tbuckley/cabot-search huggingface dataset:
Epidermal growth factor receptor mutations and stat3 phosphorylation in surgically resected non-small cell lung cancer
Authors: F. Yang, Z. Zhou, J. Wang
Journal: Journal of Clinical Oncology (2007)

18180 Background: Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene and EGFR downstream pathways in non-small-cell lung cancer (NSCLC) have generate enormous interest in the searching of biological predictors of EGFR inhibitor. Selective Akt and STAT3 pathways activation has been hypothesized from in vitro model. The goal of this study is to determine the association of EGFR mutations with phospho-STAT3 (p-STAT3) in resected lung adenocarcinoma samples. Methods: 94 consecutive lung adenocarcinoma specimens from Chinese patients were analyzed for activating EGFR mutations in exon 19 and 21 by direct sequencing and p-STAT3 expression by immunohistochemistry. Results: 18 (19%) samples harbored exon 19 deletions and 22 (23%) samples had exon 21 L858R mutaions. 46 (49%) samples were scored p-STAT3 positive defined as strong nuclear staining in more than 5% cancer cells. 25 (62%) cases with EGFR activating mutations showed positive p-STAT3 nuclear staining, compared with 21 (39%) p- STAT3 cases in the EGFR wild type group (p=0.024). Conclusions: Our data further support the hypothesis that EGFR mutations may selectively activate STAT3 pathway in NSCLC. No significant financial relationships to disclose.
DA.R-EPOCH Vs. R-CHOP for High-Risk Diffuse Large B- Cell Lymphoma: The Mayo Clinic Florida Experience
Authors: Bhagirathbhai Dholaria, Prakash Vishnu, Vivek Roy, Han W Tun, Taimur Sher, Candido E. Rivera, Sikander Ailawadhi, Nancy Diehl, David O. Hodge, Yenni Alejandro Moreno-Vanegas
Journal: Blood (2017)
Molecular profiling of long-term IDH-wildtype glioblastoma survivors
Authors: Danielle M Burgenske, Jie Yang, Paul A Decker, Thomas M Kollmeyer, Matthew L Kosel, Ann C Mladek, Alissa A Caron, Rachael A Vaubel, Shiv K Gupta, Gaspar J Kitange, Hugues Sicotte, Ryan S Youland, Dioval Remonde, Jesse S Voss, Emily G Barr Fritcher, Kathryn L Kolsky, Cristiane M Ida, Fredric B Meyer, Daniel H Lachance, Ian J Parney, Benjamin R Kipp, Caterina Giannini, Erik P Sulman, Robert B Jenkins, Jeanette E Eckel-Passow, Jann N Sarkaria
Journal: Neuro-Oncology (2019)

Abstract Background Glioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)–wildtype GBM long-term survivors (LTS) to date. Methods Retrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression. Results Of the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks. Conclusions While our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.
Paradoxical Rise in Hypoglycemia Symptoms With Development of Hyperglycemia During High-Intensity Interval Training in Type 1 Diabetes
Authors: Dana Potashner, Ruth E. Brown, Aihua Li, Michael C. Riddell, Ronnie Aronson
Journal: Diabetes Care (2019)

To assess the reliability of self-perception of glycemia during high-intensity interval training (HIIT) in subjects with type 1 diabetes.This randomized crossover study included subjects who completed four fasted HIIT sessions. Subjects answered the Edinburgh Hypoglycemia Scale, estimated their blood glucose (BG), and had plasma glucose (PG) collected throughout exercise and recovery.As PG increased throughout exercise, hypoglycemia scores increased across each category: autonomic (3.1-4.4, P < 0.05), neuroglycopenic (1.5-2.4, P < 0.05), and nonspecific (1.3-1.9, P < 0.05). Subjects' estimated BG showed a negative bias that widened as exercise progressed and peaked at -1.6 ± 3.3 mmol/L (P < 0.001) postinsulin correction.During HIIT, despite progressing hyperglycemia, subjects experience increased hypoglycemia symptoms and tend to underestimate their BG level.
Aetiology‐based clinical scenarios predict outcomes of transcatheter edge‐to‐edge tricuspid valve repair of functional tricuspid regurgitation
Authors: Florian Schlotter, Mathias Orban, Karl‐Philipp Rommel, Christian Besler, Maximilian von Roeder, Daniel Braun, Matthias Unterhuber, Michael Borger, Christian Hagl, Martin Orban, Michael Nabauer, Steffen Massberg, Holger Thiele, Jörg Hausleiter, Philipp Lurz
Journal: European Journal of Heart Failure (2019)
Impact of bladder cancer (BC) on health-related quality of life (HRQL) in 1,476 older Americans.
Authors: Chunkit Fung, Chintan Pandya, Katia Noyes, Emelian Scosyrev, Deepak M. Sahasrabudhe, Edward M. Messing, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2013)

