tbuckley/cabot-search huggingface dataset:
New frontiers in second-line treatment of Glioblastoma: Re-irradiation in combination with Fotemustine—A single institution experience.
Authors: Alicia Marin, David Büchser, Margarita Martin, Mario Lopez, Laura Fernandez, Laura Cerezo, M. Teresa Murillo
Journal: Journal of Clinical Oncology (2016)

e13511 Background: We have investigated, in a single-institution retrospective study, the use of a multimodal treatment in patients with recurrent glioblastoma previously treated with chemoradiotherapy with temozolomide. Re-irradiation is increasingly proposed as a therapeutic option with interesting results. The documented benefits of reoperation have been derived primarily from retrospective studies. Recent phase II trials have demonstrated activity of fotemustine (FTM) in recurrent glioblastoma. Methods: In this retrospective study 20 patients with recurrent pretreated glioblastoma were treated with surgery (with neuronavigation and gliolan) plus radiotherapy (IMRT/VMAT-IGRT focal, were administred in 28 daily fractions of 1.5Gy given 5 days per week, for a total of 42Gy) plus concomitant and maintenance FTM (Addeo schedule: Induction/concomitant phase with 80mg/m2 on days 1, 15, 30, 45 and 60. Followed by a 4 weeks rest period. After this period, a maintenance therapy was given with FTM 80mg/m2 every 4 weeks until progression or unacceptable toxicity. Clinical end-points analyzed were: overall survival (OS), progression-free survival (PFS), survival rates, response rates (RR), toxicity, quality of life and neurocognitive impact. Survival rates were determined by Kaplan-Meier method. Differences between survival curves were analyzed by the log-rank test. Results: From October 2010 to February 2015, 20 patients were enrolled. The median follow-up time was 9.5 months. mOS, OS6, OS12 and OS14 were 10 months (95% IC 7.9-12.1 months), 83%, 26% and 13% respectively. mPFS and PFS6 were 7 months (95% IC 4.5-9.5 months) and 48 respectively. Response rates were as follows: 2RC (10%), 3RP (15%), 13SD (65%) and 2PD (10%). Long survival patients: OS > 12 months since recurrent 26.6% and OS > 1.5, 2 and 4 years for initial diagnosis 95%, 64% and 13% respectively. 104 cycles of fotemustine were administered and induction phase was completed by 75% of the patients. Grade 3-4 toxicity was 10%. Conclusions: Second-line combined treatment with fotemustine and re-irradiation using high precision techniques in recurrent glioblastoma after standar treatment, is safe and promising.
Thomas Wynter Backhouse
Authors: Michael Backhouse
Journal: BMJ (2016)

Thomas Wynter Backhouse (“Tom”) was born in Horwich, Lancashire, the only son of Canon Thomas Backhouse, vicar of St Catherine’s Church, and Mary, nee Wynter or Winter. Along with many other sons of the clergy he went to Dean Close School in Cheltenham and was expected to follow in his father’s footsteps into the ministry. However, after his ordinary certificate exams in the classics he decided that he wanted a career in medicine, so there was some rapid catching up required in the sciences. Although the school was evacuated to Monkton Combe during the early years of the war, Tom did well enough in his exams to earn a place to read natural sciences at Queens’ College, Cambridge, in 1940.

In due course he moved to the Middlesex Hospital in central London to pursue clinical studies. While there he worked on hospital trains from the south coast and undertook fire spotting duties, during air raids, from the nurses’ home roof. This required the junior doctors to pass through the underground passages to the nurses’ home while the nurses, in their night attire, passed the opposite way: a challenge for the matrons!

At university Tom continued with sports. While at school he had played for the AFA Public Schools XI, earning a write-up: “Although a head shorter than the Whalley Range centre forward, and easily brushed aside, [he] came again and again into the …
Deletion of the Semaphorin, Sema4D, but Not Inhibition of Sema4D Shedding by ADAM17, Impairs Platelet Function and Reduces Infarct Size After Myocardial Ischemia.
Authors: Li Zhu, Tao Wang, Hong Jiang, Timothy J. Stalker, Karen P. Fong, Peter J. Gruber, Lawrence F Brass
Journal: Blood (2009)
Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk: A Science Advisory From the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology
Authors: G. N. Levine, A. V. D'Amico, P. Berger, P. E. Clark, R. H. Eckel, N. L. Keating, R. V. Milani, A. I. Sagalowsky, M. R. Smith, N. Zakai
Journal: CA A Cancer Journal for Clinicians (2010)

Androgen-deprivation therapy (ADT) is a widely used treatment for prostate cancer. Recently, several studies have reported an association between ADT and an increased risk of cardiovascular events, including myocardial infarction and cardiovascular mortality.1–5 These reports have led to increased interest and discussion regarding the metabolic effects of ADT and its possible association with increased cardiovascular risk. In addition, likely as a result of these reports, internists, endocrinologists, and cardiologists are now being consulted regarding the evaluation and management of patients in whom ADT is being initiated. Most of these physicians are not aware of the possible effects of ADT on cardiovascular risk factors or the issues regarding ADT and cardiovascular disease. Therefore, this multidisciplinary writing group has been commissioned to review and summarize the metabolic effects of ADT, to evaluate the data regarding a possible relationship between ADT and cardiovascular events in patients with prostate cancer, and to generate suggestions regarding the evaluation and management of patients, both with and without known cardiac disease, in whom ADT is being initiated.

