tbuckley/cabot-search huggingface dataset:
Clinical benefit from bevacizumab (BV) in responding (R) and non-responding (NR) patients (pts) with metastatic colorectal cancer (mCRC)
Authors: R. D. Mass, S. Sarkar, S. N. Holden, H. Hurwitz
Journal: Journal of Clinical Oncology (2005)

3514 Background: BV, a monoclonal antibody to vascular endothelial growth factor, is a potent anti-angiogenic agent with demonstrated survival benefit when combined with irinotecan, 5-fluorouracil and leucovorin (IFL) in first-line mCRC. Because preclinical data suggest BV is primarily a cytostatic agent, we explored the clinical benefit of BV assessed by progression-free survival (PFS) and overall survival (OS) in R and NR subgroups. Methods: In the pivotal trial, 813 pts with untreated mCRC were randomized to receive IFL plus either BV or placebo. For this retrospective, exploratory analysis, pts were grouped by best response achieved (complete/partial responses [R] vs. stable/progressive disease or non-evaluable [NR]). For both R and NR subgroups, PFS and OS within these subgroups were estimated from Kaplan-Meier curves, and hazard ratios (HRs) for progression and death were estimated by Cox regression. Results: The BV and placebo arms in both the R and NR subgroups had similar baseline characteristics. Statistically significant improvements in HR for PFS and OS for BV-treated pts were observed in both subgroups (Table 1) and were consistent between the groups (interaction p-value for OS = 0.44; for PFS, 0.73). Conclusion: These analyses suggest that the magnitude of clinical benefit associated with BV treatment, as measured by HR for PFS and OS, is similar in mCRC regardless of objective tumor response. This response-independent survival benefit is a novel observation in mCRC, and has implications for endpoint selection in BV-based clinical trials and the routine clinical use of BV. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
Clinical outcome following lung transplantation in patients with cystic fibrosis colonised with Burkholderia cepacia complex: results from two French centres
Authors: V Boussaud, R Guillemain, D Grenet, N Coley, R Souilamas, P Bonnette, M Stern
Journal: Thorax (2008)

Infection with Burkholderia cepacia complex (BCC) is a life threatening complication of cystic fibrosis (CF), often seen as a contraindication for lung transplantation.A long term retrospective study was conducted of all patients with CF undergoing lung transplants from January 1990 to October 2006 in two French centres allowing transplantation in patients colonised with BCC.22 of the 247 lung transplant patients with CF were infected with BCC (B. cenocepacia genomovar III (n = 8), B. multivorans genomovar II (n = 11), B. vietnamiensis genomovar V (n = 2) and B. stabilis genomovar IV (n = 1)). BCC colonisation was not associated with any significant excess mortality (HR 1.5, 95% CI 0.7 to 3.2; p = 0.58). However, early mortality rates tended to be higher in the BCC group than in the non-BCC group (3 month survival: 85% vs 95%, respectively; log rank p = 0.05). Univariate analysis showed that the risk of death was significantly higher for the eight patients infected with B. cenocepacia than for the other 14 colonised patients (HR 3.2, 95% CI 1.1 to 5.9; p = 0.04). None of the other risk factors tested-primary graft failure, late extubation, septicaemia-had a significant effect. The 5 year cumulative incidence rate of bronchiolitis obliterans syndrome was not significantly higher in the BCC group than in the non-BCC group (38% vs 24%, respectively; p = 0.35).Our results suggest that BCC infection with a non-genomovar III organism may not be associated with excess mortality after lung transplantation in patients with CF and should not be seen as sufficient reason to exclude lung transplantation. However, colonisation with B. cenocepacia remains potentially detrimental.
Epit Prevents from the Induction of Anaphylaxis to Further Allergens: Role of Naive Tregs
Authors: Lucie Mondoulet, Vincent Dioszeghy, Emilie Puteaux, Mélanie Ligouis, Véronique Dhelft, Camille Plaquet, Christophe Dupont, Pierre-Henri Benhamou
Journal: Journal of Allergy and Clinical Immunology (2016)
NFAT subtypes in regulating Th2 lymphocytes
Authors: Xin Yao, Yue Teng, Hao Huang, Ian Adcock, Peter Barnes
Journal: European Respiratory Journal (2012)