9549 Background: The impact of BC on HRQL is poorly understood. To our knowledge, this is the first and largest cross-sectional study that compares HRQL of patients before and after BC diagnosis (DX). Methods: Our sample included 1,476 BC patients (≥ age 65) within the SEER-Medicare Health Outcomes Survey linkage database (1998-2007). We assessed differences in HRQL as measured by SF-36 physical (PCS) and mental (MCS) summary scores in patients who had a survey &gt;1 yr before BC DX (n=620) and those who had a survey after BC DX (n=856). We compared groups by year from BC DX using regression analyses and results were adjusted for cancer stage, race, gender, age at BC DX, marital status, education, income, smoking status, activity of daily living (ADLs), and non-cancer comorbidities. Results: Patients who had a survey after BC DX were diagnosed with BC at an older age than those with a survey before BC DX (55.9% at age ≥75 yr vs. 36.8%; P&lt;0.01). Other baseline demographic and socioeconomic characteristics were similar. Baseline HRQL were poor in patients before DX (PCS mean=40.1; MCS mean=51.1) with 50.6% and 31.9% of them having comorbidity score ≥2 and impairment of ≥1 ADLs, respectively. After BC DX, significant decreases in PCS (-2.7; 95% CI -3.8,-1.7) and MCS (-1.4; 95% CI -2.6, -0.3) were observed, with HRQL being lowest in those who had BC DX within 1 yr (PCS mean= 36.6; MCS mean=49.7). Declines in PCS during the &lt;1, 1-3, 3-5, 5-10, and 10+ yr periods after BC DX compared to before BC DX were -3.8 (P&lt;0.01), -2.5 (P&lt;0.01), -2.2 (P=0.01), -1.1 (P=0.19) and -0.8 (P=0.57) whereas decreases in MCS were -2.0 (P=0.01), -2.2 (P&lt;0.01), -1.2 (P=0.21), -0.1 (P=0.92), -0.8 (P=0.62) respectively. More advanced BC, lower educational level, higher comorbidity score, and impaired ADLs were significantly associated with both worse PCS and MCS after BC DX (P&lt;0.05). Lower income and older age at BC DX showed significant association with low PCS (P&lt;0.05). Conclusions: Older BC patients are a vulnerable population with poor baseline HRQL. HRQL of patients after BC DX is significantly worse than HRQL of patients before DX, possibly due to therapy and/or disease progression. Future research that evaluates interventions to improve HRQL in older patients with BC is critical.
MR-based biomarkers in the diagnosis and the evaluation of the therapeutic response to radiotherapy (ETRR) in prostatic carcinoma (PCa): Implementation of clinical and experimental approaches
Authors: G. Crehange, P. M. Walker, S. Parfait, P. Maingon, A. Cochet, F. Brunotte, X. Tizon, P. Provent, O. Duchamp
Journal: Journal of Clinical Oncology (2009)

e16136 Background: ETRR in PCa remains a challenging task. New biomarkers in the form of metabolites, detected with Proton Magnetic Resonance Spectroscopy ( 1 H-MRS), and quantitative Apparent Diffusion Coefficient (ADC), determined with Diffusion-Weighted Magnetic Resonance Imaging, could be of value in the ETRR for PCa. Methods: Twenty-one men with biopsy proven localized PCa were examined before external radiotherapy. 3D- 1 H-MRS was performed at 3.0T without endorectal coils. The delivered radiotherapy dose was 78 Gy in 39 fractions with 6 MV photons. MR follow-up examinations up to 36 months post-radiotherapy were performed. For the pre-clinical study, healthy rat prostate was studied in 3 nude rats. PC3-MM2 and PAC-120 tumors were subcutaneously (SC) and orthotopically (OT) xenografted in 5 nude rats, respectively. Radiotherapy anti-tumor efficacy administered as HDR-brachytherapy (SC) or X6 external beam irradiation (OT) delivering 10 Gy/5 fractions was evaluated. 1 H-MRS was performed at 4.7 T using SVS. Results: Twelve men received the 3-month examination, 8 patients are at 6-months, 4 are at 9 months and 1 has been followed for 1 year. At baseline, healthy prostate shows a low Choline (Cho)/Citrate ratio, whereas the presence of cancer considerably increases this ratio. At 3 months, we observed metabolic atrophy except for Cho. Although, higher ADC values are normally found in peripheral zone than in central gland, these differences disappear after radiotherapy. In healthy rat prostate high levels of Cho without citrate were noted. Cho and free lipids were detected in PC3-MM2 and PAC120 SC-grafted tumors, with a higher Cho content in PC3-MM2. Radiotherapy induced significant antitumor activity in PC3-MM2 (SC) (T/C% = 38%) and OT (ILS% = 58%) tumors, but was not efficient in PAC120 SC-grafted tumors (T/C% = 90%). Radiotherapy slightly modified Cho content 4 days after the end of treatment but no modification on overall metabolic profile was observed before, during and after radiotherapy. Conclusions: Combined ADC and Cho are powerful biomarkers for the detection of PCa in men and could be useful for ETRR.The use of Cho in ETRR for PCa in rats appears to be promising. No significant financial relationships to disclose.
Risk of rash associated with lenalidomide in multiple myeloma and myelodisplastic syndrome: A systematic review of the literature and meta-analysis.
Authors: Benjamin C Garden, Beatrice Nardone, Shenhong Wu, Dennis P. West, Romala Emmanuel, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2012)

