tbuckley/cabot-search huggingface dataset:
Irinotecan and bevacizumab in progressive primary brain tumors: The Cleveland Clinic experience
Authors: T. Kang, T. Jin, D. Peereboom
Journal: Journal of Clinical Oncology (2007)

2077 Background: High-grade gliomas are generally resistant to modern chemotherapy. In the case of glioblastoma multiforme, median overall survival has been less than 12 months and progression free survival of less than 4 months. For patients with recurrent GBMs, the 6 month progression free survival is 15–20%. The combination of irinotecan and bevacizumab is an active regimen in the treatment of this disease. Herein we report the experiences with this regimen at our institution with the objective of identifying a therapy with a better outcome than historical results. Methods: Single institutional, retrospective review of 27 patients with recurrent or progressive high grade gliomas treated at the Cleveland Clinic Brain Tumor Institute from 7/2005 through 10/2006. Patients had progressed on at least one prior chemotherapy. Patients with prior irinotecan or bevacizumab were excluded. Patients were analyzed on an intention-to-treat basis, and outcomes estimated by the Kaplan-Meier method. Results: The median age of the group was 46 years (range 5–69). The median number of prior therapies was 2 (range 1–10). Twenty of 27 patients have progressed (74%), and 11 of 27 patients have died (41%). Kaplan-Meier estimates for outcomes are summarized in the table . Progression-free survival at 6 months is 46 %, with median of 5.1 months. Overall survival at 6 months is 84%, with median of 12.6 months. In 7 patients, treatment was terminated early prior to progression. Significant toxicities include: one patient who developed hematuria, one patient with deep venous thrombosis and one patient who experienced intracranial hemorrhage. Conclusions: Our experience suggests that the combination of irinotecan and bevacizumab improves the 6-month progression-free survival when compared to historical figures. The rate of severe toxicities is consistent with prior reports and mandates careful selection of patients. Further randomized, phase 3 studies should be done to validate these results. [Table: see text] No significant financial relationships to disclose.
Impact of neutropenia on the outcome of decitabine (DAC) treatment in patients (pts) with myelodysplastic syndrome (MDS).
Authors: N. Pemmaraju, H. Kantarjian, S. Faderl, G. Garcia-Manero, T. M. Kadia, G. Borthakur, J. E. Cortes, F. Ravandi Kashani
Journal: Journal of Clinical Oncology (2010)

6605 Background: Pts with MDS often present with neutropenia. We investigated the effect of baseline neutropenia on outcome in pts treated with DAC for higher risk MDS. Methods: We reviewed 188 pts with intermediate and high-risk MDS receiving DAC. 99 pts received DAC 20 mg/m2 for 5 days every 4 weeks (5-day cohort) while 89 received DAC 15 mg/m2 for 3 days every 6 weeks (3-day cohort). Pts were stratified by baseline ANC: severe (<500 K/UL), moderate (500-1,000 K/UL), and mild (>1,000 K/UL). Results: Demographics were generally similar among ANC groups. In the 5-day cohort response rates (RR) were higher in the severe group; overall survival (OS) was greatest in the mild group. RR and OS in the 3-day cohort were highest in the moderate group. When stratified by ANC group, the shift from red blood cell (RBC) transfusion dependence (TD) to RBC transfusion independence (TI) in the 3-day cohort occurred in 18%, 18%, and 11% of pts, respectively; in the 5-day cohort, 38%, 6%, and 44%, respectively (Table). Most common treatment-related adverse events were neutropenia, thrombocytopenia, anemia, febrile neutropenia (FN), and leukopenia. FN developed in 20 pts in the 5-day cohort and 24 pts in the 3-day cohort with complete responses (CR) in 25% of FN pts in the 5-day cohort and 21% of FN pts in the 3-day cohort. Conclusions: DAC was effective in MDS pts with and without baseline neutropenia with meaningful and prolonged responses in all ANC groups. Development of FN did not preclude achievement of CRs in either cohort. 3-day cohort (N = 89) <500 (N = 22) 500-1,000 (N = 22) 1,000 (N =37) ORR (CR + PR) 9% N=2 27% N=6 13.5% N=5 ORI (CR+ PR + HI) 13.6% N=3 41% N=9 29.7% N=11 Days to initial resp 31.6 (15.3) 92.3 (59) 55.3 (46.3) Resp duration (days) 226.3 (56.04) 282.7 (106.2) 239.9 (133.1) Median OS (95% CI) 261 (147,384) 645 (485, NR*) 370 (252,506) TD- TI (RBC) 18.2% 18.2% 10.8% 5-day cohort (N = 99) <500 (N = 23) 500-1,000 (N = 26) 1,000 (N = 49) ORR (CR + mCR + PR) 43% N=10 12% N=3 31% N=15 ORI (CR + mCR + PR + HI) 74% N=17 46% N=2 45% N=22 Days to initial resp 50 (43, 49) 44 (29,72) 37 (29, 53) Resp duration 219 (148, NE) 280 (237, NE) 288 (195, NE) Median OS (95% CI) 447 (295,648) 420 (157,800) 627 (494,802) TD- TI (RBC) 38% 6% 44% Abbreviation: resp, response. * Not reached at time of analysis Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai
Delta 32 mutation in CCR5 gene and its association with breast cancer.
Authors: Abid Azhar, Faria Fatima, Abdul Hameed, Saima Saleem
Journal: Journal of Clinical Oncology (2015)

