tbuckley/cabot-search huggingface dataset:
Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer.
Authors: M Lise, D Nitti, A Marchet, T Sahmoud, M Buyse, N Duez, M Fiorentino, J G Dos Santos, R Labianca, P Rougier
Journal: Journal of Clinical Oncology (1995)

PURPOSE In a randomized clinical trial (European Organization for the Research and Treatment of Cancer [EORTC] no. 40813) on adjuvant chemotherapy in gastric cancer, results obtained after administration of the FAM2 regimen (fluorouracil [5-FU], doxorubicin, and mitomycin) were compared with results obtained after surgery alone to assess the effect of this regimen on overall survival, time to progression, and disease-free interval. PATIENTS AND METHODS Three hundred fourteen patients who had undergone curative resection for stage II or stage III (International Union Against Cancer [UICC] 1978) gastric adenocarcinoma were randomized to receive chemotherapy (treatment arm) or no further treatment (control arm). The chemotherapy schedule was repeated every 43 days for seven cycles. The log-rank test and the Cox model were used for statistical analysis. RESULTS Of 314 patients, 159 comprised the control group and 155 the FAM2 group. Nineteen FAM2 patients never received chemotherapy. The median number of cycles was five. Of the patients started on adjuvant treatment, severe hematologic and nonhematologic toxicity (grades 3 or 4, World Health Organization [WHO] scale) occurred, respectively, in 6% to 9% and in 1% to 29% of cases. The overall 5-year survival rate was 70% for stage II and 32% for stage III patients. No statistically significant difference was found between overall survival of the two treatment arms (P = .295). However, time to progression was significantly delayed in the FAM2 arm (P = .020) and disease-free survival showed borderline significance (P = .068). CONCLUSION FAM2, in view of its high toxicity, cannot be advocated as standard adjuvant treatment for gastric cancer. Large-scale clinical trials using more active, less toxic regimens are required to demonstrate whether adjuvant chemotherapy provides any real benefit.
Abstract 1684: Invasive Assessment of the Coronary Microcirculation: Novel Thermodilution Based Measure of Absolute Microvascular Resistance
Authors: Yen-Dong Ho, Tom C Nguyen, Akinobu Itoh, Alan C Yeung, William F Fearon
Journal: Circulation (2007)

Background: Assessment of coronary microcirculatory function would aid in understanding the pathophysiology of various disease states. Recently Pijls and colleagues introduced a novel thermodilution based measure of absolute coronary flow. We hypothesize that this method will allow quantitation of absolute microvascular resistance during cardiac catheterization. Method: Using a coronary pressure/temperature wire and subselective coronary infusion catheter, volumetric coronary flow (Q) is derived by principle of thermodilution from saline infusion rate (Q k ), saline temperature (T k ) at infusion catheter tip relative to baseline blood temperature, and distal blood temperature (T) relative to baseline blood temperature, with Q = Q k · (T k /T) · 1.08. We hypothesize that distal coronary pressure divided by calculated flow provides a measure of microvascular resistance (MR) and will correlate with true microvascular resistance (TMR), defined as distal coronary pressure divided by hyperemic flow measured with external ultrasonic flow probe. A total of 111 measurements in the left anterior descending (LAD) distribution were made in 8 Yorkshire swine at baseline and after microcirculatory disruption with microsphere embolization, with and without epicardial LAD stenosis. Results: Thermodilution based LAD flow correlated well with ultrasound based flow ( r = 0.88, p &lt; 0.0001, mean absolute difference 20 ml/min), in both presence ( r = 0.88, p &lt; 0.0001) and absence ( r = 0.87, p &lt; 0.0001) of microcirculatory disruption. Correspondingly, there was significant agreement between MR and TMR ( r = 0.66, p &lt; 0.0001). Mean MR increased significantly after microsphere injection (0.54 ± 0.11 to 0.86 ± 0.18 mmHg · mL −1 · min −1 , p &lt; 0.0001), in both presence (0.56 ± 0.12 to 0.82 ± 0.11 mmHg · mL −1 · min −1 , p &lt; 0.0001) and absence (0.49 ± 0.06 to 0.91 ± 0.27 mmHg · mL −1 · min −1 , p &lt; 0.0001) of epicardial stenosis. After microcirculatory disruption, % change in MR (164 ± 30%) was similar to % change in TMR (161 ± 36%, p = NS vs. MR % change). Conclusion: This novel thermodilution based method provides quantitative and accurate assessment of microvascular resistance in selective coronary territories and can facilitate investigation of coronary physiology during cardiac catheterization.
Stable expression of constitutively-activated STAT3 in benign prostatic epithelial cells changes their phenotype to that resembling malignant cells.
Authors: Hosea F Huang, Thomas F Murphy, Ping Shu, Arnold B Barton, Beverly E Barton
Journal: Molecular Cancer (2005)

