tbuckley/cabot-search huggingface dataset:
A hypoxia transcriptomic signature to predict benefit from hypoxia-modifying treatment for muscle-invasive bladder cancer patients.
Authors: Ananya Choudhury, Lingjian Yang, Joely J Irlam, Amanda Williamson, Helen Denley, Peter Hoskin, Catharine West
Journal: Journal of Clinical Oncology (2017)

301 Background: Hypoxia modification improves overall survival (OS) in muscle invasive bladder cancer (MIBC) patients treated with radical radiotherapy. There is evidence that hypoxic tumours benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in MIBC. Methods: Bladder cancer transcriptomic data were available from public datasets and generated for 152 tumour samples from the BCON phase III trial of radiotherapy (RT) alone or RT with carbogen and nicotinamide (CON) using Affymetrix Human 1.0 Exon ST arrays. Published hypoxia signatures were tested. A novel signature was then derived by identifying candidate hypoxia genes from the literature and evaluating their bladder cancer specificity in the publically available datasets. A gene co-expression network was built and hub genes identified to generate a signature. Results: None of the published hypoxia signatures were prognostic in public datasets or predicted benefit from hypoxia modification in the BCON patients. A novel 24-gene signature was derived and its prognostic significance was validated in 7 surgical cohorts. The signature was then independently validated in BCON patients. Patients categorised as high- versus low-hypoxia by the signature had a poor local progression free survival (LPFS) following radiotherapy alone (HR 2.37, 95% CI 1.26-4.47, P= 0.0076). The signature also predicted benefit from CON with high-hypoxia patients receiving CON having a better LPFS than those receiving radiotherapy alone (HR 0.47, 95% CI 0.26-0.86, P= 0.0147). Prognostic and predictive significance remained after adjusting for clinicopathological variables (including gender, necrosis, age, stage and carcinoma in situ). Conclusions: A 24-gene hypoxia signature has strong, independent prognostic and predictive value with the potential for stratifying patients with MIBC for treatment with hypoxia-modification strategies.
ASCO 2014: High prevalence of FLT-3 ITD mutations in patients (pts) with AML who present with CNS relapse.
Authors: Simon Abi Aad, Naval Guastad Daver, Paolo Strati, Jorge E. Cortes, Guillermo Garcia-Manero, Michael Mathisen, Farhad Ravandi, Tapan M. Kadia, Susan Mary O'Brien, Carol Bivins, Sherry Pierce, Hagop M. Kantarjian, Elias Jabbour
Journal: Journal of Clinical Oncology (2014)

7074 Background: Despite CR rates of 70% with modern chemotherapeutic regimens, most pts with AML relapse. CNS relapses have become uncommon with the use of high-dose cytarabine based regimens. The features associated with a higher risk of CNS relapse are not defined. Methods: We analyzed adults who presented with AML and CNS relapses from 2000 until 2014. CNS leukemia was diagnosed by the presence of blasts in a cytocentrifuge preparation of CSF. Pts with blasts in the CSF together with high numbers of red blood cells (> 5) were not considered to have CNS disease if the blasts were high in the PB. Results: Of the 1312 pts with AML treated at our institution, 71 (5%) had CNS disease. Median age was 57 years. CNS involvement was detected after a median of 8 months from the initial diagnosis. 4 pts (6%) had isolated CNS relapse that was followed by systemic relapse after a median of 2 weeks. CNS involvement was detected in the setting of refractory AML in 31 pts (44%). 64 pts (90%) received previous high-dose cytarabine. 54 pts (76%) had neurologic symptoms at time of CNS relapse. CNS imaging was performed in 67 pts (94%): 41 (61%) had abnormal findings by MRI suggestive of CNS disease. 4 pts had zero cells with blasts detected on cytocentrifuge preparation only. None of the 4 pts had circulating blasts and all had abnormal findings on brain MRI suggestive of CNS relapse. 18 pts (25%) were FLT3-ITD mutated. CNS involvement was more commonly observed in young pts with increased WBC, BM blasts, and LDH, with M4/M5 phenotype, and FLT3/ITD mutated (12% versus 5%, p=0.003). Treatment for CNS disease consisted of IT chemotherapy in all pts, whole brain radiation therapy in 14, and spinal radiation in 8. Therapy was successful in clearing all signs of CNS disease in 29 (41%). 19 of the 29 pts (65%) subsequently had additional CNS relapses after a median of 3 months. The 2-year survival rate after CNS relapse was 13%. There was no difference in overall survival among patients with or without CNS disease. Conclusions: CNS relapse is a rare occurrence in AML (5%) and is associated with a poor prognosis. A high prevalence of FLT3-ITD mutations was observed in these pts. FLT3 mutational status and LDH level may identify patients with AML who may benefit from CNS prophylaxis.
Real-world symptom burden and early treatment discontinuation in first-line metastatic breast cancer (MBC).
Authors: Mark S. Walker, Anthony Masaquel, Jiandong Kerr, Deepa Lalla, Oyewale O. Abidoye, Obiageli Uchenna Ogbata, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2013)

