affective and situational process than a habit, physiological or social pressure. Findings from this study may help develop tailored community smoking relapse prevention strategies or programs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rb-Sr mantle isochrons from oceanic regions

Energy Technology Data Exchange (ETDEWEB)

Brooks, C; Hart, S R; Hofmann, A; James, D E [Carnegie Institution of Washington, D.C. (USA). Dept. of Terrestrial Magnetism

1976-09-01

Existing data for /sup 87/Sr//sup 86/Sr and Rb/Sr ratios of basalts from oceanic islands and mid-ocean spreading ridges show significant positive correlations on a Rb-Sr isochron diagram (when data are averaged by island group). Furthermore, tholeiites and alkali basalts occupy distinct non-overlapping fields on this plot. The tholeiite correlation is interpreted as a mantle isochron, and the agreement of this age (1.6+-0.2 b.y.) with that reported for Pb-Pb isochrons from oceanic basalts lends strong support to the use of such isochrons for tracing mantle evolution. Oceanic basalts are apparently sampling a mantle in which chemical heterogeneities have persisted for at least 1.5-2.0 b.y. The data support a kinematic model for the mantle in which a relatively uniform and non-radiogenic asthenosphere is penetrated by, and mixed with, blobs or plumes derived from an isolated (1.5-2 b.y.) and chemically heterogeneous mesosphere.

Mantle helium in the Red Sea brines

International Nuclear Information System (INIS)

Lupton, J.E.; Weiss, R.F.; Craig, H.

1977-01-01

It is stated that He isotope studies of terrestrial samples have shown the existence of two He components that are clearly distinct from atmospheric He. These are termed 'crustal' He and 'mantle' He; the latter was discovered as 'excess 3 He' in deep ocean water and attributed to a flux of primordial He from the mantle. Studies of the 3 He/ 4 He ratio in deep Pacific water and in He trapped in submarine basalt glasses showed that this 'mantle' component is characterised by ratios about ten times the atmospheric ratio and 100 times the ratio in 'crustal' He. Basalt glasses from other deep sea waters also showed similar ratios, and it is indicated that 'mantle' He in areas in which new lithosphere is being formed has a unique and uniform isotopic signature. Measurements of He and Ne are here reported that reveal additional information on the origin of Red Sea brines and their relationship to the Red Sea rifts. (U.K.)

Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer

International Nuclear Information System (INIS)

Ono, Hiroshi; Motoi, Noriko; Nagano, Hiroko; Miyauchi, Eisaku; Ushijima, Masaru; Matsuura, Masaaki; Okumura, Sakae; Nishio, Makoto; Hirose, Tetsuro; Inase, Naohiko; Ishikawa, Yuichi

2014-01-01

Small-cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. To identify accurate predictive biomarkers and effective therapeutic modalities, we focus on a long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR), and investigated its expression, cellular functions, and clinical relevance in SCLC. In this study, HOTAIR expression was assessed in 35 surgical SCLC samples and 10 SCLC cell lines. The efficacy of knockdown of HOTAIR by siRNA transfection was evaluated in SBC-3 cells in vitro, and the gene expression was analyzed using microarray. HOTAIR was expressed highly in pure, rather than combined, SCLC (P = 0.012), that the subgroup with high expression had significantly more pure SCLC (P = 0.04), more lymphatic invasion (P = 0.03) and more relapse (P = 0.04) than the low-expression subgroup. The knockdown of HOTAIR in SBC-3 cells led to decreased proliferation activity and decreased invasiveness in vitro. Gene expression analysis indicated that depletion of HOTAIR resulted in upregulation of cell adhesion-related genes such as ASTN1, PCDHA1, and mucin production-related genes such as MUC5AC, and downregulation of genes involved in neuronal growth and signal transduction including NTM and PTK2B. Our results suggest that HOTAIR has an oncogenic role in SCLC and could be a prognostic biomarker and therapeutic target

Continental smokers couple mantle degassing and distinctive microbiology within continents

Science.gov (United States)

Crossey, Laura J.; Karlstrom, Karl E.; Schmandt, Brandon; Crow, Ryan R.; Colman, Daniel R.; Cron, Brandi; Takacs-Vesbach, Cristina D.; Dahm, Clifford N.; Northup, Diana E.; Hilton, David R.; Ricketts, Jason W.; Lowry, Anthony R.

2016-02-01

The discovery of oceanic black (and white) smokers revolutionized our understanding of mid-ocean ridges and led to the recognition of new organisms and ecosystems. Continental smokers, defined here to include a broad range of carbonic springs, hot springs, and fumaroles that vent mantle-derived fluids in continental settings, exhibit many of the same processes of heat and mass transfer and ecosystem niche differentiation. Helium isotope (3He/4He) analyses indicate that widespread mantle degassing is taking place in the western U.S.A., and that variations in mantle helium values correlate best with low seismic-velocity domains in the mantle and lateral contrasts in mantle velocity rather than crustal parameters such as GPS, proximity to volcanoes, crustal velocity, or composition. Microbial community analyses indicate that these springs can host novel microorganisms. A targeted analysis of four springs in New Mexico yield the first published occurrence of chemolithoautotrophic Zetaproteobacteria in a continental setting. These observations lead to two linked hypotheses: that mantle-derived volatiles transit through conduits in extending continental lithosphere preferentially above and at the edges of mantle low velocity domains. High CO2 and other constituents ultimately derived from mantle volatiles drive water-rock interactions and heterogeneous fluid mixing that help structure diverse and distinctive microbial communities.

Tectonic predictions with mantle convection models

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Coltice, Nicolas; Shephard, Grace E.

2018-04-01

Over the past 15 yr, numerical models of convection in Earth's mantle have made a leap forward: they can now produce self-consistent plate-like behaviour at the surface together with deep mantle circulation. These digital tools provide a new window into the intimate connections between plate tectonics and mantle dynamics, and can therefore be used for tectonic predictions, in principle. This contribution explores this assumption. First, initial conditions at 30, 20, 10 and 0 Ma are generated by driving a convective flow with imposed plate velocities at the surface. We then compute instantaneous mantle flows in response to the guessed temperature fields without imposing any boundary conditions. Plate boundaries self-consistently emerge at correct locations with respect to reconstructions, except for small plates close to subduction zones. As already observed for other types of instantaneous flow calculations, the structure of the top boundary layer and upper-mantle slab is the dominant character that leads to accurate predictions of surface velocities. Perturbations of the rheological parameters have little impact on the resulting surface velocities. We then compute fully dynamic model evolution from 30 and 10 to 0 Ma, without imposing plate boundaries or plate velocities. Contrary to instantaneous calculations, errors in kinematic predictions are substantial, although the plate layout and kinematics in several areas remain consistent with the expectations for the Earth. For these calculations, varying the rheological parameters makes a difference for plate boundary evolution. Also, identified errors in initial conditions contribute to first-order kinematic errors. This experiment shows that the tectonic predictions of dynamic models over 10 My are highly sensitive to uncertainties of rheological parameters and initial temperature field in comparison to instantaneous flow calculations. Indeed, the initial conditions and the rheological parameters can be good enough

Pb evolution in the Martian mantle

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Bellucci, J. J.; Nemchin, A. A.; Whitehouse, M. J.; Snape, J. F.; Bland, P.; Benedix, G. K.; Roszjar, J.