17 Background: Chemokine C-C motif receptor type 5 (CCR5) is a chemokine receptor protein, which is present on the cell surface. Its potential role in cancer progression and metastasis has been implicated. Deletion mutation of 32 base pairs (bp) in the open reading frame of the CCR5 gene (CCR5Δ32) may lead to the malformation of the protein. This study aimed to examine the role of CCR5Δ32 mutation and its association with breast cancer. Methods: Blood samples of 500 breast cancer patients were included in the study. The samples were compared with age and sex matched healthy controls. Mutation of CCR5Δ32 was analyzed by sequence specific primers by polymerase chain reaction (PCR). They were examined on agarose gel electrophoresis. Statistical analyses were performed using software SPSS 17.0 (Chicago, IL., USA). The genotypic frequencies of patients and controls were tested by applying the chi‐square test. Results: Two types of CCR5 allelic mutations were found in the breast cancer samples. The mutation was of a 32 (bp) DNA fragment. Homozygous insertion (I/I) and heterozygous deletion (I/D) was found in the open reading frame of the regulatory region of the gene. The chi square analyses showed significant positive association between I/I and I/D allele in breast can patients with CCR5 delta 32 mutation (χ2 15.07, p &lt; 0.01). Conclusions: This deletion in the promoter region of the CCR5 gene produces a non-functional receptor which may increase inflammation, leading to the enhanced progression of tumor.
Myocardial iron content and mitochondrial function in human heart failure: a direct tissue analysis
Authors: Vojtech Melenovsky, Jiri Petrak, Tomas Mracek, Jan Benes, Barry A. Borlaug, Hana Nuskova, Tomas Pluhacek, Jaroslav Spatenka, Jana Kovalcikova, Zdenek Drahota, Josef Kautzner, Jan Pirk, Josef Houstek
Journal: European Journal of Heart Failure (2016)
Plasma cholesterol concentration and mortality. The Whitehall Study
Authors: G. D. Smith
Journal: JAMA (1992)