9619 Background: Treatment options in 1 st line metastatic breast cancer (MBC) vary and may include chemotherapy, targeted, and hormone therapy. Some patients (pts) do not complete therapy as planned, perhaps due to treatment related toxicities. The current study examined the association of symptom burden with early treatment discontinuation (ETD) of 1 st line therapy of MBC in real-world settings. Methods: Data were abstracted from medical records of pts at 9 community oncology practices. Eligible pts had stage IV breast cancer with start of 1 st line therapy on 1/2004 to 6/2012, were ≥ 18 years, and had ≥ 1 Patient Care Monitor (PCM) survey during 1 st line. The PCM is an 86-item survey of cancer-related symptoms collected as part of routine clinical care. Age, race, HER2 status, hormone status, oral and infused agents, dates of diagnosis, treatment, progression, and death were recorded. ETD was defined by direct indication of early stopping in the medical record, or by treatment duration ≤ 6 weeks without evidence of disease progression. Cox regression of ETD with time varying covariates was used to examine the impact of 23 separate symptoms as well as an overall composite symptom burden score based on pt responses on each symptom. Results: 797 pts were included, with mean age of 58.4 years, 62.1% White; with 340 on Chemotherapy (CT), 349 on CT + Targeted therapy (T) and 108 on Hormone therapy only (H). Overall, ETD occurred in 95 (11.9%) pts, with rates highest among CT (15.3%), followed by T (10.0%) and H (7.4%). Cox regression showed that 21 of 23 symptoms each increased the risk of ETD. In the composite symptom burden score (median 7.1; range 0 - 21) analysis, overall symptom burden was found to be significant (HR = 1.124, p &lt; 0.0001), indicating a 12.4% increased risk of ETD with each additional symptom. Pts with 10+ symptom score had a significantly increased risk of ETD (HR = 3.09, p &lt; 0.0001) compared to pts with &lt; 5 symptom score. Pts with 15+ symptom score had the highest risk of ETD (HR = 5.75, p &lt; 0.0001). Conclusions: Pts treated with CT for 1 st line MBC had the highest rate of ETD. The likelihood of ETD increased as the number of symptoms increased. Future research is needed to evaluate ETD on pt outcomes, including overall survival.
Regulatory T-cell inhibition plus antitumor immunotherapy targeted against cytomegalovirus (CMV) in patients with newly diagnosed glioblastoma multiforme (GBM).
Authors: Gordana Vlahovic, Gerald E. Archer, Denise Lally-Goss, Sharon Norman, Annick Desjardins, Katherine B. Peters, Tulika Ranjan, Jason Watts, Patrick Healy, James Emmett Herndon, Henry S. Friedman, Allan H. Friedman, Darell D. Bigner, John Howard Sampson
Journal: Journal of Clinical Oncology (2014)

3069 Background: Despite aggressive surgery, high-dose focused radiation, and toxic, multimechanistic chemotherapy, malignant gliomas (MG) remain almost universally fatal. The inherent biologic specificity of immunotherapy offers the prospect of targeting neoplastic cells more precisely. Dendritic cells (DCs) are endowed with an extraordinary ability to activate CD4+ and CD8+ T-cells, and DCs loaded with antigens derived from tumor cells (CMV pp65-LAMP mRNA) have the potential to induce potent antitumor immunity. Furthermore, regulatory T-cells (TRegs) which induce a state of reversible immunosuppression in MG and can be functionally inactivated with anti-CD25 antibody (Ab), while dramatically enhancing vaccine-induced immune responses. Methods: Eligible were gross totally resected patients (pts) with newly diagnosed GBM. Pts underwent leukapheresis followed by standard of care radiation/temozolomide (XRT/TMZ) therapy. After completion of XRT/TMZ, up to 12 cycles of TMZ 200 mg/m2/x5d were administered. Around Day 21 of the 1st cycle pts also received: anti-CD25 Ab treatment, vaccine #1, and non-specific autologous lymphocyte transfer (ALT). Vaccines #2 and #3 were given biweekly following vaccine#1. A 2nd leukapheresis was conducted prior to the 2nd cycle of TMZ. On Day 21 of the 2ndTMZ cycle Vaccine #4 was administered. Pts were followed with serial MRIs until disease progression. Results: 7 patients (5 males) were treated. No adverse events attributable to vaccine treatment were observed. Median progression free survival was 23.5 months (95% CI:1.7 to 54.1). Median overall survival was 30.3 months (95% CI:11.8 to 60.8). Overall survival was calculated from the start of vaccine therapy to time of death or last contact if alive. Conclusions: Treatment with XRT/TMZ, DC vaccine and anti- CD25 Ab was well tolerated and results are promising. Due to the lack of adverse events, the protocol has been amended for future patients in this ongoing study. The number of vaccines had been increased to 8 (vs. 4) and anti-CD25 antibody is being given with the first two cycles (vs. with 1st cycle only) of adjuvant TMZ. Clinical trial information: 00626483.
Unique genetic characteristics of BRCA mutation carriers in a cohort of Arab American women.
Authors: Seerin Viviane Shatavi, Lindsay Dohany, Mohammad Muhsin Chisti, Ishmael A. Jaiyesimi, Dana Zakalik
Journal: Journal of Clinical Oncology (2013)