2018-03-01

The initial Pb compositions of one enriched shergottite, one intermediate shergottite, two depleted shergottites, and Nakhla have been measured by Secondary Ion Mass Spectrometry (SIMS). These values, in addition to data from previous studies using an identical analytical method performed on three enriched shergottites, ALH 84001, and Chassigny, are used to construct a unified and internally consistent model for the differentiation history of the Martian mantle and crystallization ages for Martian meteorites. The differentiation history of the shergottites and Nakhla/Chassigny are fundamentally different, which is in agreement with short-lived radiogenic isotope systematics. The initial Pb compositions of Nakhla/Chassigny are best explained by the late addition of a Pb-enriched component with a primitive, non-radiogenic composition. In contrast, the Pb isotopic compositions of the shergottite group indicate a relatively simple evolutionary history of the Martian mantle that can be modeled based on recent results from the Sm-Nd system. The shergottites have been linked to a single mantle differentiation event at 4504 Ma. Thus, the shergottite Pb isotopic model here reflects a two-stage history 1) pre-silicate differentiation (4504 Ma) and 2) post-silicate differentiation to the age of eruption (as determined by concordant radiogenic isochron ages). The μ-values (238U/204Pb) obtained for these two different stages of Pb growth are μ1 of 1.8 and a range of μ2 from 1.4-4.7, respectively. The μ1-value of 1.8 is in broad agreement with enstatite and ordinary chondrites and that proposed for proto Earth, suggesting this is the initial μ-value for inner Solar System bodies. When plotted against other source radiogenic isotopic variables (Sri, γ187Os, ε143Nd, and ε176Hf), the second stage mantle evolution range in observed mantle μ-values display excellent linear correlations (r2 > 0.85) and represent a spectrum of Martian mantle mixing-end members (depleted

CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies.

Science.gov (United States)

Zhang, Li-Na; Song, Yongping; Liu, Delong

2018-03-15

The prognosis of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains dismal even at this day and age. With salvage chemotherapy, only 29% (range 18 to 44%) of the patients with R/R ALL can be induced into complete remission (CR), with a median overall survival (OS) of 4 months (range 2-6 months). Blinatumomab and inotuzumab ozogamycin (IO) are immunotherapeutic agents that increased CR to 80% and extended survival to 7.7 months in this high-risk population of patients. In the last few years, chimeric antigen receptor (CAR)--engineered T cells have led to major progress in cancer immunotherapy. CD-19 CAR-T cells have been recently approved for high-risk R/R ALL and lymphoma. The data from long-term follow-up of a single-center phase I study of 19-28z CAR-T cell therapy for adult R/R ALL were just published. At the same time, a multicenter phase II study of 19-41BB CAR-T cell therapy for children and young adults with R/R B cell ALL was also published. The two studies provided fresh information with long-term follow-up. This research highlight analyzed the data and proposed future perspectives for further investigation in this rapidly evolving field.

Therapeutic efficacy of monthly subcutaneous injection of daclizumab in relapsing multiple sclerosis

Science.gov (United States)

Cohan, Stanley

2016-01-01

Despite the availability of multiple disease-modifying therapies for relapsing multiple sclerosis (MS), there remains a need for highly efficacious targeted therapy with a favorable benefit–risk profile and attributes that encourage a high level of treatment adherence. Daclizumab is a humanized monoclonal antibody directed against CD25, the α subunit of the high-affinity interleukin 2 (IL-2) receptor, that reversibly modulates IL-2 signaling. Daclizumab treatment leads to antagonism of proinflammatory, activated T lymphocyte function and expansion of immunoregulatory CD56bright natural killer cells, and has the potential to, at least in part, rectify the imbalance between immune tolerance and autoimmunity in relapsing MS. The clinical pharmacology, efficacy, and safety of subcutaneous daclizumab have been evaluated extensively in a large clinical study program. In pivotal studies, daclizumab demonstrated superior efficacy in reducing clinical and radiologic measures of MS disease activity compared with placebo or intramuscular interferon beta-1a, a standard-of-care therapy for relapsing MS. The risk of hepatic disorders, cutaneous events, and infections was modestly increased. The monthly subcutaneous self-injection dosing regimen of daclizumab may be advantageous in maintaining patient adherence to treatment, which is important for optimal outcomes with MS disease-modifying therapy. Daclizumab has been approved in the US and in the European Union and represents an effective new treatment option for patients with relapsing forms of MS, and is currently under review by other regulatory agencies. PMID:27672308

Thermally-Driven Mantle Plumes Reconcile Hot-spot Observations

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Davies, D.; Davies, J.

2008-12-01

Hot-spots are anomalous regions of magmatism that cannot be directly associated with plate tectonic processes (e.g. Morgan, 1972). They are widely regarded as the surface expression of upwelling mantle plumes. Hot-spots exhibit variable life-spans, magmatic productivity and fixity (e.g. Ito and van Keken, 2007). This suggests that a wide-range of upwelling structures coexist within Earth's mantle, a view supported by geochemical and seismic evidence, but, thus far, not reproduced by numerical models. Here, results from a new, global, 3-D spherical, mantle convection model are presented, which better reconcile hot-spot observations, the key modification from previous models being increased convective vigor. Model upwellings show broad-ranging dynamics; some drift slowly, while others are more mobile, displaying variable life-spans, intensities and migration velocities. Such behavior is consistent with hot-spot observations, indicating that the mantle must be simulated at the correct vigor and in the appropriate geometry to reproduce Earth-like dynamics. Thermally-driven mantle plumes can explain the principal features of hot-spot volcanism on Earth.

Extinction of relapsed fear does not require the basolateral amygdala.

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Lingawi, Nura W; Westbrook, R Frederick; Laurent, Vincent

2017-03-01

It is well established that extinguished fears are restored with the passage of time or a change in physical context. These fear restoration phenomena are believed to mimic the conditions under which relapse occurs in patients that have been treated for anxiety disorders by means of cue-exposure therapy. Here, we used a rodent model to extinguish relapsed fear and assess whether this new extinction prevents further relapse. We found that activity in the basolateral amygdala (BLA) is required to initially extinguish conditioned fear, but this activity was not necessary to subsequently extinguish relapsed fear. That is, extinction of spontaneously recovered or renewed fear was spared by BLA inactivation. Yet, this BLA-independent learning of extinction did not protect against further relapse: extinction of relapsed fear conducted without BLA activity was still likely to return after the passage of time or a shift in physical context. These findings have important clinical implications. They indicate that pharmacological agents with anxiolytic properties may disrupt initial cue-exposure therapy but may be useful when therapy is again needed due to relapse. However, they also suggest that these agents will not protect against further relapse, implying the need for developing drugs that target other brain regions involved in fear inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

Outcome following late marrow relapse in childhood acute lymphoblastic leukemia

International Nuclear Information System (INIS)

Chessells, J.; Leiper, A.; Rogers, D.

1984-01-01

Thirty-four children with acute lymphoblastic leukemia, who developed bone marrow relapse after treatment was electively stopped, received reinduction, consolidation, continuing therapy, and intrathecal (IT) methotrexate (MTX). Sixteen children who relapsed within six months of stopping treatment had a median second-remission duration of 26 weeks; all next relapses occurred in the bone marrow. In 18 children who relapsed later, the median duration of second remission was in excess of two years, but after a minimum of four years follow-up, 16 patients have so far relapsed again (six in the CNS). CNS relapse occurred as a next event in four of 17 children who received five IT MTX injections only and in two of 14 children who received additional regular IT MTX. Although children with late marrow relapses may achieve long second remissions, their long-term out-look is poor, and regular IT MTX does not afford adequate CNS prophylaxis. It remains to be seen whether more intensive chemotherapy, including high-dose chemoradiotherapy and bone marrow transplantation, will improve the prognosis in this group of patients

Preventing relapse after incentivized choice treatment: A laboratory model.