Signal transducers and activators of transcription (STATs) are involved in growth regulation of cells. They are usually activated by phosphorylation at specific tyrosine residues. In neoplastic cells, constitutive activation of STATs accompanies growth dysregulation and resistance to apoptosis through changes in gene expression, such as enhanced anti-apoptotic gene expression or reduced pro-apoptotic gene expression. Activated STAT3 is thought to play an important role in prostate cancer (PCA) progression. Because we are interested in how persistently-activated STAT3 changes the cellular phenotype to a malignant one in prostate cancer, we used expression vectors containing a gene for constitutively-activated STAT3, called S3c, into NRP-152 rat and BPH-1 human benign prostatic epithelial cells. We observed that prostatic cell lines stably expressing S3c required STAT3 expression for survival, because they became sensitive to antisense oligonucleotide for STAT3. However, S3c-transfected cells were not sensitive to the effects of JAK inhibitors, meaning that STAT3 was constitutively-activated in these transfected cell lines. NRP-152 prostatic epithelial cells lost the requirement for exogenous growth factors. Furthermore, we observed that NRP-152 expressing S3c had enhanced mRNA levels of retinoic acid receptor (RAR)-α, reduced mRNA levels of RAR-β and -γ, while BPH-1 cells transfected with S3c became insensitive to the effects of androgen, and also to the effects of a testosterone antagonist. Both S3c-transfected cell lines grew in soft agar after stable transfection with S3c, however neither S3c-transfected cell line was tumorigenic in severe-combined immunodeficient mice. We conclude, based on our findings, that persistently-activated STAT3 is an important molecular marker of prostate cancer, which develops in formerly benign prostate cells and changes their phenotype to one more closely resembling transformed prostate cells. That the S3c-transfected cell lines require the continued expression of S3c demonstrates that a significant phenotypic change occurred in the cells. These conclusions are based on our data with respect to loss of growth factor requirement, loss of androgen response, gain of growth in soft agar, and changes in RAR subunit expression, all of which are consistent with a malignant phenotype in prostate cancer. However, an additional genetic change may be required for S3c-transfected prostate cells to become tumorigenic.
<i>Mycobacterium chelonae</i>Eye Infections Associated with Humidifier Use in an Outpatient LASIK Clinic — Ohio, 2015
Authors: Chris Edens, Lauren Liebich, Alison Laufer Halpin, Heather Moulton-Meissner, Samantha Eitniear, Eric Zgodzinski, Larry Vasko, David Grossman, Joseph F. Perz, Marika C. Mohr
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Laser-assisted in situ keratomileusis (LASIK) eye surgery is increasingly common, with approximately 600,000 procedures performed each year in the United States. LASIK eye surgery is typically performed in an outpatient setting and involves the use of a machine-guided laser to reshape the lens of the eye to correct vision irregularities. Clinic A is an ambulatory surgery center that performs this procedure on 1 day each month. On February 5, 2015, the Toledo-Lucas County Health Department (TLCHD) in Ohio was notified of eye infections in two of the six patients who had undergone LASIK procedures at clinic A on January 9, 2015. The two patients experienced eye pain after the procedures and received diagnoses of infection with Mycobacterium chelonae, an environmental organism found in soil and water.
Effect of increased concentrations of atmospheric carbon dioxide on the global threat of zinc deficiency: a modelling study
Authors: Samuel S Myers, K Ryan Wessells, Itai Kloog, Antonella Zanobetti, Joel Schwartz
Journal: The Lancet Global Health (2015)