1541 Background: Worldwide ethnic variations in the distribution of BRCA1 and BRCA2 mutations of breast cancer patients have been recently recognized. This has led to investigations of the epidemiology, genetics and clinical characteristics of BRCA positive individuals within specific populations. This study aims to describe the findings of BRCA genetic testing in a cohort of Arab American women. Methods: A total of 73 women of Arab ancestry were evaluated in the Beaumont Cancer Genetics Program from Jan 2008 to Jan 2013. Criteria for genetic testing included a personal or family history suggestive of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Patients underwent comprehensive genetic counseling, followed by full sequence analysis for germline mutations in BRCA1 and BRCA2. Results: 63 women of Arab ancestry underwent genetic testing for BRCA1 and BRCA2. 13 (21%) patients were found to be mutation carriers, of whom 10 (16%) of the 63 had deleterious mutations (7 in BRCA2, and 3 in BRCA1), and 3 (5%) had variants of undetermined significance (VUS) in BRCA2. Of the 10 patients with deleterious mutations, 4 (40%) unrelated individuals had the same mutation, 5804del4, in exon 11 of BRCA2. The remaining patients had deleterious mutations in exon 2, exon 20, and exon 13 of BRCA2; one patient had a BRCA1 and BRCA2 mutation (exon 18). 7 of 10 patients with deleterious mutations had a cancer diagnosis, of which 5 had breast cancer, 1 had ovarian cancer, 1 had pancreatic cancer, and 3 were unaffected. Conclusions: This study demonstrates that BRCA mutations (predominantly in BRCA2) were seen in a significant proportion of Arab American women undergoing genetic testing for HBOC. A mutation in BRCA2, 5804del4, was seen in nearly half (4/10) of the carriers of deleterious mutations. This mutation, in exon 11, has not previously been associated with Arab ethnicity and may represent a founder mutation. Knowledge of the genetic spectrum, frequency, and clinical characteristics of BRCA mutation carriers will lead to greater understanding of hereditary cancer in Arab American women.
Genotype in Patients with Thalassemia Major Has No Impact on Risk of Liver Fibrosis
Authors: Murtadha K. Al-Khabori, Shahina Daar, Shoaib Al-Zedjali, Al Ghaliya Al Omairi, Moez Hassan, Sarah Al Rahbi, Abubakr Ibnouf, Said Al Busaifi
Journal: Blood (2016)
Bevacizumab in combination with taxane versus non-taxane-containing regimens for advanced/metastatic nonsquamous non-small-cell lung cancer (NSCLC): A systematic review.
Authors: Madhusmita Behera, Rathi Narayana Pillai, Taofeek Kunle Owonikoko, Sungjin Kim, Zhengjia Chen, Nabil F. Saba, Chandra Prakash Belani, Fadlo Raja Khuri, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2013)