Background   Nuclear factor of activate T cells (NFAT), consists of five members and plays a pivotal role in regulating T lymphocyte activation. Among the five subtypes of NFAT, NFAT1, NFAT2 and NFAT4 were recognized as the key family members associated with allergic diseases. However, evidence regarding the functions of NFAT1 and NFAT2 in Th2 cells are still conflicting.   Aims and objectives   Therefore, we explored the functions of NFAT1 and NFAT2 on Th2 lymphocytes.   Methods   Knockdown of NFAT1 and NFAT2 using small interfering RNA (siRNA) was performed in the murine Th2 lymphocyte cell line (D10.G4.1). Real-time qPCR, Western Blotting and ELISA were performed to test the relatively expression ofTh2 cytokine mRNA and protein in cells and culture supernatant.   Results    D10 cells express IL-4, IL-5, IL13 and GATA3mRNA level. NFAT1 siRNA and NFAT2 siRNA selectively suppressed the expression of NFAT1 and NFAT2 respectively at both the mRNA and protein level. Higher levels of IL-4, IL-5 and IL-13 were seen in NFAT1 siRNA treated Th2 cells. This suggests that NFAT1 may play a negative role in Th2 cytokine expression. Interestingly, the opposite effect was seen with NFAT2 siRNA. NFAT2 siRNA down-regulated the expression of IL-4, IL-5 and IL13 mRNA levels. This was associated with a reduction in the expression of GATA3 mRNA and protein.   Conclusions    NFAT1 may play a negative role in regulating Th2 cytokines whilst NFAT2 may have the opposite effect.
Novel genetic predictors of venous thromboembolism risk in African Americans
Authors: Wenndy Hernandez, Eric R. Gamazon, Erin Smithberger, Travis J. O’Brien, Arthur F. Harralson, Matthew Tuck, April Barbour, Rick A. Kittles, Larisa H. Cavallari, Minoli A. Perera
Journal: Blood (2016)
Phase I study of the novel anticancer drug PM00104 as a 24-hour IV infusion every 3 weeks (q3w) in patients (pts) with advanced solid tumors or lymphoma
Authors: J. Capdevila, S. Clive, J. Tabernero, P. Lardelli, A. Soto-Matos, J. Baselga, A. Piera, I. Pardos, R. Rye, J. F. Smyth
Journal: Journal of Clinical Oncology (2009)

2568 Background: PM00104 is a novel synthetic alkaloid related to the marine compounds jorumycin and renieramycins. Preliminary preclinical studies suggest changes in cell cycle and DNA binding properties and transcriptional inhibition as main mechanisms of action. PM00104 has shown broad in vitro and in vivo anti-tumor activity (IC 50 ≤ 10 -8 M) with an acceptable toxicology profile. Methods: The aim of this phase I study was to assess the safety profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), relationship between PK and pharmacodynamics (PD) and anti-tumor activity of PM00104 administered as a 24-hour i.v. infusion q3w. Sequential cohorts of 3–6 pts were treated at 133, 266, 400, 800, 900, 1600, 3200, 4000 and 5000 μg/m 2 . Results: Twenty nine pts have been treated (18 male, 11 female; median age: 59, range: 44–78; ECOG PS ≤2). Five pts developed DLTs: 2 pts at 5000 μg/m 2 (grade 4 thrombocytopenia/neutropenia and grade 3 nausea/vomiting in 1 pt; and grade 3 nausea in 1 pt); 1 at 4000 μg/m 2 (grade 4 neutropenia/thrombocytopenia and grade 3 asthenia); 1 at 3200 μg/m 2 (grade 3 tumor pain) and 1 at 266 μg/m 2 (grade 3 transaminase increase). The MTD was reached at 5000 μg/m 2 and the RD at 4000 μg/m 2 . At the RD 6 more pts have been included in order to further evaluate the safety profile and anti-tumor activity. Other adverse events included nausea and vomiting (more frequent at doses ≥800 μg/m 2 ), fatigue, anorexia and diarrhea; most of them being of ≤grade 2 severity. No objective responses were seen but 3 pts with pancreatic adenocarcinoma, hepatocarcinoma and lower esophagus adenocarcinoma presented stable disease lasting &gt;3 months. PM00104 shows a dose-proportional PK profile, the half-life being 20–30 hours and the volume of distribution around 1000 L. Conclusions: PM00104 has shown an acceptable safety profile with signs of anti-tumor activity in pts with advanced malignancies when administered as a 24-hour i.v. infusion q3w. PM00104 is also being evaluated with other administration schedules as monotherapy and in combination with other anti-tumor agents. [Table: see text]
Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases
Authors: Yashodhara Dasgupta, Mateusz Koptyra, Grazyna Hoser, Kanchan Kantekure, Darshan Roy, Barbara Gornicka, Margaret Nieborowska-Skorska, Elisabeth Bolton-Gillespie, Sabine Cerny-Reiterer, Markus Müschen, Peter Valent, Mariusz A. Wasik, Christine Richardson, Oliver Hantschel, Heiko van der Kuip, Tomasz Stoklosa, Tomasz Skorski
Journal: Blood (2016)
Impact of Prostate Cancer Diagnosis on Noncancer Hospitalizations Among Elderly Medicare Beneficiaries With Incident Prostate Cancer
Authors: Amit D. Raval, Suresh Madhavan, Malcolm D. Mattes, Mohamad Salkini, Usha Sambamoorthi
Journal: Journal of the National Comprehensive Cancer Network (2016)