Increasing concentrations of atmospheric carbon dioxide (CO2) lower the content of zinc and other nutrients in important food crops. Zinc deficiency is currently responsible for large burdens of disease globally, and the populations who are at highest risk of zinc deficiency also receive most of their dietary zinc from crops. By modelling dietary intake of bioavailable zinc for the populations of 188 countries under both an ambient CO2 and elevated CO2 scenario, we sought to estimate the effect of anthropogenic CO2 emissions on the global risk of zinc deficiency.
Establishment and characterization of a primary effusion (body cavity- based) lymphoma cell line (BC-3) harboring kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus
Authors: L Arvanitakis, EA Mesri, RG Nador, JW Said, AS Asch, DM Knowles, E Cesarman
Journal: Blood (1996)
TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis
Authors: Adam M. Collison, Leon A. Sokulsky, Joseph D. Sherrill, Scott Nightingale, Luke Hatchwell, Nicholas J. Talley, Marjorie M. Walker, Marc E. Rothenberg, Joerg Mattes
Journal: Journal of Allergy and Clinical Immunology (2015)
Loss of Heterozygosity Analysis and DNA Copy Number Measurement on 8p in Bladder Cancer Reveals Two Mechanisms of Allelic Loss
Authors: Jacqui Adams, Sarah V. Williams, Joanne S. Aveyard, Margaret A. Knowles
Journal: Cancer Research (2005)

Abstract Many epithelial tumors show deletion of the short arm of chromosome 8 that is related to aggressive disease or adverse prognosis. In undissected samples of urothelial cell carcinoma of the bladder, at least two regions of loss of heterozygosity (LOH) were identified previously within a small region of 8p11-p12. LOH analysis on a panel of pure tumor DNA samples confirmed this and identified tumors with allelic imbalance, some with clear breakpoints in 8p12. This suggests either that these samples contained genetically distinct subclones or that breakpoints in 8p12 may confer a selective advantage without LOH. To assess the mechanism of LOH and to map breakpoints precisely, a panel of bladder cancer cell lines was examined. Microsatellite analysis of 8p markers identified regions of contiguous homozygosity that coincided with regions of LOH in tumors. Fluorescence in situ hybridization analysis was carried out on seven cell lines predicted to have 8p LOH using a chromosome 8 paint, a chromosome 8 centromeric probe, and a series of single-copy genomic probes. This revealed overall underrepresentation of 8p and overrepresentation of 8q. Several breakpoints and one interstitial deletion were identified in 8p12. Two cell lines with extensive interstitial regions of homozygosity showed no reduction in DNA copy number by fluorescence in situ hybridization analysis, indicating that, in addition to large deletions and rearrangements of 8p, small regions of interstitial LOH on 8p12 may be generated by mitotic recombination. This implicates both major DNA double-strand break repair mechanisms in the generation of 8p alterations.
Compliance with guidelines for elderly patients undergoing cancer therapy
Authors: M. J. Ribeiro, H. Patterson, M. Shumate, W. B. Harris, J. Jacobs, P. Nadella, T. W. Gillespie
Journal: Journal of Clinical Oncology (2004)

6148 Background: More than 50% of all cancers and deaths occur in individuals over age 65.Clinical decision-making for older patients may focus on patient chronological age rather than functional status, due to concerns about tolerance of more intensive and potentially curative regimens. However, published data demonstrate efficacy of standard therapy with similar outcomes in elderly patients. Practice guidelines could establish standards of care that, if followed, may prevent ageism in decision-making and improve clinical outcomes. Methods: This study (N=57) prospectively evaluated rate of compliance with practice guidelines, as well as toxicities and relative dose intensity (RDI) associated with therapy delivered. Published evidence, NCCN guidelines for the elderly, and consensus of heme-onc clinicians at the Atlanta Veterans Affairs Medical Center (VAMC) were used to develop treatment standards for all stages/cell types of non-small cell lung cancer (NSCLC) (N=39) or non-Hodgkin's lymphoma (NHL) (N=18). Consenting patients at point of clinical decision-making were enrolled into Cohort A (age ≥ 65; N=29) or Cohort B (age 50–64; N=28). All patients were screened for functionality and given an objective score based on the Screening Geriatric Assessment (SGA) tool at time of enrollment. Results: No difference in rates of compliance with practice guidelines were seen when comparing Cohort A (98%) and Cohort B (90%). NCCN guidelines for the elderly were followed less often (32%) than practice standards. Age, performance status and stage of disease did not affect compliance. For patients receiving chemotherapy, significantly more older patients (N=18; 75%) were able to finish their prescribed treatment compared to the younger cohort (N=10; 47%) (p=0.012). Compliance was a significant negative predictor for dose reduction (p=0.021). Conclusions: Adherence to evidence-and consensus-based guidelines can standardize clinical care and potentially improve outcomes in elderly cancer patients. Compliance with standards can promote optimal therapy and completion of treatment plan, avoiding dose reductions and decision-making based primarily on chronological age. No significant financial relationships to disclose.
Adjuvant breast cancer: FDA approval overview
Authors: P. Cortazar, J. Johnson, R. Justice, R. Pazdur
Journal: Journal of Clinical Oncology (2009)