e19094 Background: In pre-clinical studies, the efficacy of anti-angiogenic agents depends on the specific chemotherapy given in combination. This appears to result from abrogation of activated circulating endothelial progenitor cells by cytotoxic agents, with the most favorable results noted with the combination of anti-angiogenic therapy with taxanes. We conducted a systematic review of published clinical trials that evaluated the efficacy of bevacizumab in combination with taxane or non-taxane containing regimens for untreated, non-squamous NSCLC patients. Methods: An extensive search of published clinical trials was conducted from electronic databases (MEDLINE, EMBASE, Cochrane) and meeting proceedings using relevant search criteria. Single arm phase II studies or randomized trials reporting the efficacy of bevacizumab combined with taxane or non-taxane regimens were selected. A systematic analysis of extracted data was performed using Comprehensive Meta Analysis (Version 2.2.048) software under the random effect model. Clinical outcome in patients treated with taxane versus non-taxane regimen was compared using point estimates for weighted values of median overall survival (OS), progression free survival (PFS), and response rate (RR). Results: Twenty-five studies reported between 2005-2013 were eligible. A total of 4,279 patients (1663 and 2616 in the taxane and non-taxane groups respectively) were included. The most common chemotherapy agents used with bevacizumab among non-taxane regimens were gemcitabine (65%), vinorelbine (12%) and pemetrexed (11%). The weighted median age of the population was 59 years (Males-60%; Adenocarcinoma-82%; ECOG performance status 0/1(%)- 39/58). The weighted median OS was 15.1 vs. 13.7 months (p= 0.07); PFS was 7.4 vs. 7.1 months (p=0.27); RR was 39.6% vs. 37.7% (p=0.29) for taxane and non-taxane groups respectively. Conclusions: The combination of bevacizumab with taxane containing regimens is associated with a trend towards improved survival, but not RR and PFS, over non-taxane regimens for first-line therapy of advanced non-squamous NSCLC.
PRESICION EN LA ESTIMACION DEL TAMAÑO DE LOS POLIPOS POR LOS ENDOSCOPISTAS
Authors: D Avila Carpio Ansel, L Aguilera, I Araujo, L Rivero-Sanchez, S Carballal, ML Leoz, E Ricart, M Cuatrecasas, J Llach, M Pellisé
Journal: Endoscopy (2015)

El tamaño de los pólipos es un criterio primordial para establecer el riesgo de CCR. La estimación en el tamaño de los pólipos colónicos por los endoscopistas es subjetiva.
CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression
Authors: Vinicio Carloni, Matteo Lulli, Stefania Madiai, Tommaso Mello, Andrew Hall, Tu Vinh Luong, Massimo Pinzani, Krista Rombouts, Andrea Galli
Journal: Gut (2017)

Objective Chromosomal instability (CIN) is the most common form of genomic instability, which promotes hepatocellular carcinoma (HCC) progression by enhancing tumour heterogeneity, drug resistance and immunity escape. CIN per se is an important factor of DNA damage, sustaining structural chromosome abnormalities but the underlying mechanisms are unknown. Design DNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model of diethylnitrosamine-induced HCC characterised by DNA damage and elevated mitotic errors. Chk2 was also determined in two discrete cohorts of human HCC specimens. To assess the functional role of Chk2, gain on and loss-of-function, mutagenesis, karyotyping and immunofluorescence/live imaging were performed by using HCT116, Huh7 and human hepatocytes immortalised with hTERT gene (HuS). Results We demonstrate that mitotic errors during HCC tumorigenesis cause lagging chromosomes/DNA damage and activation of Chk2. Overexpression/phosphorylation and mislocalisation within the mitotic spindle of Chk2 contributes to induce lagging chromosomes. Lagging chromosomes and mitotic activity are reversed by knockdown of Chk2. Furthermore, upregulated Chk2 maintains mitotic activity interacting with Aurora B kinase for chromosome condensation and cytokinesis. The forkhead-associated domain of Chk2 is required for Chk2 mislocalisation to mitotic structures. In addition, retinoblastoma protein phosphorylation contributes to defective mitoses. A cohort and independent validation cohort show a strong cytoplasm to nuclear Chk2 translocation in a subset of patients with HCC. Conclusions The study reveals a new mechanistic insight in the coinvolvement of Chk2 in HCC progression. These findings propose Chk2 as a putative biomarker to detect CIN in HCC providing a valuable support for clinical/therapeutical management of patients.
Neratinib to inhibit the growth of triple-negative breast cancer cells.
Authors: Maeve Mullooly, Dylan Conklin, Patricia M. McGowan, Neil A. O'Brien, Norma O'Donovan, Dennis J. Slamon, John Crown, Richard S. Finn, Michael J. Duffy
Journal: Journal of Clinical Oncology (2015)