Science.gov (United States)

Bouton, Mark E; Thrailkill, Eric A; Bergeria, Cecilia L; Davis, Danielle R

2017-08-01

Two experiments with rats examined relapse of an operant behavior that occurred after the behavior was suppressed by reinforcing (incentivizing) an alternative behavior. In the first phase, a target response (R1) was reinforced. In a treatment phase, R1 was still reinforced, but a new response (R2) was introduced and associated with a larger reinforcer. As in human contingency management treatments, incentivizing R2 this way was effective at suppressing R1. However, when R2's reinforcement was discontinued, there was a robust and immediate relapse to R1. Experiment 1 found that the strength of R1 during relapse testing was not different from that seen in a no treatment control. Experiment 2 found that relapse could nevertheless be reduced by presenting reinforcers not contingent on responding during the test. Either the reinforcer for R1 or the reinforcer for R2 (which were qualitatively different types of food pellets) were effective. The experiments introduce a laboratory method for studying relapse and how to prevent it after contingency management treatments, and suggest at least one treatment that discourages relapse. The incentivized choice paradigm differs from other models of relapse of operant behavior (e.g., resurgence, renewal, reinstatement) in that it does not focus on the return of behaviors that are inhibited by extinction. Copyright © 2017 Elsevier B.V. All rights reserved.

Lithology and temperature: How key mantle variables control rift volcanism

Science.gov (United States)

Shorttle, O.; Hoggard, M.; Matthews, S.; Maclennan, J.

2015-12-01

Continental rifting is often associated with extensive magmatic activity, emplacing millions of cubic kilometres of basalt and triggering environmental change. The lasting geological record of this volcanic catastrophism are the large igneous provinces found at the margins of many continents and abrupt extinctions in the fossil record, most strikingly that found at the Permo-Triassic boundary. Rather than being considered purely a passive plate tectonic phenomenon, these episodes are frequently explained by the involvement of mantle plumes, upwellings of mantle rock made buoyant by their high temperatures. However, there has been debate over the relative role of the mantle's temperature and composition in generating the large volumes of magma involved in rift and intra-plate volcanism, and even when the mantle is inferred to be hot, this has been variously attributed to mantle plumes or continental insulation effects. To help resolve these uncertainties we have combined geochemical, geophysical and modelling results in a two stage approach: Firstly, we have investigated how mantle composition and temperature contribute to melting beneath Iceland, the present day manifestation of the mantle plume implicated in the 54Ma break up of the North Atlantic. By considering both the igneous crustal production on Iceland and the chemistry of its basalts we have been able to place stringent constraints on the viable temperature and lithology of the Icelandic mantle. Although a >100°C excess temperature is required to generate Iceland's thick igneous crust, geochemistry also indicates that pyroxenite comprises 10% of its source. Therefore, the dynamics of rifting on Iceland are modulated both by thermal and compositional mantle anomalies. Secondly, we have performed a global assessment of the mantle's post break-up thermal history to determine the amplitude and longevity of continental insulation in driving excess volcanism. Using seismically constrained igneous crustal

Dynamical links between small- and large-scale mantle heterogeneity: Seismological evidence

Science.gov (United States)

Frost, Daniel A.; Garnero, Edward J.; Rost, Sebastian

2018-01-01

We identify PKP • PKP scattered waves (also known as P‧ •P‧) from earthquakes recorded at small-aperture seismic arrays at distances less than 65°. P‧ •P‧ energy travels as a PKP wave through the core, up into the mantle, then scatters back down through the core to the receiver as a second PKP. P‧ •P‧ waves are unique in that they allow scattering heterogeneities throughout the mantle to be imaged. We use array-processing methods to amplify low amplitude, coherent scattered energy signals and resolve their incoming direction. We deterministically map scattering heterogeneity locations from the core-mantle boundary to the surface. We use an extensive dataset with sensitivity to a large volume of the mantle and a location method allowing us to resolve and map more heterogeneities than have previously been possible, representing a significant increase in our understanding of small-scale structure within the mantle. Our results demonstrate that the distribution of scattering heterogeneities varies both radially and laterally. Scattering is most abundant in the uppermost and lowermost mantle, and a minimum in the mid-mantle, resembling the radial distribution of tomographically derived whole-mantle velocity heterogeneity. We investigate the spatial correlation of scattering heterogeneities with large-scale tomographic velocities, lateral velocity gradients, the locations of deep-seated hotspots and subducted slabs. In the lowermost 1500 km of the mantle, small-scale heterogeneities correlate with regions of low seismic velocity, high lateral seismic gradient, and proximity to hotspots. In the upper 1000 km of the mantle there is no significant correlation between scattering heterogeneity location and subducted slabs. Between 600 and 900 km depth, scattering heterogeneities are more common in the regions most remote from slabs, and close to hotspots. Scattering heterogeneities show an affinity for regions close to slabs within the upper 200 km of the

Flow in the Deep Mantle from Seisimc Anisotropy: Progress and Prospects

Science.gov (United States)

Long, M. D.

2017-12-01

Observations of seismic anisotropy, or the directional dependence of seismic wavespeeds, provide one some of the most direct constraints on the pattern of flow in the Earth's mantle. In particular, as our understanding of crystallographic preferred orientation (CPO) of olivine aggregates under a range of deformation conditions has improved, our ability to exploit observations of upper mantle anisotropy has led to fundamental discoveries about the patterns of flow in the upper mantle and the drivers of that flow. It has been a challenge, however, to develop a similar framework for understanding flow in the deep mantle (transition zone, uppermost lower mantle, and lowermost mantle), even though there is convincing observational evidence for seismic anisotropy at these depths. Recent progress on the observational front has allowed for an increasingly detailed view of mid-mantle anisotropy (transition zone and uppermost lower mantle), particularly in subduction systems, which may eventually lead to a better understanding of mid-mantle deformation and the dynamics of slab interaction with the surrounding mid-mantle. New approaches to the observation and modeling of lowermost mantle anisotropy, in combination with constraints from mineral physics, are progressing towards interpretive frameworks that allow for the discrimination of different mantle flow geometries in different regions of D". In particular, observational strategies that involve the use of multiple types of body wave phases sampled over a range of propagation azimuths enable detailed forward modeling approaches that can discriminate between different mechanisms for D" anisotropy (e.g., CPO of post-perovskite, bridgmanite, or ferropericlase, or shape preferred orientation of partial melt) and identify plausible anisotropic orientations. We have recently begun to move towards a full waveform modeling approach in this work, which allows for a more accurate simulation for seismic wave propagation. Ongoing

Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial

Directory of Open Access Journals (Sweden)

Francine Foss

2016-03-01

Full Text Available Abstract Background Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD. Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25 % (33/130, including 15 % with confirmed/unconfirmed complete response and a median duration of response of 28 months. Our objective was to further study the clinical benefits of romidepsin in patients that had the best response of SD. Methods Patients with PTCL relapsed/refractory to ≥1 prior therapy were treated with the approved dose of 14 mg/m2 romidepsin on days 1, 8, and 15 of six 28-day cycles; patients with SD or response after cycle 6 were allowed to continue on study until progression. By protocol amendment, patients treated for ≥12 cycles could receive maintenance dosing twice per cycle; after cycle 24, dosing could be further reduced to once per cycle in those who had received maintenance dosing for ≥6 months. Results Of the 32 patients (25 % with the best response of SD, 22 had SD for ≥90 days (SD90; cycle 4 response assessment. The longest SD was >3 years in a patient who received maintenance dosing of 14 mg/m2 on days 1 and 15 beginning in cycle 13. Patients with the best response of SD90 or partial response achieved similar overall and progression-free survival. Prolonged dosing of romidepsin was well tolerated. Conclusions We concluded that patients who achieve SD may consider continuing treatment because the clinical benefits of romidepsin may extend beyond objective responses. Trial registration NCT00426764

Quantifying mantle structure and dynamics using plume tracing in seismic tomography

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O'Farrell, K. A.; Eakin, C. M.; Jackson, M. G.; Jones, T. D.; Lekic, V.; Lithgow-Bertelloni, C. R.