The writing group emphasizes that the purpose of this advisory is strictly informative. This advisory should thus not be construed as dictating clinical practice or superseding the clinical judgment of physicians, and it should not be used for medicolegal purposes.

Androgens, produced mainly in the testicles, stimulate prostate cancer cells to grow. Lowering androgen levels can eliminate prostate cancer cells that require androgens to survive.6 ADT reduces levels of androgens in circulation, with the goal of improving outcomes in men with prostate cancer. Gonadotropin-releasing hormone (GnRH) agonists (eg, leuprolide, goserelin, and triptorelin) currently are the most common form of ADT and have largely supplanted the use of bilateral orchiectomy. Antiandrogens (eg, flutamide and bicalutamide) are a form of prostate cancer therapy that blocks the binding of androgen to …
Author’s reply to Woodward
Authors: Johanna A A G Damen
Journal: BMJ (2016)

We highly appreciate Woodward’s comment on our systematic review of prediction models for cardiovascular disease (CVD) risk in the general population.1 2 Woodward refers to the development and validation of a relatively new prediction model in this field, Globorisk.

At first sight this is just another development of a model to predict CVD, which can be added to the list of 363 prediction models already described in our systematic review. As already …
The Significance Of Fli1 and p53 For The Effective Megakaryopoiesis In 5q- Syndrome and The Effect Of Lenalidomide Treatment
Authors: Radana Neuwirtova, Jan Stritesky, Ota Fuchs, Martin Vostry, Arnost Kostecka, Monika Belickova, Magdalena Siskova, Kyra Michalova, prof., Jaroslav Cermak, Ass. Prof., Anna T Jonasova
Journal: Blood (2013)
Autologous T Cells Expressing CD30 Chimeric Antigen Receptors for Relapsed or Refractory Hodgkin Lymphoma: An Open-Label Phase I Trial
Authors: Chun-Meng Wang, Zhi-Qiang Wu, Yao Wang, Ye-Lei Guo, Han-Ren Dai, Xiao-Hui Wang, Xiang Li, Ya-Jing Zhang, Wen-Ying Zhang, Mei-Xia Chen, Yan Zhang, Kai-Chao Feng, Yang Liu, Su-Xia Li, Qing-Ming Yang, Wei-Dong Han
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Relapsed or refractory Hodgkin lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma. Experimental Design: Patients with relapsed or refractory Hodgkin lymphoma received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR). Results: Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions and received a mean of 1.56 × 107 CAR-positive T cell per kg (SD, 0.25; range, 1.1–2.1) in total during infusion. CART-30 cell infusion was tolerated, with grade ≥3 toxicities occurring only in two of 18 patients. Of 18 patients, seven achieved partial remission and six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors. Conclusions: CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment. Clin Cancer Res; 23(5); 1156–66. ©2016 AACR.
Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype
Authors: Christian Brendel, Swaroopa Guda, Raffaele Renella, Daniel E. Bauer, Matthew C. Canver, Young-Jo Kim, Matthew M. Heeney, Denise Klatt, Jonathan Fogel, Michael D. Milsom, Stuart H. Orkin, Richard I. Gregory, David A. Williams
Journal: Journal of Clinical Investigation (2016)

Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities. BCL11A knockdown was associated with a substantial increase in S/G2-phase human HSCs after engraftment into immunodeficient (NSG) mice, a phenotype that is associated with HSC exhaustion. Lineage-specific, shRNAmiR-mediated suppression of BCL11A in erythroid cells led to stable long-term engraftment of gene-modified cells. Transduced primary normal or SCD human HSCs expressing the lineage-specific BCL11A shRNAmiR gave rise to erythroid cells with up to 90% reduction of BCL11A protein. These erythrocytes demonstrated 60%-70% γ-chain expression (vs. < 10% for negative control) and a corresponding increase in HbF. Transplantation of gene-modified murine HSCs from Berkeley sickle cell mice led to a substantial improvement of sickle-associated hemolytic anemia and reticulocytosis, key pathophysiological biomarkers of SCD. These data form the basis for a clinical trial application for treating sickle cell disease.
Brazilian attorneys demand abortion rights for women infected with Zika
Authors: Cláudia Collucci
Journal: BMJ (2016)

A public attorneys’ association has asked Brazil’s Supreme Court to allow women who have contracted the Zika virus and are in a state of “great mental suffering” to have access to abortions.