e18571 Background: Indications of lenalidomide (Len) include treatment of multiple myeloma (MM) in combination with dexamethasone (Dex) and myelodyplastic syndrome (MDS). The reported incidence and risk of rash varies widely and has been inconsistently reported in trials. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing rash. Methods: Relevant studies were identified from PubMed (1998-2011), abstracts presented at ASCO conferences (2004-2011) and the Web of Science database (1998-2011). Eligible studies were limited to prospective Phase II-III clinical trials in which patients received daily Len doses of either 10mg or 25 mg with or without 40mg of Dex. Incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on heterogeneity of included studies. Results: Data from a total of 1,127 patients in 15 trials were available for analysis. The overall incidence of all-grade and high-grade (grade ≥3) rash was 29.9% (95% CI: 24.8- 35.5) and 3.8% (95% CI: 2.7-5.5), respectively. Len was associated with increased risk of all-grade rash (RR=1.7, 95% CI: 1.3-2.3; P&lt;0.001) when compared to patients treated with a placebo and Dex. Risk of high-grade rash was increased (RR=3.7, 95% CI: 0.8-16.0) with a trend toward statistical significance (P=0.08). No significant difference in incidence of all-grade rash between patients receiving LEN doses of 10mg or 25mg (25.6%, 95% CI: 19.6-32.8% vs. 30.8%, 95% CI: 24.7-37.7%, respectively, p=0.28) was observed. Similarly, no difference was observed between patients receiving LEN monotherapy or in combination with Dex (31.0%, 95% CI: 26.6-43.3% and 23.8%, 95% CI: 14.9-35.8%, respectively, p=0.17). Conclusions: Patients with MM or MDS who are treated with Len are at significant risk for developing rash. The risk appears to be independent of LEN dosage or in combination with Dex. Further studies for prevention and treatment of this untoward toxicity are needed in order to maintain patient’s quality of life and minimize the need for dose modification, all of which may impact clinical outcome.
Chemoradiotherapy for locally advanced esophageal cancer using carboplatin, paclitaxel.
Authors: Jodie E. Battley, Margaret O'Keeffe, Erica Mulvihill, Seamus O'Reilly, Michael William Bennett, Criostoir O Suilleabhain, Aileen Flavin, Thomas J Murphy, Derek Gerard Power
Journal: Journal of Clinical Oncology (2012)