2017-12-01

Directly linking deep mantle processes with surface features and dynamics is a complex problem. Hotspot volcanism gives us surface observables of mantle signatures, but the depth and source of the mantle plumes feeding these hotspots are highly debated. To address these issues, it is necessary to consider the entire journey of a plume through the mantle. By analyzing the behavior of mantle plumes we can constrain the vigor of mantle convection, the net rotation of the mantle and the role of thermal versus chemical anomalies as well as the bulk physical properties such as the viscosity profile. To do this, we developed a new algorithm to trace plume-like features in shear-wave (Vs) seismic tomography models based on picking local minima in the velocity and searching for continuous features with depth. We applied this method to recent tomographic models and find 60+ continuous plume conduits that are > 750 km long. Approximately a third of these can be associated with known hotspots at the surface. We analyze the morphology of these continuous conduits and infer large scale mantle flow patterns and properties. We find the largest lateral deflections in the conduits occur near the base of the lower mantle and in the upper mantle (near the thermal boundary layers). The preferred orientation of the plume deflections show large variability at all depths and indicate no net mantle rotation. Plate by plate analysis shows little agreement in deflection below particular plates, indicating these deflected features might be long lived and not caused by plate shearing. Changes in the gradient of plume deflection are inferred to correspond with viscosity contrasts in the mantle and found below the transition zone as well as at 1000 km depth. From this inferred viscosity structure, we explore the dynamics of a plume through these viscosity jumps. We also retrieve the Vs profiles for the conduits and compare with the velocity profiles predicted for different mantle adiabat

Radiological safety assessment of gas mantle industries in India

International Nuclear Information System (INIS)

Sadagopan, G.; Venkataraman, G.

1994-01-01

Thorium, a radioactive element of actinide family was discovered by Berzelius in 1828 and named by him in honor of the Scandinavian God open-quote Thor close-quote. Following its discovery the earliest known use of thorium was in the making of gas mantles. The other use as an X-ray contrast medium open-quote Thorotrast close-quote has since long been discontinued, where as even today its use in gas mantles is continued. Gas lights have been used as a source of light since 1800's. In India, although electric bulbs have replaced most of the gas lights, even today in villages and in urban areas where there is no continuous power supply and in outdoor lightings gas lamps are used. The mantle which is used in these lamps is called the Welsbach mantle and is a netted hose that is impregnated with thorium nitrate and other metals. The function of a gas mantle is to produce a bright light during operation of the lighting device (gas or kerosene lamp) in which the mantle is placed. When placed in a lighting device and heated to 1300-1800 degree Celcius thorium in the mantle incandesces and gives off bright light. In India presently there are about 70 manufacturing units handling 150 metric tons of thorium nitrate annually. There are about four hundred persons involved in manufacturing 200 million mantles per year. Thorium is chosen because of its property of incadescence, however since it is radioactive, radiation safety of the workplace, handling personnel and safe environmental condition for members of public have to be maintained

Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial

DEFF Research Database (Denmark)

Kuhlen, Michaela; Willasch, Andre M; Dalle, Jean-Hugues

2018-01-01

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We...... analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years....... The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative...

Relapsing-Remitting MS (RRMS)

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Executive Summary: “Mantle Frontier” Workshop

Directory of Open Access Journals (Sweden)

Workshop Report Writing Group

2011-03-01

Full Text Available The workshop on “Reaching the Mantle Frontier: Moho and Beyond” was held at the Broad Branch Road Campus of the Carnegie Institution of Washington on 9–11 September 2010. The workshop attracted seventy-four scientists and engineers from academia and industry in North America, Asia, and Europe.Reaching and sampling the mantle through penetration of the entire oceanic crust and the Mohorovičić discontinuity (Moho has been a longstanding goal of the Earth science community. The Moho is a seismic transition, often sharp, from a region with compressional wave velocities (Vp less than 7.5 km s-1 to velocities ~8 km s-1. It is interpreted in many tectonic settings, and particularly in tectonic exposures of oceanic lower crust, as the transition from igneous crust to mantle rocks that are the residues of melt extraction. Revealing the in situ geological meaning of the Moho is the heart of the Mohole project. Documenting ocean-crust exchanges and the nature and extent of the subseafloor biosphere have also become integral components of the endeavor. The purpose of the “Mantle Frontier” workshop was to identify key scientific objectives associated with innovative technology solutions along with associated timelines and costs for developments and implementation of this grandchallenge.

Incidence of extramedullary relapse after haploidentical SCT for advanced AML/myelodysplastic syndrome.

Science.gov (United States)

Yoshihara, S; Ikegame, K; Kaida, K; Taniguchi, K; Kato, R; Inoue, T; Fujioka, T; Tamaki, H; Okada, M; Soma, T; Ogawa, H

2012-05-01

Extramedullary (EM) relapse of leukemia after allo-SCT in patients with AML/myelodysplastic syndrome has been increasingly reported. The reduced effectiveness of the GVL effect in EM sites, as compared with BM, has been suggested to underlie this problem. We retrospectively analyzed the pattern of relapse after haploidentical SCT (haplo-SCT), performed as the first or second SCT. Among 38 patients who received haplo-SCT as their first SCT, the cumulative incidences of BM and EM relapse at 3 years were 40.5 and 10.9%, respectively. Among 19 patients who received haplo-SCT as their second SCT, the cumulative incidences of BM and EM relapse were 30.9 and 31.9%, respectively. Moreover, most of the patients who underwent repeat haplo-SCT for the treatment of EM relapse had further EM relapse at other sites. Post-relapse survival did not differ significantly with different patterns of relapse. The frequent occurrence of EM relapse after haplo-SCT, particularly when performed as a second SCT, suggests that the potent GVL effect elicited by an HLA disparity also occurs preferentially in BM. Our findings emphasize the need for a treatment strategy for EM relapse that recognizes the reduced susceptibility of EM relapse to the GVL effect.

Reconciling laboratory and observational models of mantle rheology in geodynamic modelling

Science.gov (United States)

King, Scott D.

2016-10-01

Experimental and geophysical observations constraining mantle rheology are reviewed with an emphasis on their impact on mantle geodynamic modelling. For olivine, the most studied and best-constrained mantle mineral, the tradeoffs associated with the uncertainties in the activation energy, activation volume, grain-size and water content allow the construction of upper mantle rheology models ranging from nearly uniform with depth to linearly increasing from the base of the lithosphere to the top of the transition zone. Radial rheology models derived from geophysical observations allow for either a weak upper mantle or a weak transition zone. Experimental constraints show that wadsleyite and ringwoodite are stronger than olivine at the top of the transition zone; however the uncertainty in the concentration of water in the transition zone precludes ruling out a weak transition zone. Both observational and experimental constraints allow for strong or weak slabs and the most promising constraints on slab rheology may come from comparing inferred slab geometry from seismic tomography with systematic studies of slab morphology from dynamic models. Experimental constraints on perovskite and ferropericlase strength are consistent with general feature of rheology models derived from geophysical observations and suggest that the increase in viscosity through the top of the upper mantle could be due to the increase in the strength of ferropericlase from 20-65 GPa. The decrease in viscosity in the bottom half of the lower mantle could be the result of approaching the melting temperature of perovskite. Both lines of research are consistent with a high-viscosity lithosphere, a low viscosity either in the upper mantle or transition zone, and high viscosity in the lower mantle, increasing through the upper half of the lower mantle and decreasing in the bottom half of the lower mantle, with a low viscosity above the core. Significant regions of the mantle, including high

Lithospheric mantle evolution in the Afro-Arabian domain: Insights from Bir Ali mantle xenoliths (Yemen)

Science.gov (United States)

Sgualdo, P.; Aviado, K.; Beccaluva, L.; Bianchini, G.; Blichert-Toft, J.; Bryce, J. G.; Graham, D. W.; Natali, C.; Siena, F.