Objectives: The purpose of this study was to analyze the impact of cancer diagnosis on noncancer hospitalizations (NCHs) by comparing these hospitalizations between the precancer and postcancer periods in a cohort of fee-for-service Medicare beneficiaries with incident prostate cancer. Methods: A population-based retrospective cohort study was conducted using the SEER-Medicare linked database for 2000 through 2010. The study cohort consisted of 57,489 elderly men (aged ≥67 years) with incident prostate cancer. NCHs were identified in 6 periods (t1–t6) before and after the incidence of prostate cancer. Each period consisted of 120 days. For each period, NCHs were defined as inpatient admissions with primary diagnosis codes not related to prostate cancer, prostate cancer–related procedures, or bowel, sexual, and urinary dysfunction. Bivariate and multivariate comparisons on rates of NCHs between the precancer and postcancer periods accounted for the repeated measures design. Results: The rate of NCHs was higher during the postcancer period (5.1%) compared with the precancer period (3.2%). In both unadjusted and adjusted models, elderly men were 37% (odds ratio [OR], 1.37; 95% CI, 1.32, 1.41) and 38% (adjusted OR, 1.38; 95% CI, 1.33, 1.46) more likely to have any NCHs during the postcancer period compared with the precancer period. Conclusions: Elderly men with prostate cancer had a significant increase in the risk of NCHs after the diagnosis of prostate cancer. This study highlights the need to design interventions for reducing the excess NCHs after prostate cancer diagnosis among elderly men.
Abstract 13901: Unexplained Chest Pain Linked With High Rates of Recidivism and Costs - A Prospective Gender Specific Analysis
Authors: Basmah Safdar, James Dziura, Harini Bathulapalli, Douglas L Leslie, Melissa Skanderson, Cynthia Brandt, Sally Haskell
Journal: Circulation (2013)

Context: Recidivism for non-specific or unexplained chest pain (UCP) is common in patients with and without coronary artery disease (CAD). Objectives: To compare chest pain recidivism (a) between p...
AIDS Due to HIV-2 Infection—New Jersey
Journal: JAMA (1988)

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A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The RILOMET-2 trial.
Authors: Toshihiko Doi, Yoon-Koo Kang, Kei Muro, Yizhou Jiang, Rajul K. Jain, Richard Lizambri
Journal: Journal of Clinical Oncology (2015)