Under Brazilian law, abortion is permitted only in cases of rape, when there is a threat to the mother’s life, or if the fetus has anencephaly.

The petition, which was delivered on 24 August, proposes that the mental suffering of pregnant women seeking abortions must be verified by medical and psychological reports. “[Abortion] would only occur in very exceptional cases,” said Joaquim Neto, president of the National Association of Public Defenders.

The guiding principle …
Reduced frequency of circulating CD4+CD25brightCD127lowFOXP3+ regulatory T cells in primary myelofibrosis
Authors: Margherita Massa, Rita Campanelli, Gabriela Fois, Laura Villani, Elisa Bonetti, Paolo Catarsi, Valentina Poletto, Gianluca Viarengo, Mara De Amici, Vittorio Rosti, Robert Peter Gale, Giovanni Barosi
Journal: Blood (2016)
Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumors
Authors: Y. Nieto, S.-M. Tu, R. Bassett, R.B. Jones, A.M. Gulbis, N. Tannir, A. Kingham, C. Ledesma, K. Margolin, L. Holmberg, R. Champlin, L. Pagliaro
Journal: Annals of Oncology (2015)

Ann Oncol 2015; 26: 2125–2132 (doi: 10.1093/annonc/mdv310) In the original manuscript, there were some errors. The corrected paragraph and Figure 3 legend are as below. We enrolled 43 male patients between May 2008 and August 2014, pretreated with a median 4 (2–9) regimens (Table 2). Two female patients enrolled are not included in this analysis. Twenty patients had absolute cisplatin refractory disease (defined as PD as best response), 17 refractory disease (relapse/PD within 4 weeks) disease and 6 had cisplatin-sensitive disease. Disease was nonresponsive in 24 patients (22 PD, 2 SD), and responsive in 19 patients (8 PRm+, 7 PRm-, 4 CR—one surgical—) right before HDC (individual treatment histories in supplementary Table S1, available at Annals of Oncology online). Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumorsAnnals of OncologyVol. 26Issue 10PreviewHigh-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease. Full-Text PDF Open Archive
Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study
Authors: Tanya I. Coulter, Anita Chandra, Chris M. Bacon, Judith Babar, James Curtis, Nick Screaton, John R. Goodlad, George Farmer, Cathal Laurence Steele, Timothy Ronan Leahy, Rainer Doffinger, Helen Baxendale, Jolanta Bernatoniene, J. David M. Edgar, Hilary J. Longhurst, Stephan Ehl, Carsten Speckmann, Bodo Grimbacher, Anna Sediva, Tomas Milota, Saul N. Faust, Anthony P. Williams, Grant Hayman, Zeynep Yesim Kucuk, Rosie Hague, Paul French, Richard Brooker, Peter Forsyth, Richard Herriot, Caterina Cancrini, Paolo Palma, Paola Ariganello, Niall Conlon, Conleth Feighery, Patrick J. Gavin, Alison Jones, Kohsuke Imai, Mohammad A.A. Ibrahim, Gašper Markelj, Mario Abinun, Frédéric Rieux-Laucat, Sylvain Latour, Isabelle Pellier, Alain Fischer, Fabien Touzot, Jean-Laurent Casanova, Anne Durandy, Siobhan O. Burns, Sinisa Savic, D.S. Kumararatne, Despina Moshous, Sven Kracker, Bart Vanhaesebroeck, Klaus Okkenhaug, Capucine Picard, Sergey Nejentsev, Alison M. Condliffe, Andrew James Cant
Journal: Journal of Allergy and Clinical Immunology (2016)

BackgroundActivated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).ObjectiveWe sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.MethodsWe applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.ResultsRecurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.ConclusionAPDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
MuSE: accounting for tumor heterogeneity using a sample-specific error model improves sensitivity and specificity in mutation calling from sequencing data
Authors: Yu Fan, Liu Xi, Daniel S. T. Hughes, Jianjun Zhang, Jianhua Zhang, P. Andrew Futreal, David A. Wheeler, Wenyi Wang
Journal: Genome biology (2016)

Subclonal mutations reveal important features of the genetic architecture of tumors. However, accurate detection of mutations in genetically heterogeneous tumor cell populations using next-generation sequencing remains challenging. We develop MuSE ( http://bioinformatics.mdanderson.org/main/MuSE ), Mutation calling using a Markov Substitution model for Evolution, a novel approach for modeling the evolution of the allelic composition of the tumor and normal tissue at each reference base. MuSE adopts a sample-specific error model that reflects the underlying tumor heterogeneity to greatly improve the overall accuracy. We demonstrate the accuracy of MuSE in calling subclonal mutations in the context of large-scale tumor sequencing projects using whole exome and whole genome sequencing.
Survival and Evolution of a Large Multidrug Resistance Plasmid in New Clinical Bacterial Hosts
Authors: Andreas Porse, Kristian Schønning, Christian Munck, Morten O.A. Sommer
Journal: Molecular Biology and Evolution (2016)