e14666 Background: Localized esophageal adenocarcinoma is usually treated with multi-modality therapy, i.e., chemotherapy or chemoradiotherapy (CRT) followed by surgery. Standard treatment for localized squamous cell carcinoma is controversial as definitive CRT can offer the same overall survival as CRT followed by surgery. Cisplatin and infusional 5FU is the accepted chemotherapy in combination with RT. However this regimen is cumbersome to administer and is associated with significant toxicities. Based on recent data combining weekly paclitaxel with radiotherapy in both the neoadjuvant and definitive settings we report our early experience with this regimen. Methods: All patients (pts) were staged with CT, EUS and PET/CT. Pts with localized, operable or inoperable disease were included. CRT consisted of paclitaxel 50mg/m 2 and carboplatin AUC = 2 on days 1, 8, 15, 22, 29, 35 with concurrent RT (5 days/wk, 41.4-50.4Gy). Results: From December 2010 to January 2012, 24 pts: male/female 20/4, median age 67 yrs (29-88), adeno/squamous carcinoma 14/10, lymph node involvement (21pts) were treated. 13 pts treated with neoadjuvant (NA) intent, 11 pts underwent definitive CRT. In the NA group grade 3/4 toxicities were non-hematologic: cardiac (1pt), fatigue (1pt), 2 pts died from progression of disease prior to surgery. Eight pts have undergone surgery (3 awaited). RO resection rate 87.5%, 1 pt had a pCR, 4 pts had a near pCR. At 3mth follow-up 3 pts had no clinical or radiological evidence of disease, 5 pts await repeat imaging. In the definitive group grade 3/4 toxicities included hematologic: neutropenic fever (1pt), non-hematologic: esophagitis (3pts). At 3mth follow-up 7 pts have stable disease, 4 pts await repeat imaging. Dysphagia improved in 21 pts, worsened in 3 pts, and 5 pts required a feeding tube (4 prior to CRT). Conclusions: Carboplatin and paclitaxel combined with radiotherapy is a tolerable regimen in either the neo-adjuvant or definitive setting for locally advanced esophageal cancer. Rates of toxicity compare favorably to standard cisplatin and infusional 5FU. Prospective data with long-term follow-up using this regimen have been reported in the neo-adjuvant setting and are awaited in the definitive setting.
Personalized Therapy Design for Early T-Cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) Using Computational Biology Modeling with in Vitro Validation
Authors: Madeleine Turcotte, Raphael Charles Bosse, Kimberly E. Hawkins, Amy Meacham, Vindhya Vijay, Girish Chinnaswamy, Manju Sengar, Ansu Kumar, Shwetha K, Anisha Kamath, Anjana T. Nair, Karthik S. Raju, Taher Abbasi, Shireen Vali, Christopher R. Cogle, Leylah M. Drusbosky
Journal: Blood (2017)
Effect of voluntary licences for hepatitis C medicines on access to treatment: a difference-in-differences analysis
Authors: Bryony Simmons, Graham S Cooke, Marisa Miraldo
Journal: The Lancet Global Health (2019)

BackgroundVoluntary licences are increasingly being used to expand access to patented essential medicines in low-income and middle-income countries (LMICs). Since 2014, non-exclusive voluntary licences have been issued by Gilead and Bristol-Myers Squibb for key drugs for hepatitis C virus (HCV) infection. We aimed to evaluate the effect of these licences on access to HCV treatment.MethodsWe conducted a difference-in-differences analysis, exploiting the staggered and selective introduction of voluntary licensing in different countries, to identify the effect of voluntary licensing agreements on treatment uptake. We extracted Polaris Observatory data on the total number of people infected with HCV, diagnosed with HCV, and treated for HCV, and constructed a longitudinal panel of LMICs over a 13-year period (2004–16). Countries were included if they were classified as LMICs by the World Bank in 2014, and had available data on HCV outcomes. The exposure was defined as inclusion in any voluntary licence agreement for HCV drugs. Treatment uptake was calculated as the number of people treated for HCV in a given year per 1000 living people ever diagnosed with HCV. We fit difference-in-differences linear regression models controlling for different confounders that could influence treatment access and uptake, including country and year fixed effects and a range of country-level factors. We additionally assessed the dynamics of the effect and the robustness of our findings.Findings35 countries were included in the panel: 19 in the intervention group and 16 in the control group. In the simplest model, adjusting only for country and year fixed effects, voluntary licences were associated with an increase in the annual number of people accessing HCV treatment of 69·3 per 1000 diagnosed (95% CI 46·7–91·9; p=0·0060). After adjusting for country-level covariates, this increase was 53·6 per 1000 diagnosed (25·8–81·5; p=0·0354). The effect of licensing increased over time, and was largest in the second year after implementation. Results were robust to alternative specifications.InterpretationVoluntary licensing initiatives appear to substantially improve HCV treatment uptake in eligible countries. This evidence supports the expansion of licensing strategies to include more countries and more treatments.FundingUnitaid and Médecins Sans Frontières.
Gene fusions evidence in a KIT/PDGFRA wild-type GIST without mutations in SDH units identified by a whole transcriptome study.
Authors: Milena Urbini, Annalisa Astolfi, Valentina Indio, Maristella Saponara, Margherita Nannini, Cristian Lolli, Anna Mandrioli, Lidia Gatto, Maria Caterina Pallotti, Guido Biasco, Maria A. Pantaleo
Journal: Journal of Clinical Oncology (2013)