TPS226 Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor, the only known ligand of the MET receptor. In a phase 2 study, trends toward improved progression-free survival (PFS) and overall survival (OS) were seen with rilotumumab plus epirubicin, cisplatin and capecitabine (ECX) vs ECX alone in pts with G/GEJ cancer; the treatment effect of rilotumumab was enhanced in MET-positive pts (Iveson et al. Lancet Oncol 2014;15:1007). In a phase 1/1b study, rilotumumab plus CX had manageable toxicities and a favorable pharmacokinetic (PK) profile in Japanese pts with MET-positive G/GEJ cancer (Doi et al. J Clin Oncol 2014;32:5s,abstract 4051). Methods: In this phase 3 study, 450 pts from Asian countries are randomized 1:1 to CX (intravenous [IV] cisplatin 80 mg/m 2 on day 1 and oral capecitabine 1000 mg/m 2 twice daily on days 1−14) plus double-blind rilotumumab 15 mg/kg or placebo IV on day 1 every 3 weeks for up to 6 cycles. After cycle 6, pts will receive capecitabine plus rilotumumab or placebo. Randomization is stratified by disease extent (locally advanced vs metastatic), prior surgery for G/GEJ or esophageal cancer (yes vs no), and country (China vs other). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ≥20 years, ECOG score ≤1, MET-positive by centralized immunohistochemistry, HER2-negative, adequate organ function, and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoints are PFS and OS. A log-rank test stratified by the randomization factors will compare PFS and OS between arms. Key secondary endpoints include 12-month survival rate, time to progression, objective response and disease control rates, duration of/time to response, safety, and PK. Enrollment began in July 2014, and the trial continues to recruit participants. The study is overseen by an independent data monitoring committee. ClinicalTrials.gov: NCT02137343. Sponsor: Amgen Inc. Clinical trial information: NCT02137343.
PIK3CA, BCL-6, MLL and FOXP1 in the transformation and prognosis of MALT lymphoma
Authors: L. Z. Zhai, Y. Huang, S. S. Wang, Y. B. Cao, J. Xiao, X. Fu, S. Ye, C. C. Guo, Y. Tian, T. Y. Lin
Journal: Journal of Clinical Oncology (2008)

8577 Background: Recent study showed that the most common gene abnomalities in gastrointestinal MALT lymphoma included 3q26.2 -27,11q23–24 amplifications and t(3;14) (p14.1;q32). MALT lymphoma shared the same aberrations with DLBCL but with a lower rate, suggesting a clonal transformation from low to high-grade lymphoma. Four important oncogenes were found to be involved in these aberrations, including PIK3CA, BCL-6, MLL and FOXP1. Rare studies about the role of expression of 4 oncogenes in the transformation and prognosis of MALT lymphoma were seen. Methods: We conducted this research to explore the expression of PIK3CA, BCL-6, MLL and FOXP1 in 40 gastrointestinal MALT lymphoma cases that were classified to large-cell (involving 5%-20% large cells in the specimen) or non- large cell (involving <5% large cells) pathologic subtype and 10 transformed gastrointestinal DLBCL specimens (involving >20% large cells with residual small-cell components) through immunohistochemistry staining. Prognostic significance of 4 indexes was also analyzed. Results: In 40 gastrointestinal MALT lymphoma cases, large-cell subtype were found in 7 (17.5%). The percentage of positive expression of PIK3CA, BCL-6, MLL and FOXP1 in non-large cell subtype was 42.4%, 15.2%, 66.7% and 12.0%, while in large-cell subtype the percentage was 42.9%, 28.6%, 100% and 28.0%, respectively. Among non-large cell subtype, large-cell subtype of MALT lymphoma and transformed DLBCL, only the rate of FOXP1 expression (>75% positive staining cells) was raised up in order (12.0%, 28.0% and 40%, P=0.046). PIK3CA expression (18/40) was an independent negative prognostic variable on the PFS (P=0.008) .The positive expression of BCL-6, MLL and FOXP1 did not show any significant prognostic value. Conclusions: Our data suggests that PIK3CA, a novel molecular index, can predict a worse prognosis in gastrointestinal MALT lymphoma. The study also provides some clues to further genetic research that will finally demonstrate the role of FOXP1 in the transformation from MALT lymphoma to DLBCL. No significant financial relationships to disclose.
Sequence-dependent cytoxicity of docetaxel and erlotinib in head and neck squamous cell carcinoma (HNSCC)
Authors: B. S. Glisson, B. Saigal, Y. Xu, F. M. Johnson
Journal: Journal of Clinical Oncology (2007)