2015-05-01

Detailed petrological and geochemical investigations of an extensive sampling of mantle xenoliths from the Neogene-Quaternary Bir Ali diatreme (southern Yemen) indicate that the underlying lithospheric mantle consists predominantly of medium- to fine-grained (often foliated) spinel-peridotites (85-90%) and spinel-pyroxenites (10-15%) showing thermobarometric estimates in the P-T range of 0.9-2.0 GPa and 900-1150 °C. Peridotites, including lherzolites, harzburgites and dunites delineate continuous chemical, modal and mineralogical variations compatible with large extractions of basic melts occurring since the late Proterozoic (~ 2 Ga, according to Lu-Hf model ages). Pyroxenites may represent intrusions of subalkaline basic melts interacting and equilibrated with the host peridotite. Subsequent metasomatism has led to modal changes, with evidence of reaction patches and clinopyroxene and spinel destabilization, as well as formation of new phases (glass, amphibole and feldspar). These changes are accompanied by enrichment of the most incompatible elements and isotopic compositions. 143Nd/144Nd ranges from 0.51419 to 0.51209 (εNd from + 30.3 to - 10.5), 176Hf/177Hf from 0.28459 to 0.28239 (εHf from + 64.4 to - 13.6), and 208Pb/204Pb from 36.85 to 41.56, thus extending from the depleted mantle (DM) towards the enriched OIB mantle (EM and HIMU) components. 3He/4He (R/RA) ratios vary from 7.2 to 7.9 with He concentrations co-varying with the most incompatible element enrichment, in parallel with metasomatic effects. These metasomatic events, particularly effective in harzburgites and dunites, are attributable to the variable interaction with alkaline basic melts related to the general extensional and rifting regime affecting the East Africa-Arabian domain during the Cenozoic. In this respect, Bir Ali mantle xenoliths resemble those occurring along the Arabian margins and the East Africa Rift system, similarly affected by alkaline metasomatism, whereas they are

Synergistic suppression of the PI3K inhibitor CAL-101 with bortezomib on mantle cell lymphoma growth

International Nuclear Information System (INIS)

Qu, Fu-Lian; Xia, Bing; Li, Su-Xia; Tian, Chen; Yang, Hong-Liang; Li, Qian; Wang, Ya-Fei; Yu, Yong; Zhang, Yi-Zhuo

2015-01-01

To investigate the effects of CAL-101, particularly when combined with bortezomib (BTZ) on mantle cell lymphoma (MCL) cells, and to explore its relative mechanisms. MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B (NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups. CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment. Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ

Beyond low-level activity: On a 'non-radioactive' gas mantle

International Nuclear Information System (INIS)

Poljanc, Karin; Steinhauser, Georg; Sterba, Johannes H.; Buchtela, Karl; Bichler, Max

2007-01-01

Gas mantles for camping gas lanterns sometimes contain thorium compounds. During the last years, the use of thorium-free gas mantles has become more and more popular due to the avoidance of a radioactive heavy metal. We investigated a gas mantle type that is declared to be 'non-radioactive' and that can be bought in Austria at the moment. Methods used were Instrumental Neutron Activation Analysis (INAA), γ-spectroscopy, and Liquid Scintillation Counting (LSC). We found massive thorium contents of up to 259 mg per gas mantle. Leaching experiments showed that only 0.4% of the Th but approximately 90% of the decay products of 232 Th can be leached under conditions simulating sucking and chewing with human saliva. In this paper, the investigation of these gas mantles including the consideration of the environmental hazard caused by disposed mantles and the health hazard for unsuspecting consumers is presented and legal consequences are discussed for this fraud

[Clinical and biological prognostic factors in relapsed acute myeloid leukemia patients].

Science.gov (United States)

Yébenes-Ramírez, Manuel; Serrano, Josefina; Martínez-Losada, Carmen; Sánchez-García, Joaquín

2016-09-02

Acute myeloid leukemia (AML) is the most frequent type of acute leukemia in adults. Despite recent advances in the characterization of pathogenesis of AML, the cure rates are under 40%, being leukemia relapse the most common cause of treatment failure. Leukaemia relapse occurs due to clonal evolution or clonal escape. In this study, we aimed to analyze the clinical and biological factors influencing outcomes in patients with AML relapse. We included a total of 75 AML patients who experienced leukaemia relapse after achieving complete remission. We performed complete immunophenotyping and conventional karyotyping in bone marrow aspirates obtained at diagnosis and at leukemia relapse. Overall survival (OS) of the series was 3.7%±2.3, leukaemia progression being the most common cause of death. Patients relapsing before 12 months and those with adverse cytogenetic-molecular risk had statistically significant worse outcomes. A percentage of 52.5 of patients showed phenotypic changes and 50% cytogenetic changes at relapse. We did not find significant clinical factors predicting clonal evolution. The presence of clonal evolution at relapse did not have a significant impact on outcome. Patients with relapsed AML have a dismal prognosis, especially those with early relapse and adverse cytogenetic-molecular risk. Clonal evolution with phenotypic and cytogenetic changes occurred in half of the patients without predictive clinical factors or impact on outcome. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Intraplate mantle oxidation by volatile-rich silicic magmas

Energy Technology Data Exchange (ETDEWEB)

Martin, Audrey M.; Médard, Etienne; Righter, Kevin; Lanzirotti, Antonio

2017-11-01

The upper subcontinental lithospheric mantle below the French Massif Central is more oxidized than the average continental lithosphere, although the origin of this anomaly remains unknown. Using iron oxidation analysis in clinopyroxene, oxybarometry, and melt inclusions in mantle xenoliths, we show that widespread infiltration of volatile (HCSO)-rich silicic melts played a major role in this oxidation. We propose the first comprehensive model of magmatism and mantle oxidation at an intraplate setting. Two oxidizing events occurred: (1) a 365–286 Ma old magmatic episode that produced alkaline vaugnerites, potassic lamprophyres, and K-rich calc-alkaline granitoids, related to the N–S Rhenohercynian subduction, and (2) < 30 Ma old magmatism related to W–E extension, producing carbonatites and hydrous potassic trachytes. These melts were capable of locally increasing the subcontinental lithospheric mantle fO2 to FMQ + 2.4. Both events originate from the melting of a metasomatized lithosphere containing carbonate + phlogopite ± amphibole. The persistence of this volatile-rich lithospheric source implies the potential for new episodes of volatile-rich magmatism. Similarities with worldwide magmatism also show that the importance of volatiles and the oxidation of the mantle in intraplate regions is underestimated.

De Novo CD5 Negative Blastic Mantle Cell Lymphoma Presented with Massive Bone Marrow Necrosis without Adenopathy or Organomegaly

Directory of Open Access Journals (Sweden)

Ghaleb Elyamany

2015-01-01

Full Text Available The recent World Health Organization (WHO classification defines mantle cell lymphoma (MCL as a distinct entity characterized by a unique immunophenotype and a molecular hallmark of chromosomal translocation t(11;14(q13;q32. We report an unusual case of an advanced stage of CD5 negative MCL with a blastoid variant with a massive bone marrow (BM necrosis as an initial presenting feature, with no adenopathy or hepatosplenomegaly. The pathologic features showed blastoid variant of MCL and flow cytometry showed that the tumor cells were CD5−, CD19+, CD20+, FMC-7+, CD23−, and lambda light chain restricted. Chromosomal analysis, using karyotype and fluorescent in situ hybridization (FISH, demonstrated karyotypic abnormalities in addition to the t(11;14. Our case study may be reported as a unique case of CD5− blastic MCL with unusual presentation and findings which made the diagnosis of MCL difficult.

Postpartum smoking relapse--a thematic synthesis of qualitative studies.