1099 Background: An urgent problem in breast cancer treatment is the identification and validation of a targeted therapy for triple-negative breast cancer (TNBC), ie, breast cancer negative for ER, PR and HER2. Neratinib is a low molecular weight irreversible pan-HER inhibitor that selectively targets the tyrosine kinase activity of EGFR, HER2 and HER4. To-date, neratinib has been exclusively investigated in HER2-positive tumors. However, as neratinib also targets EGFR expression, we hypothesised that it may also have clinical efficacy in TNBC. Methods: The anti-proliferative effects of neratinib were investigated in 14 TNBC cell lines. To identify potential biomarkers of response, we examined the expression of baseline EGFR, HER2, HER3 and HER4 using reverse phase protein array (RPPA) analysis and flow cytometry analysis. Results: IC50 values for neratinib across the 14 TNBC cell lines ranged from 0.06 µM to 1.9 µM. However, basal A-type cells were significantly more sensitive to neratinib than basal B-type cells (p = 0.024). No relationship was observed between IC50 values for neratinib and levels of EGFR, phospho-EGFR, HER2 or phosphor-HER2. In contrast, a significant correlation was detected between response and HER3 levels (with flow cytometry, r = -0.612, p = 0.020; with reverse phase protein arrays, r = -0.55, p = 0.043), suggesting that levels of HER3 may identify response to neratinib in this subset. Using a larger panel of 35 breast cancer cell lines of all molecular subtype, we found a significant relationship between the IC50values for neratinib and those previously reported for another pan-HER inhibitor, i.e., dacomitinib (p < 0.001; r = 0.65). Conclusions: Based on our findings in vitro, further studies are required to further investigate the clinical potential of neratinib treatment in TNBC. Acknowledgements: The authors wish to thank Science Foundation Ireland, Strategic Research Cluster Award (08/SRC/B1410) to MTCI and the Science Foundation Ireland Short Term Travel Fellowship Award for funding this work.
Outcomes of Follicular Lymphoma Patients By Dynamic FLIPI at Diagnosis and Initial Treatment in the Post-Rituximab Era
Authors: Connie Batlevi, Anna Alperovich, Katy Smith, Zhitao Ying, Jacob D Soumerai, Amanda R Copeland, Erel Joffe, Philip Caron, Pamela Drullinsky, John F Gerecitano, Audrey Hamilton, Paul A Hamlin, Steven M Horwitz, Andrew M Intlekofer, Anita Kumar, Matthew J. Matasar, Alison J. Moskowitz, Craig H Moskowitz, Ariela Noy, Maria Lia Palomba, Carol S Portlock, Craig S Sauter, David J Straus, Andrew D. Zelenetz, Ai Ni, Venkatraman E Seshan, Anas Younes
Journal: Blood (2016)
Risk of Monoclonal Gammopathy of Undetermined Significance in First-Degree Relatives of Multiple Myeloma Cases By Cytogenetic Subtype
Authors: Alyssa I. Clay, Abdul Rishi, Shaji Kumar, S. Vincent Rajkumar, Alexandra J. Greenberg, Dirk R Larson, Megan M. O'Byrne, Susan L. Slager, Celine M. Vachon
Journal: Blood (2016)
Methadone Prescribing and Overdose and the Association with Medicaid Preferred Drug List Policies — United States, 2007–2014
Authors: Mark Faul, Michele Bohm, Caleb Alexander
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Drug overdose is a leading cause of injury death in the United States; 47,055 fatal drug overdoses were reported in 2014, a 6.5% increase from the previous year (1), driven by opioid use disorder (2,3). Methadone is an opioid prescribed for pain management and is also provided through opioid treatment programs to treat opioid use disorders. Because methadone might remain in a person's system long after the pain-relieving benefits have been exhausted, it can cause slow or shallow breathing and dangerous changes in heartbeat that might not be perceived by the patient (4,5). In December 2006, the Food and Drug Administration issued a Public Health Advisory that alerted health care professionals to reports of death and life-threatening adverse events, such as respiratory depression and cardiac arrhythmias, in patients receiving methadone (4); in January 2008, a voluntary manufacturer restriction limited distribution of the 40 mg formulation of methadone.* CDC analyzed state mortality and health care data and preferred drug list (PDL) policies to 1) compare the percentage of deaths involving methadone with the rate of prescribing methadone for pain, 2) characterize variation in methadone prescribing among payers and states, and 3) assess whether an association existed between state Medicaid reimbursement PDL policies and methadone overdose rates. The analyses found that, from 2007 to 2014, large declines in methadone-related overdose deaths occurred. Prescriptions for methadone accounted for 0.85% of all opioid prescriptions for pain in the commercially insured population and 1.1% in the Medicaid population. In addition, an association was observed between Medicaid PDLs requiring prior authorization for methadone and lower rates of methadone overdose among Medicaid enrollees. PDL policies requiring prior authorization might help to reduce the number of methadone overdoses.