<h3>Objective.</h3> —To examine the relationship between plasma cholesterol concentration and mortality from major causes of death. <h3>Design.</h3> —Cohort study. <h3>Setting.</h3> —Civil service offices in London, England. <h3>Participants.</h3> —There were 17718 male civil servants aged 40 through 64 years at the time of study entry between 1967 and 1969. <h3>Main Outcome Measure.</h3> —Mortality from major cause groups. <h3>Results.</h3> —There were 4022 deaths in the cohort over the 18 years of follow-up. Total mortality increased with cholesterol level, although mortality in the small group with very low cholesterol levels (5% of study population) was nonsignificantly higher (<i>P</i>&gt;.5) than that of the remainder of the lowest quintile cholesterol group. Coronary heart disease mortality increased with increasing cholesterol concentration from the lowest levels (<i>P</i>&lt;.001 for trend). The cancer mortality rate in the group below the fifth centile of the cholesterol distribution was higher than in the remainder of the cohort for lung (<i>P</i>&lt;.001), pancreas (<i>P</i>=.05), liver (<i>P</i>=.09), and all smoking-related cancers (<i>P</i>=.02). Only for lung cancer was there a consistent inverse trend with cholesterol level (<i>P</i>&lt;.01). Rates of mortality due to non-neoplastic respiratory disease were inversely related to cholesterol level (<i>P</i>&lt;.001). Health state at the time of examination and socioeconomic position were related to cholesterol concentration—subjects in lower employment grades, with disease at baseline, with a history of recent unexplained weight loss, or who had been widowed had lower initial cholesterol levels. These associations largely accounted for the relationships between cholesterol level and noncardiovascular mortality. <h3>Conclusions.</h3> —The inverse associations between plasma cholesterol concentration and mortality from certain causes of death seen in cohort studies could be because the participants with low cholesterol levels possess other characteristics that place them at an elevated risk of death. (<i>JAMA</i>. 1992;267:70-76)
PD-0024 Phase I/II Study of Folfiri Plus the MEK1/2 Inhibitor Pimasertib (MSC1936369B) as Second-Line Treatment for KRAS Mutated Metastatic Colorectal Cancer
Authors: Teresa Macarulla, Josep Tabernero, Andrés Cervantes, Susana Roselló, Eric Van Cutsem, Sabine Tejpar, Hans Prenen, Erika Martinelli, Teresa Troiani, Fank Campana, Bernard Laffranchi, Virginie Jego, Oliver von Richter, Fortunato Ciardiello
Journal: Annals of Oncology (2012)
P0548 : Impaired anti-HBV vaccine response in non-cirrhotic chronic HCV patients compared to healthy controls
Authors: M.G. Pessoa, R.P. Medeiros, M. Lopes, D. Mazo, C.P. Oliveira, P.M. Zitelli, J.R. Pinho, F.J. Carrilho
Journal: Journal of Hepatology (2015)
Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models
Authors: Joel Chappell, Jennifer L. Harman, Vagheesh M. Narasimhan, Haixiang Yu, Kirsty Foote, Benjamin D. Simons, Martin R. Bennett, Helle F. Jørgensen
Journal: Circulation Research (2016)

Rationale: Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, which underlie vascular disease, remain unresolved. In particular, it is not known whether all VSMCs proliferate and display plasticity or whether individual cells can switch to multiple phenotypes. Objective: To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells. Methods and Results: Using multicolor lineage labeling, we demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligoclonal, derived from few expanding cells. Lineage tracing also revealed that the progeny of individual VSMCs contributes to both alpha smooth muscle actin (aSma)–positive fibrous cap and Mac3-expressing macrophage-like plaque core cells. Costaining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained the expression of VSMC markers and the upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease. Conclusions: We demonstrate that extensive proliferation of a low proportion of highly plastic VSMCs results in the observed VSMC accumulation after injury and in atherosclerotic plaques. Therapeutic targeting of these hyperproliferating VSMCs might effectively reduce vascular disease without affecting vascular integrity.
Cytomegalovirus (CMV) infection accelerates the development of atherosclerosis in apolipoproteinE (apoE) knock-out mice
Authors: Inge Vliegen, Marjorie Nelissen-Vrancken, Roel Koch, Gert Grauls, Joanne Van Dam, Andre Van der Ven, Mihai Netea, Mat Daemen, Cathrien Bruggeman
Journal: Circulation (2000)
Metabolic syndrome increases cardiovascular events but not hepatic events and death in patients with chronic hepatitis B
Authors: Jenny Yeuk‐Ki Cheng, Vincent Wai‐Sun Wong, Yee‐Kit Tse, Angel Mei‐Ling Chim, Henry Lik‐Yuen Chan, Grace Lai‐Hung Wong
Journal: Hepatology (2016)