Science.gov (United States)

Notley, Caitlin; Blyth, Annie; Craig, Jean; Edwards, Alice; Holland, Richard

2015-11-01

Many women quit smoking during pregnancy, but relapse after the baby is born. To understand why and identify ways of preventing this, this study reviewed the qualitative literature on women's experience of postpartum smoking relapse. A systematic review of qualitative studies and process evaluations of trials. We undertook a thematic synthesis of published qualitative data. We screened 1336 papers. Twenty-two papers reporting on 16 studies were included, reporting on the views of 1031 postpartum women. Factors affecting relapse and barriers and facilitators to relapse prevention were identified around the key themes of beliefs, social influences, motivation, physiological factors and identity. Women's beliefs about smoking as a means of coping with stress and the need for social support, especially from a partner, emerged as important. Extrinsic motivation to quit during the pregnancy (for the health of the fetus) appeared to be a factor in prompting relapse after the baby was born. During the immediate postpartum period women believed that physiological changes influence cigarette cravings. The stress of caring for a newborn, sleeplessness and adjusting to a new mothering identity were also reported to be important. Among women who quit smoking during pregnancy, those who relapse postpartum talk commonly about no longer needing to protect the baby and the effects of stress. Partner support and a sense of changed identity are cited as factors preventing relapse. © 2015 Society for the Study of Addiction.

A multicentre phase-II feasibility study evaluating gemcitabine /vinorelbine / prednisolone combination chemotherapy in relapsed / refractory hodgkin's lymphoma

International Nuclear Information System (INIS)

Naqi, N.; Ahmad, S.; Shah, I.; Khattak, J.

2013-01-01

Objective: To determine the efficacy and toxicity of Gemcitabine, Vinorelbine and Prednisolone (GVP) salvage chemotherapy in relapsed / refractory Hodgkin's Lymphoma (HL). Study Design: A phase-II non-randomized single arm study. Place and Duration of Study: This study was conducted at Combined Military Hospital and Medical College Lahore, Mayo Hospital, King Edward Medical University, Lahore, Allied Hospital, Punjab Medical College, Faisalabad and Combined Military Hospital, Rawalpindi, from January 2007 to December 2007. Methodology: Fifty adult patients with relapsed/refractory HL, adequate marrow reserve, hepatorenal and pulmonary functions, with radiological measurable disease and Karnofsky performance status of 0 - 2 non-candidates for stem cell transplantation, were enrolled. Four 28 days cycles of GVP (Gemcitabine 1000 mg/m2, Vinorelbine 30 mg/m2 on day 1 and 8 intravenously with oral Prednisolone 100 mg/day on day 1 - 5) were given. Response evaluation done according to Cotswolds meeting recommendations and toxicity was evaluated with NCI-CTC (National Cancer Institute - Common Terminology Criteria for adverse events v 3.0). Results: Forty patients completing 4 cycles of GVP, 14 refractory/early relapse and 26 late relapsed (one year postprimary treatment with ABVD) were available for evaluation. The overall response (CRu+PR) rate was 77.5% with better response 85% in late relapsed patients. Haematological toxicity was most common and seen in 70% of cases. Conclusion: GVP is well-tolerated regimen with high response rate and needs to be tested in late relapsed HL. (author)

Water in geodynamical models of mantle convection and plate tectonics

Science.gov (United States)

Rodríguez-González, J.; Van Hunen, J.; Chotalia, K.; Lithgow-Bertelloni, C. R.; Rozel, A.; Tackley, P. J.; Nakagawa, T.

2017-12-01

The presence of water in the the mantle has a significant effect in the dynamical and thermal evolution of Earth, which partially explains the differences with other planets and is a key factor for the presence of life on Earth. First, a small amount of water can decrease the mantle viscosity by a several orders of magnitude, thereby changing the convection regime and affecting the thermal evolution. Second, the presence of water significantly changes the solidus curve, with crucial implications for melting. Third, water in the mantle can change the Clapeyron slope of mantle materials, which changes the depth at which phase transitions take place. The thermal and dynamical evolution of Earth under the presence of water in the mantle has been the focus of recent studies, but many questions remain unanswered. In this project we intend to investigate how the maximum water capacity of different mantle regions affects water transport and Earth's convective regime. We will study the effect phase transitions under the presence of water, which can change the buoyancy of slabs in the transition zone. We present preliminary results numerical models of global mantle convection for the whole history of earth using the numerical geodynamics software tool StagYY. We will use a new parametrisation of dehydration processes, obtained from high-resolution numerical simulations, to implement a more accurate description of the water released from the slab as it travels through the mantle. We have integrated recent experimental results of the water capacity of deep mantle minerals to study the water circulation and the total water budget. We use data from the most recent experiments and ab-inito calculations to implement a realistic rheology.

Solar combi system based on a mantle tank

DEFF Research Database (Denmark)

Yazdanshenas, Eshagh; Furbo, Simon

2007-01-01

A solar combisystem based on a mantle tank is investigated numerically and experimentally. Three different houses with four different radiator systems are considered for the simulations. The needed temperature for the auxiliary heater is determined for different houses and radiator systems....... The thermal performance of the solar combisystem is compared to the thermal performance of a solar domestic hot water system based on a mantle tank. In the experimental study, tank temperatures and the heat transfer coefficient for the top mantle for a discharge test is determined. The investigations showed...

Mantle temperature under drifting deformable continents during the supercontinent cycle

Science.gov (United States)

Yoshida, Masaki

2013-04-01

The thermal heterogeneity of the Earth's mantle under the drifting continents during a supercontinent cycle is a controversial issue in earth science. Here, a series of numerical simulations of mantle convection are performed in 3D spherical-shell geometry, incorporating drifting deformable continents and self-consistent plate tectonics, to evaluate the subcontinental mantle temperature during a supercontinent cycle. Results show that the laterally averaged temperature anomaly of the subcontinental mantle remains within several tens of degrees (±50 °C) throughout the simulation time. Even after the formation of the supercontinent and the development of subcontinental plumes due to the subduction of the oceanic plates, the laterally averaged temperature anomaly of the deep mantle under the continent is within +10 °C. This implies that there is no substantial temperature difference between the subcontinental and suboceanic mantles during a supercontinent cycle. The temperature anomaly immediately beneath the supercontinent is generally positive owing to the thermal insulation effect and the active upwelling plumes from the core-mantle boundary. In the present simulation, the formation of a supercontinent causes the laterally averaged subcontinental temperature to increase by a maximum of 50 °C, which would produce sufficient tensional force to break up the supercontinent. The periodic assembly and dispersal of continental fragments, referred to as the supercontinent cycle, bear close relation to the evolution of mantle convection and plate tectonics. Supercontinent formation involves complex processes of introversion, extroversion or a combination of these in uniting dispersed continental fragments, as against the simple opening and closing of individual oceans envisaged in Wilson cycle. In the present study, I evaluate supercontinent processes in a realistic mantle convection regime. Results show that the assembly of supercontinents is accompanied by a

Relapse Prevention: An Overview of Marlatts Cognitive- Behavioral Model

Directory of Open Access Journals (Sweden)

2008-11-01

Full Text Available Relapse prevention(RPis an important component of alcoholism treatment. The RP model proposed by Marlatt and Gordon suggests that both immediate determinants (e.g.,high- risk situations, coping skills, outcome expectancies, and the abstinence violation effect and covert antecedents (e.g., lifestyle factor and urges and cravings can contribute to relapse.The RP model also incorporates numerous specific and global intervention strategies that allow therapist and client to address each step of the relapse process. Specific interventions include identifying specific high-risk situations for each client and enhancing the client's skills for coping with those situations, increasing the client's self- efficacy, eliminating myths regarding alcohol's effects, managing lapses, and restructuring the client's perceptions of the relapse process. Global strategies comprise balancing the client's lifestyle and helping him or her develop positive addictions, employing stimulus control techniques and urgemanagement techniques, and developing relapse road maps. Several studies have provided theoretical and practical support for the RP model.

Predictive factors for relapse in patients on buprenorphine maintenance.