6084 More effective systemic treatment is needed for HNSCC. The taxoids are the most efficacious single agents identified. Epidermal growth factor receptor (EGFR) is almost universally expressed by HNSCC tumors but inhibitors have only modest activity as single agents in clinical studies. However, the combination of the taxoids with EGFR inhibition has additive anti-tumor effects in HNSCC in vitro and in animals. Despite similar pre-clinical data in lung cancer, clinical trials showed no benefit when EGFR inhibitors were added to chemotherapy. In vitro studies in lung, breast and colon cancer cell lines demonstrate that the separation of EGFR TKI from chemotherapy and the order in which these agents are administered influences efficacy. We sought to determine if a similar sequence-dependent effect exists in HNSCC in order to help design future clinical trials with these agents. We chose three human HNSCC cell lines with diverse levels of basal EGFR expression and activation. None had EGFR mutations, which are very rare in HNSCC. Cells were treated with single agent docetaxel or erlotinib or combinations for 72 h and cytotoxicity was measured with an MTT assay. Concurrent treatment with docetaxel and erlotinib resulted in more cytotoxicity than single agents and calculated combination indices demonstrated additive effects. When erlotinib was added 4 to 24 h prior to docetaxel, the efficacy was similar to or less than that of concurrent therapy regardless of whether the erlotinib was washed off prior to the docetaxel or left in the cell medium. In contrast, when docetaxel was added ≥ 10 h prior to erlotinib, cytotoxicity was enhanced as compared to concurrent therapy. The most efficacious combination was docetaxel treatment for 24 h followed by erlotinib for 48 h. This combination was chosen for further analysis. Consistent with previously published studies in other cell types, erlotinib resulted in G1 cell cycle arrest and docetaxel in G2-M arrest. On-going studies to investigate the mechanism for the sequence-dependent cytotoxicity include examination of the effects of the sequence on cell cycle and apoptosis, tubulin expression, and cell signaling molecules that mediate pro-survival signals from EGFR. [Table: see text]
Comparative efficacy of adjuvant chemoradiation versus chemotherapy in surgically resected adenocarcinoma of stomach
Authors: S. A. Aziz, M. A. Banday, M. H. Mir
Journal: Journal of Clinical Oncology (2009)

e15639 Background: Outcome of carcinoma of stomach has not changed over the past decades and surgery remains the time tested primary modality of treatment. Attempts to improve survival have been strengthened by recent studies of adjuvant chemoradiation in these patients. The present study focuses to compare the efficacy of adjuvant chemoradiation Vs Chemotherapy alone in surgically resected adenocarcinoma of stomach. Methods: Over a two years period (Nov. 2006 to Oct 2008) 60 patients were enrolled and randomized to two arms with 30 patients in each arm. ArmA received adjuvant chemoradiation and arm B received chemotherapy only. Chemoradiation protocol included Inj. 5 - FU 425mg/m 2 and Inj. CLV 20mg/m 2 I/V d1 - d5 followed by EBRT (45 GY) over 20 #s starting on d29. During first 4 days and last 3 days of radiation patients also received inj. 5 - FU 400mg/m 2 I/V and CLV 20mg/m 2 I/V bolus. Arm B received chemotherapy alone with Inj Cisplatin 100mg/m 2 divided over 3 days, Inj 5- FU 500 mg/m 2 I/V bolus d1 - d3 and Inj. CLV 20 mg/m 2 /IV d1 - d3 q 21 days × 6 cycles. Results: All patients were followed post treatment for EFS and PFS for a maximum period of 24 months with a median followup of 19 months. EFS and PFS for two arms were; Arm A - 17.7 months and 19.0 months and Arm B - 16.0 months and 17.4 months respectively. Treatment related morbidity was significant in arm B. General well being and surrogate laboratory markers including hemogram were compared as well, favouring arm A. Conclusions: Although interim survival trends favour adjuvant chemoradiation, yet results are not statistically significant necessitating a longer followup of these patients to arrive at a definite conclusion as for as decision regarding efficacy of chemoradiation is established. Also these findings need to be reproduced by further studies. No significant financial relationships to disclose.