Metabolic syndrome is an independent risk factor of liver cirrhosis in chronic hepatitis B (CHB). Whether metabolic syndrome affects the long‐term prognosis of CHB patients in terms of hepatic events, cardiovascular events, and death remains unknown. We aimed to determine the incidences of hepatic events, cardiovascular events, and death in CHB patients with or without metabolic syndrome. From 2006 to 2008, we prospectively recruited 1,466 CHB patients for liver stiffness measurement (LSM) with transient elastography together with detailed metabolic profiling as baseline assessment. Patients were prospectively followed for any clinical events. The impact of LSM and metabolic syndrome on hepatic events, cardiovascular events, and death was evaluated. At baseline visit, the mean age was 46 ± 12 years, LSM value was 8.4 ± 6.3 kPa, and 188 patients (12.8%) had metabolic syndrome. At a mean follow‐up of 88 ± 20 months, 93 and 44 patients developed hepatic and cardiovascular events, respectively; 70 patients died. Patients with baseline LSM &gt;8.0 kPa had higher cumulative probability of hepatic events than those with LSM ≤8.0kPa at 8 years (12.3% versus 3.1%, P &lt; 0.001). Patients with metabolic syndrome had higher cumulative probability of cardiovascular events than those without (8.0% versus 2.1%, P &lt; 0.001). High LSM had no impact on cardiovascular events; neither did metabolic syndrome on hepatic events. LSM &gt;8.0 kPa but not metabolic syndrome was an independent risk factor of death, with adjusted hazard ratios of 1.9 (95% confidence interval 1.1‐3.2, P = 0.023) and 1.3 (95% confidence interval 0.8‐2.4, P = 0.310), respectively. Conclusions: Metabolic syndrome increased the risk of cardiovascular events but not hepatic events and death; LSM was the important risk factor of hepatic events and death in CHB patients. (H epatology 2016;64:1507‐1517)
Vital Directions for US Health Care
Authors: C. David Naylor
Journal: JAMA (2016)

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Association of Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sectional study
Authors: Maria Baudin, Ammar M Jumaa, Huda J E Jomma, Mubarak S Karsany, Göran Bucht, Jonas Näslund, Clas Ahlm, Magnus Evander, Nahla Mohamed
Journal: The Lancet Global Health (2016)

Rift Valley fever virus is an emerging mosquito-borne virus that causes infections in animals and human beings in Africa and the Arabian Peninsula. Outbreaks of Rift Valley fever lead to mass abortions in livestock, but such abortions have not been identified in human beings. Our aim was to investigate the cause of miscarriages in febrile pregnant women in an area endemic for Rift Valley fever.Pregnant women with fever of unknown origin who attended the governmental hospital of Port Sudan, Sudan, between June 30, 2011, and Nov 17, 2012, were sampled at admission and included in this cross-sectional study. Medical records were retrieved and haematological tests were done on patient samples. Presence of viral RNA as well as antibodies against a variety of viruses were analysed. Any association of viral infections, symptoms, and laboratory parameters to pregnancy outcome was investigated using Pearson's χ2 test.Of 130 pregnant women with febrile disease, 28 were infected with Rift Valley fever virus and 31 with chikungunya virus, with typical clinical and laboratory findings for the infection in question. 15 (54%) of 28 women with an acute Rift Valley fever virus infection had miscarriages compared with 12 (12%) of 102 women negative for Rift Valley fever virus (p<0·0001). In a multiple logistic regression analysis, adjusting for age, haemorrhagic disease, and chikungunya virus infection, an acute Rift Valley fever virus infection was an independent predictor of having a miscarriage (odds ratio 7·4, 95% CI 2·7-20·1; p<0·0001).This study is the first to show an association between infection with Rift Valley fever virus and miscarriage in pregnant women. Further studies are warranted to investigate the possible mechanisms. Our findings have implications for implementation of preventive measures, and evidence-based information to the public in endemic countries should be strongly recommended during Rift Valley fever outbreaks.Schlumberger Faculty for the Future, CRDF Global (31141), the Swedish International Development Cooperation Agency, the County Council of Västerbotten, and the Faculty of Medicine, Umeå University.
P1-167: The association between inflammation in resected lung tissue and prognosis in patients with NSCLC
Authors: Hee Joung Kim, Hye Sook Min, Doo Hyun Chung, Young Tae Kim, Sook Whan Sung, Joo Hyun Kim, Sung Koo Han, Young-Soo Shim, Young Whan Kim
Journal: Journal of Thoracic Oncology (2007)
Viral Load Kinetics of MERS Coronavirus Infection
Authors: Myoung-Don Oh, Wan Beom Park, Pyoeng Gyun Choe, Su-Jin Choi, Jong-Il Kim, Jeesoo Chae, Sung Sup Park, Eui-Chong Kim, Hong Sang Oh, Eun Jung Kim, Eun Young Nam, Sun Hee Na, Dong Ki Kim, Sang-Min Lee, Kyoung-Ho Song, Ji Hwan Bang, Eu Suk Kim, Hong Bin Kim, Sang Won Park, Nam Joong Kim
Journal: New England Journal of Medicine (2016)