Science.gov (United States)

Ferri, Michael; Finlayson, Alistair J Reid; Wang, Li; Martin, Peter R

2014-01-01

Despite the dramatic increase in the use of buprenorphine for the treatment of opioid dependence, clinical outcomes of this treatment approach continue to need evaluation. This study examines factors associated with relapse and retention during buprenorphine treatment in a sample of opioid dependent outpatients. In a retrospective chart review of 62 patients with opioid dependence, relapse was determined by self-report, urine toxicology screens, and by checking the state controlled substance monitoring database. Data was analyzed using two-way tests of association and logistic regression. Patients with comorbid anxiety disorders, active benzodiazepine use (contrary to clinic policy), or active alcohol abuse, were significantly more likely to relapse. Patients who relapsed were also more likely to be on a higher buprenorphine maintenance dose. This study identifies relapse risk factors during buprenorphine treatment for opioid dependence. Future research is needed to determine whether modifying these factors may lead to improved treatment outcomes. © American Academy of Addiction Psychiatry.

The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma.

Science.gov (United States)

Ruella, Marco; Kenderian, Saad S; Shestova, Olga; Fraietta, Joseph A; Qayyum, Sohail; Zhang, Qian; Maus, Marcela V; Liu, Xiaobin; Nunez-Cruz, Selene; Klichinsky, Michael; Kawalekar, Omkar U; Milone, Michael; Lacey, Simon F; Mato, Anthony; Schuster, Stephen J; Kalos, Michael; June, Carl H; Gill, Saar; Wasik, Mariusz A

2016-06-01

Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner. MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models. MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 + ibrutinib arm and 0% to 20% of mice in the CTL019 arm, respectively, remained in long-term remission (P ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma. Clin Cancer Res; 22(11); 2684-96. ©2016 AACR. ©2016 American Association for Cancer Research.

Coldspots and hotspots - Global tectonics and mantle dynamics of Venus

Science.gov (United States)

Bindschadler, Duane L.; Schubert, Gerald; Kaula, William M.

1992-01-01

Based on geologic observations provided by Magellan's first cycle of data collection and recent models of mantle convection in spherical shells and crustal deformation, the major topographic and geologic features of Venus are incorporated into a model of global mantle dynamics. Consideration is given to volcanic rises, such as Beta Regio and Atla Regio, plateau-shaped highlands dominated by complex ridged terrain (e.g., Ovda Regio and Alpha Regio), and circular lowland regions, such as Atalanta Planitia. Each of these features is related to either mantle plumes (hotspots) or mantle downwellings (coldspots).

Osmium Isotopic Evolution of the Mantle Sources of Precambrian Ultramafic Rocks

Science.gov (United States)

Gangopadhyay, A.; Walker, R. J.

2006-12-01

The Os isotopic composition of the modern mantle, as recorded collectively by ocean island basalts, mid- oceanic ridge basalts (MORB) and abyssal peridotites, is evidently highly heterogeneous (γ Os(I) ranging from +25). One important question, therefore, is how and when the Earth's mantle developed such large-scale Os isotopic heterogeneities. Previous Os isotopic studies of ancient ultramafic systems, including komatiites and picrites, have shown that the Os isotopic heterogeneity of the terrestrial mantle can be traced as far back as the late-Archean (~ 2.7-2.8 Ga). This observation is based on the initial Os isotopic ratios obtained for the mantle sources of some of the ancient ultramafic rocks determined through analyses of numerous Os-rich whole-rock and/or mineral samples. In some cases, the closed-system behavior of these ancient ultramafic rocks was demonstrated via the generation of isochrons of precise ages, consistent with those obtained from other radiogenic isotopic systems. Thus, a compilation of the published initial ^{187}Os/^{188}Os ratios reported for the mantle sources of komatiitic and picritic rocks is now possible that covers a large range of geologic time spanning from the Mesozoic (ca. 89 Ma Gorgona komatiites) to the Mid-Archean (e.g., ca. 3.3 Ga Commondale komatiites), which provides a comprehensive picture of the Os isotopic evolution of their mantle sources through geologic time. Several Precambrian komatiite/picrite systems are characterized by suprachondritic initial ^{187}Os/^{188}Os ratios (e.g., Belingwe, Kostomuksha, Pechenga). Such long-term enrichments in ^{187}Os of the mantle sources for these rocks may be explained via recycling of old mafic oceanic crust or incorporation of putative suprachondritic outer core materials entrained into their mantle sources. The relative importance of the two processes for some modern mantle-derived systems (e.g., Hawaiian picrites) is an issue of substantial debate. Importantly, however, the

Spiritual Well-Being and Associated Factors with Relapse in Opioid Addicts.

Science.gov (United States)

Noormohammadi, Mohammad-Reza; Nikfarjam, Masoud; Deris, Fatemeh; Parvin, Neda

2017-03-01

Opioid dependence relapse is a complex and multidimensional problem, and lack of spiritual well-being is a major concern in opioid addicts. This study was conducted to determine spiritual well-being and factors associated with relapse among opioid addicts. This cross-sectional study was conducted from April 2015 to September 2015. According to purposive sampling, 312 eligible addicted patients were enrolled in the study. The patients had at least an attempt of detoxification in the past six months and referred to an outpatient detoxification clinic in Shahrekord (Southwest, Iran). They completed Paloutzian and Ellison's Spiritual Well-being Scale. A researcher-developed questionnaire consisting of demographic characteristics and 20 questions about associated factors with relapse was administered. Data were analysed by version 16.0 (SPSS Inc.,Chicago, IL) using one-way ANOVA, Pearson's correlation test, chi-square, Friedman test, and student's t-test. The most important factors associated with opioid dependence relapse consist of relation with an addict friend, unemployment, living expenses, family conflicts, and somatic pain. In the present study, 157 patients had never experienced relapse while the mean of relapse in the rest participants was (3.25±1.53) times. Furthermore, the addicted patients with relapse had significantly lower scores of spiritual well-being and its subscales compared with non-relapse patients (pspiritual well-being, family and economical, personal, and occupational factors as crucial factors in opiate addiction relapse.

Predictors of Exercise Relapse in a College Population.

Science.gov (United States)

Sullum, Julie; Clark, Matthew M.; King, Teresa K.

2000-01-01

Investigated factors that predicted exercise relapse among college students. Physically active undergraduates completed questionnaires measuring Prochaska's 10 processes for change of exercise, self-efficacy, and decisional balance. Exercise levels were assessed at baseline and 8 weeks later. At baseline, relapsers had significantly lower…

Increases in IgE, Eosinophils, and Mast Cells Can be Used in Diagnosis and to Predict Relapse of IgG4-Related Disease.

Science.gov (United States)

Culver, Emma L; Sadler, Ross; Bateman, Adrian C; Makuch, Mateusz; Cargill, Tamsin; Ferry, Berne; Aalberse, Rob; Barnes, Eleanor; Rispens, Theo

2017-09-01

IgG subclass 4-related disease (IgG4-RD) is characterized by increased serum levels of IgG4 and infiltration of biliary, pancreatic, and other tissues by IgG4-positive plasma cells. We assessed the prevalence of allergy and/or atopy, serum, and tissue IgE antibodies, and blood and tissue eosinophils in patients with IgG4-RD. We investigated the association between serum IgE and diagnosis and relapse of this disease. We performed a prospective study of 48 patients with IgG4-RD, 42 patients with an increased serum level of IgG4 with other inflammatory and autoimmune conditions (disease control subjects), and 51 healthy individuals (healthy control subjects) recruited from Oxford, United Kingdom from March 2010 through March 2014, and followed for a median of 41 months (range, 3-73 months). Serum levels of immunoglobulin were measured at diagnosis, during steroid treatment, and at disease relapse for patients with IgG4-RD; levels at diagnosis were compared with baseline levels of control subjects. Allergen-specific IgEs were measured using the IgE ImmunoCAP. Levels and distribution of IgG4 and IgE antibodies in lymphoid, biliary, and pancreatic tissues from patients with IgG4-RD and disease control subjects were measured by immunohistochemistry. We analyzed data using the Spearman rank correlation and receiver operating characteristic curves. Serum levels of IgG4 increased to 1.4 g/L or more, and IgE increased to 125 kIU/L or more, in 81% and 54% of patients with IgG4-RD, respectively, compared with 6% and 16% of healthy control subjects (P IgG4-RD versus 9% of healthy control subjects (P = .004). Of patients with IgG4-RD, 63% had a history of allergy and 40% had a history of atopy with an IgE-specific response; these values were 60% and 53% in patients with increased serum levels of IgE (P 480 kIU/L distinguished patients with IgG4-RD from disease control subjects with 86% specificity, 36% sensitivity, and a likelihood ratio of 3.2. Level of IgE at diagnosis >380 k

Magnitude corrections for attenuation in the upper mantle

International Nuclear Information System (INIS)

Anon.