Large conjugative plasmids are important drivers of bacterial evolution and contribute significantly to the dissemination of antibiotic resistance. Although plasmid borne multidrug resistance is recognized as one of the main challenges in modern medicine, the adaptive forces shaping the evolution of these plasmids within pathogenic hosts are poorly understood. Here we study plasmid-host adaptations following transfer of a 73 kb conjugative multidrug resistance plasmid to naïve clinical isolates of Klebsiella pneumoniae and Escherichia coli. We use experimental evolution, mathematical modelling and population sequencing to show that the long-term persistence and molecular integrity of the plasmid is highly influenced by multiple factors within a 25 kb plasmid region constituting a host-dependent burden. In the E. coli hosts investigated here, improved plasmid stability readily evolves via IS26 mediated deletions of costly regions from the plasmid backbone, effectively expanding the host-range of the plasmid. Although these adaptations were also beneficial to plasmid persistence in a naïve K. pneumoniae host, they were never observed in this species, indicating that differential evolvability can limit opportunities of plasmid adaptation. While insertion sequences are well known to supply plasmids with adaptive traits, our findings suggest that they also play an important role in plasmid evolution by maintaining the plasticity necessary to alleviate plasmid-host constrains. Further, the observed evolutionary strategy consistently followed by all evolved E. coli lineages exposes a trade-off between horizontal and vertical transmission that may ultimately limit the dissemination potential of clinical multidrug resistance plasmids in these hosts.
SSBP2-CSF1R Is a Recurrent Fusion in B-Other Acute Lymphoblastic Leukaemia with Variable Clinical Outcome
Authors: Claire Schwab, Rebecca Andrews, Lucy Chilton, Alannah Elliott, Stacey Richardson, Sarra L. Ryan, Amy Logan, Adele K. Fielding, Nicholas Goulden, Ajay J. Vora, Anthony V. Moorman, Christine A. Macartney, Christine J. Harrison
Journal: Blood (2014)
Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer
Authors: Yaqi Li, Lei Liang, Weixing Dai, Guoxiang Cai, Ye Xu, Xinxiang Li, Qingguo Li, Sanjun Cai
Journal: Molecular Cancer (2016)

Colorectal cancer (CRC) is 3rd most commonly diagnosed cancer in males and the second in females. PD-1/PD-L1 axis, as an immune checkpoint, is up-regulated in many tumors and their microenvironment. However, the prognostic value of PD-1/PD-L1 in CRC remains unclear.The Cancer Genome Atlas (TCGA) database (N = 356) and Fudan University Shanghai Cancer Center (FUSCC) cohort of patients (N = 276) were adopted to analyze the prognostic value of PD-L1 in colorectal tumor cells (TCs) and of PD-1 in tumor infiltrating cells (TILs) for CRC. Subgroup analyses were conducted in FUSCC cohort according to patients' status of mismatch repair.In TCGA cohort, the cut-off values of PD-1 and PD-L1 expression were determined by X-tile program, which were 4.40 and 2.92, respectively. Kaplan-Meier analysis indicated that higher PD-1 and PD-L1 expressions correlated with better OS (P = 0.032 and P = 0.002, respectively). In FUSCC cohort, expressions of PD-1 on TILs and PD-L1 on TCs were analyzed separately by immunohistochemistry (IHC) staining based on a TMA sample (N = 276) and revealed that both TILs-PD-1 and TCs-PD-L1 were associated with OS (P = 0.006 and P = 0.002, respectively) and DFS (P = 0.025 and P = 0.004, respectively) of CRC patients. Multivariate Cox regression analysis indicated TILs-PD-1 was an independent prognostic factor both for OS and DFS of CRC patients (P < 0.05). Subgroup analyses showed that TILs-PD-1 was an independent prognostic factor for both OS and DFS in CRC patients in MSS-proficient subgroup (P < 0.05), while neither of them correlated with OS or DFS in MSS-deficient subgroup (P > 0.05).Higher expressions of PD-1 and PD-L1 correlates with better prognosis of CRC patients. TILs-PD-1 is an independent prognostic factor for OS and DFS of CRC patients, especially for MMR-proficient subgroup.
Serum Levels and Pharmacokinetic of Rituximab in Bi-Weekly R-CHOP in Elderly Patients with DLBCL Treated in the RICOVER-60 Trial.
Authors: Marcel Reiser, Michael K. Wenger, Christina Nickenig, N. Peter, Christian Kuhn, Bernd Metzner, Martin Theisohn, Michael Pfreundschuh
Journal: Blood (2006)