e21523 Background: A subset of KIT/PDGFRA wild-type GIST (WT) harbour mutations in SDH units. In the majority of the remaining cases of WT GIST no other molecular events are identified.We performed a RNA-seq in a WT GIST without mutations in SDH genes using next generation approach to discover molecular events in this GIST population. Methods: In 2003, a 63-year old woman underwent surgery for an ileal GIST (size 6 cm, MI 6/50HPF).After 6 years, she developed a recurrence with a single hepatic lesion. The KIT and PDGFRA analysis of the lesion did not show mutations. Therefore, she did not receive imatinib but she underwent a surgical removal. The analysis of all SDH units did not show mutations. So paired-end RNA-seq (75X2) was performed with Illumina HiScanSQ platform. After mapping the short reads on the human genome(HG19), SNVs and InDels were called by SNVMix2 with an accurate filtering procedures including predictors of mutations effect at protein level. Gene fusions discovery was done considering the agreement between DeFuse, ChimeraScan and FusionMap tools and validated by SangerSequencing using primers spanning the mRNA breakpoints. Results: Four different gene fusions and 206 non-synonymous SNVs were discovered, of which 62 were called deleterious by at least one predictor, and they are undergoing further validation. SPRED2-NELFCD gene fusion originated from an interchromosomal translocation-inversion between chr 20 and 2. The event involved exon1 of SPRED2 and exon11 of NELFCD, probably leading to inactivation of both genes. NELFCD encodes a component of the NELF complex that negatively regulates transcription elongation by RNA pol II, while SPRED2 is a member of the Sprouty /SPRED family that repress growth factor-induced activation of the MAPK/ERK pathway. The other three events were intrachromosomal aberrations: MARK2-PPFIA1 and PLA2G16-ATL3 on chr 11 and ASCC1-C10orf11 on chr 10. Only the first event led to an in-frame fusion (MARK2 ex1- PPFIA1 ex2) probably dysregulating the expression of the downstream gene. Conclusions: This is the first evidence of gene fusions in GIST. The oncogenetic role and the tumor frequency of these events deserve to be studied.
Potential applications of circulating melanoma cells (CMCs) expressing γ-H2AX.
Authors: Elisabetta Rossi, Antonella Facchinetti, Angela Grassi, Carlo Riccardo Rossi, Silvia Stragliotto, Jacopo Pigozzo, Vanna Chiarion-Sileni, Alberto Amadori, Paola Zanovello, Rita Zamarchi
Journal: Journal of Clinical Oncology (2013)

e22036 Background: The CMC analysis was recently improved by the CellSearch platform that offers an accurate (and reproducible) assessment of tumor burden, to be used as prognosticator and predictor of treatment response.Moreover, not only decreased total circulating cells numbers but also increased fraction of apoptotic cells may represent response-related markers. To monitor changes in the balance between live and apoptotic Circulating Tumor Cells (CTCs) ( Rossi, Basso et al. 2010 ) during therapy, a novel CTCs assay with a companion algorithm (the ΔAUC) was reported to be a pharmacodynamic marker, as documented by consistent radiological findings in MBC and mRCC patients. Methods: Fluorescent anti γ-H2AX mAb (specific for the phosphorylated form of H2AX) was integrated in the standard CMC assay to assess DNA damage and to measure cell viability and apoptosis in spreading melanoma cells. The integrated test was developed using MCF-7 and SK23mel cells line and tested in melanoma patients. From June-2011 till now, basal blood samples from 64 patients (pts) in stage IV were collected; median age 62 (range: 27-85). Both considering the cost of the CMC assay and the little already known about this new method in melanoma, to evaluate the feasibility of CMC retrieval and ΔAUC calculation an interim analysis was specified in the study protocol and conducted at September 2012 on the first 40 pts. Results: At baseline, in Padova’s cohort 72.6% of pts are CMC-positive. The CMC number ranged from 1 to 94. The γ-H2AX-positive CMCs ranged from 0% to 100% (median 67%). Shorter median Progression-free survival PFS was observed for patients who had &gt; 2 CMCs (n=26, 162 days) compared with &lt; 2 CMCs patients (n=14, 203 days, P value = 0.0270). No significant differences were found with the ΔAUC criterion (i.e. exceeding live vs apoptotic CMCs). Furthermore, a significant association was found between CMC-positive status at baseline and disease sites at progression (visceral and CNS, Chi-square = 8,521 with 3 df, P value = 0.036). Conclusions: Accrual is ongoing. Updated data including evaluations on prognostic value of total and apoptotic CMCs and correlation with clinical stage, tumor burden, metastatic sites and survival will be available and presented at the meeting.