Middle East respiratory syndrome coronavirus continues to circulate in the Middle East. During a recent outbreak in Korea, changes in MERS coronavirus viral load were determined during the course of illness in 17 patients.
LUX-breast 1: Randomized, phase III trial of afatinib and vinorelbine versus trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment.
Authors: Nadia Harbeck, Seock-Ah Im, Chiun-Sheng Huang, Young-Hyuck Im, Binghe Xu, Sara A. Hurvitz, Keun-Seok Lee, Jin-Hee Ahn, Ajay O. Mehta, Rajender Singh Arora, Qiang Sun, Shukui Qin, Linu Abraham Jacob, Jacek Jassem, Elzbieta Staroslawka, Jozef Sufliarsky, Marek Wojtukiewicz, Annick Lahogue, Martina Maria Uttenreuther-Fischer, Martine J. Piccart-Gebhart
Journal: Journal of Clinical Oncology (2012)

TPS649 Background: Afatinib is an ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers. Afatinib is being developed in EGFR (ErbB1)-driven (NSCLC/HNSCC) and HER2 (ErbB2)-driven (breast) malignancies. In trastuzumab-resistant, HER2-positive (SUM190) xenografts, afatinib showed antitumor activity which was superior to lapatinib and increased by addition of IV vinorelbine. Afatinib monotherapy also demonstrated clinical activity (progression-free survival [PFS] = 15.1 wk; objective response [OR] = 10%) in an open-label, single-arm, Phase II trial in patients with HER2-positive MBC after progression on trastuzumab. Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label, multicenter trial evaluating the efficacy and safety of afatinib + vinorelbine vs. trastuzumab + vinorelbine in patients with HER2-overexpressing MBC who progressed on, or after one prior trastuzumab-based treatment regimen. Patients are randomized 2:1 to afatinib (40 mg/d oral) + vinorelbine (IV 25 mg/m 2 /wk) or trastuzumab (IV 2 mg/kg/wk after 4 mg/kg loading dose) + vinorelbine (IV 25 mg/m 2 /wk). Patients receive continuous treatment in the absence of disease progression or adverse events. Key eligibility criteria include histologically-confirmed HER2-positive BC, stage IV disease; no prior treatment with vinorelbine or HER2-targeted treatment other than trastuzumab; progression on one prior trastuzumab based regimen in either the adjuvant (or &lt;12 months after trastuzumab completion) or first-line (or &lt;6 months after trastuzumab completion) setting; prior anthracycline and/or taxane chemotherapy; ECOG score 0 or 1. The primary endpoint is PFS and secondary endpoints include OR, overall survival and safety. Serum and tissue biomarkers will be assessed on archival tissue. HER-receptor and HER-ligand reprogramming, putative resistance markers and EGFR response signature will be explored in fresh tissue biopsies. Enrollment began in June 2010 and is ongoing, targeting &gt;240 sites with a recruitment target of 780 patients.
Hypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD
Authors: Xiaofang Huo, Agoston T Agoston, Kerry B Dunbar, Daisha J Cipher, Xi Zhang, Chunhua Yu, Edaire Cheng, Qiuyang Zhang, Thai H Pham, Uttam K Tambar, Richard K Bruick, David H Wang, Robert D Odze, Stuart J Spechler, Rhonda F Souza
Journal: Gut (2016)

In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs).Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2 weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs. We exposed human oesophageal squamous cell lines to acidic bile salts, and evaluated effects on HIF activation, p65 function, pro-inflammatory molecule production and immune cell migration.In patient biopsies, increased immunostaining for HIF-2α and phospho-p65, and increased pro-inflammatory molecule mRNA levels were seen when RO redeveloped 1 or 2 weeks after stopping PPIs. In oesophageal cells, exposure to acidic bile salts increased intracellular reactive oxygen species, which decreased prolyl hydroxylase function and stabilised HIF-2α, causing a p65-dependent increase in pro-inflammatory molecules; conditioned media from these cells increased T cell migration rates. HIF-2α inhibition by small hairpin RNA or selective small molecule antagonist blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts.In patients developing RO, increases in oesophageal HIF-2α correlate with increased pro-inflammatory molecule expression. In oesophageal epithelial cells, acidic bile salts stabilise HIF-2α, which mediates expression of pro-inflammatory molecules. HIF-2α appears to have a role in RO pathogenesis.NCT01733810; Results.