1978-01-01

Since 1969, a consistent discrepancy in seismic magnitudes of nuclear detonations at NTS compared with magnitudes of detonations elsewhere in the world has been observed. This discrepancy can be explained in terms of a relatively high seismic attenuation for compressional waves in the upper mantle beneath the NTS and in certain other locations. A correction has been developed for this attenuation based on a relationship between the velocity of compressional waves at the top of the earth's mantle (just beneath the Mohorovicic discontinuity) and the seismic attenuation further down in the upper mantle. Our new definition of body-wave magnitude includes corrections for attenuation in the upper mantle at both ends of the teleseismic body-wave path. These corrections bring the NTS oservations into line with measurements of foreign events, and enable one to make more reliable estimates of yields of underground nuclear explosions, wherever the explosion occurs

Temporal changes in incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council Trials, 1985–2001

Science.gov (United States)

Krishnan, Shekhar; Wade, Rachel; Moorman, Anthony V; Mitchell, Chris; Kinsey, Sally E; Eden, TOB; Parker, Catriona; Vora, Ajay; Richards, Sue; Saha, Vaskar

2009-01-01

Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled on four successive MRC-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics assessed. Factors affecting post-relapse outcome were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (≥30 months from diagnosis) relapses (p<0·0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white cell count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced post-relapse outcomes. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends while in High Hyperdiploidy ALL, these appear to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimisation using currently available chemotherapy. PMID:20016529

Tumor relapse present in oncologic nasal repair

International Nuclear Information System (INIS)

Galvez Chavez, Julio Cesar; Sanchez Wals, Lenia; Monzon Fernandez, Abel Nicolas; Morales Tirado, Roxana

2009-01-01

Tumor relapse is one of the more fearsome complications of the oncologic course and also to obscure the life prognosis, causing the loss of many reconstructions and of exhausting the repairing surgical possibilities. The aim of this study was to determine the relapse frequency, the repercussion on the repair and the subsequent medical course of patients operated on malign nasal tumors

Assessment of local and regional isotopic equilibrium in the mantle

Energy Technology Data Exchange (ETDEWEB)

Hofmann, A W; Hart, S R [Carnegie Institution of Washington, D.C. (USA). Dept. of Terrestrial Magnetism

1978-02-01

The assumption of local equilibrium during partial melting is fundamental to the interpretation of isotope and trace element data for mantle-derived rocks. If disequilibrium melting is significant, the scale of the chemical and isotopic heterogeneity in the mantle indicated by the data could be as small as the grain size of the mantle rock, and the isotope data themselves are then of doubtful value to the understanding of mantle processes. To assess the scale of isotopic heterogeneity in a partially molten asthenosphere the authors review the Sr isotopic data of volcanic rocks from oceanic regions and the available experimental data on diffusion kinetics in minerals and melts similar to those existing in the mantle. Although diffusion data are scarce and afflicted with uncertainties, most of the diffusion coefficients for cations in mantle minerals at temperatures of 1000 to 1200/sup 0/C appear to be greater than 10/sup -13/ cm/sup 2/ s/sup -1/. Struntium diffusion in liquid basalt is more rapid, with diffusion coefficients of D = 10/sup -7/ to 10/sup -6/ cm/sup 2/ s/sup -1/ near 1300/sup 0/C. Simple model calculations show that, with these D values, a fluid-free mantle can maintain a state of disequilibrium on a centimeter scale for periods of 10/sup 8/ to 10/sup 9/ years. The state of disequilibrium found in many mantle-derived xenoliths is thus easily explained. A partially molten mantle, on the other hand, will tend to equilibrate locally in less than 10/sup 5/ to 10/sup 6/ years. The analytical data on natural rocks likewise indicate that the inhomogeneities are both old (> 1.5 b.y.) and regional in character and that the consistent isotopic differences between ocean island and ocean floor volcanics cannot be explained by small-scall hetorogeneity of the source rock.

Seismic Evidence for Lower Mantle Plume Under the Yellowstone Hotspot

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Nelson, P.; Grand, S.

2017-12-01

The mantle plume hypothesis for the origin of intraplate volcanism has been controversial since its inception in the 1970s. The hypothesis proposes hot narrow upwelling of rock rooted at the core mantle boundary (CMB) rise through the mantle and interact with the base of the lithosphere forming linear volcanic systems such as Hawaii and Yellowstone. Recently, broad lower mantle (>500 km in diameter) slow velocity conduits, most likely thermochemical in origin, have been associated with some intraplate volcanic provinces (French and Romanowicz, 2015). However, the direct detection of a classical thin thermal plume in the lower mantle using travel time tomography has remained elusive (Anderson and Natland, 2014). Here we present a new shear wave tomography model for the mantle beneath the western United States that is optimized to find short wavelength, sub-vertical structures in the lower mantle. Our approach uses carefully measured SKS and SKKS travel times recorded by dense North American seismic networks in conjunction with finite frequency kernels to build on existing tomography models. We find the presence of a narrow ( 300 km diameter) well isolated cylindrically shaped slow anomaly in the lower most mantle which we associate with the Yellowstone Hotspot. The conduit has a 2% reduction in shear velocity and is rooted at the CMB near the California/Arizona/Nevada border. A cross sectional view through the anomaly shows that it is slightly tilted toward the north until about 1300 km depth where it appears to weaken and deflect toward the surficial positon of the hotspot. Given the anomaly's strength, proximity to the Yellowstone Hotspot, and morphology we argue that a thermal plume interpretation is the most reasonable. Our results provide strong support for a lower mantle plume origin of the Yellowstone hotspot and more importantly the existence of deep thermal plumes.

Effectiveness of Mindfulness-Based Relapse Prevention in opioid Dependence Treatment &Mental Health

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2008-11-01

Findings: therapy compliance, retention in treatment, decrease in somatic symptoms, anxiety, social dysfunction and increase in health was significantly in both combination of psychological intervention method than the Naltroxan group. Mindfulness-based on relapse prevention was more effective than CBT relapse prevention in decreasing of, social dysfunction, relapse prevention, increase of therapy compliance, and health. Results: Mindfulness based relapse prevention was superior to CBT and Naltroxan and considerably increased effectiveness of opioid relapse prevention therapy.

Steady state toroidal magnetic field at earth's core-mantle boundary

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Levy, Eugene H.; Pearce, Steven J.

1991-01-01

Measurements of the dc electrical potential near the top of earth's mantle have been extrapolated into the deep mantle in order to estimate the strength of the toroidal magnetic field component at the core-mantle interface. Recent measurements have been interpreted as indicating that at the core-mantle interface, the magnetic toroidal and poloidal field components are approximately equal in magnitude. A motivation for such measurements is to obtain an estimate of the strength of the toroidal magnetic field in the core, a quantity important to our understanding of the geomagnetic field's dynamo generation. Through the use of several simple and idealized calculation, this paper discusses the theoretical relationship between the amplitude of the toroidal magnetic field at the core-mantle boundary and the actual amplitude within the core. Even with a very low inferred value of the toroidal field amplitude at the core-mantle boundary, (a few gauss), the toroidal field amplitude within the core could be consistent with a magnetohydrodynamic dynamo dominated by nonuniform rotation and having a strong toroidal magnetic field.

Profile of blinatumomab and its potential in the treatment of relapsed/refractory acute lymphoblastic leukemia

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