e11529 Background: Improved disease-free survival (DFS) in randomized controlled trials (RCT) is the primary basis for approval of adjuvant breast cancer (ABC) treatments. Methods: Review of clinical trials leading to new drug approvals for ABC. Results: DFS is a composite endpoint defined as the time from randomization to the earliest occurrence of invasive loco-regional recurrence, invasive contralateral breast cancer, DCIS, distant metastases, second primary tumors or death from any cause. Trials supporting marketing approval have used inconsistent DFS definitions that included different components of this endpoint. Basis of paclitaxel approval following AC was superior DFS (HR= 0.78; 95% CI 0.67–0.91, p=0.002) and overall survival (HR=0.74; 95% CI 0.60–0.92, p=0.0065). Trastuzumab approval as part of a treatment regimen was based on 4 clinical trials that showed improved DFS. Docetaxel approval was based on improved DFS of the docetaxel-containing combination regimen TAC compared to FAC (HR: 0.74; 2- sided 95% CI=0.60–0.92, p=0.0047). Doxorubicin approval was based on a meta-analysis of six ABC trials comparing doxorubicin- containing regimens to CMF. Analyses demonstrated that doxorubicin-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS (HR: 0.91; 95% CI 0.82–1.01) and OS (HR: 0.91; 95% CI 0.81–1.03). Epirubicin approval was based on a longer relapse free survival (RFS) of the epirubicin-containing combination therapy (CEF-120) compared to CMF (HR=0.76; 95% CI 0.60–0.96, p=0.013). Tamoxifen approval was based on an overview of tamoxifen adjuvant therapy. Ten-year survival was 61.4% for tamoxifen vs. 50.5% for control (p &lt; 0.00001) and RFS was 59.7% for tamoxifen vs. 44.5% for control (p &lt; 0.00001). Anastrozole approval was based on a longer DFS (HR: 0.87; 95% CI=0.78–0.97, p=0.0127). Letrozole was based on a superior DFS (HR= 0.62; 95% CI 0.49–0.78, p=0.00003). Exemestane approval was based on improved DFS (HR: 0.65; 95% CI=0.53–0.79, p=0.00001). Conclusions: Although DFS was the basis for approval in most of the ABC clinical trials, the endpoint definition varies between trials. DFS definition should be standardized in ABC clinical trials to permit consistent interpretation and analysis and to facilitate cross-trial comparisons. No significant financial relationships to disclose.
Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial
Authors: G D Tollefson, C M Beasley, P V Tran, J S Street, J A Krueger, R N Tamura, K A Graffeo, M E Thieme
Journal: American Journal of Psychiatry (1997)

This international, multicenter double-blind trial was designed to compare the therapeutic profile of an atypical antipsychotic, olanzapine, with that of a conventional dopamine D2 antagonist, haloperidol.A total of 1,996 patients at 174 sites in Europe and North America were randomly assigned to treatment with olanzapine (N = 1,336) or haloperidol (N = 660) over 6 weeks. The primary efficacy analysis involved the mean change from baseline to endpoint in total scores on the Brief Psychiatric Rating Scale (BPRS). Secondary analyses included comparisons of the mean change in positive and negative symptoms, comorbid depression, extrapyramidal symptoms, and overall drug safety.Olanzapine demonstrated clinical results superior to those of haloperidol on overall improvement according to the BPRS and on every secondary measure, including depression. Olanzapine was also associated with significantly fewer discontinuations of treatment due to lack of drug efficacy or adverse events. Substantially more olanzapine-treated patients (66.5%) than haloperidol-treated patients (46.8%) completed 6 weeks of therapy. Statistically significant advantages of olanzapine treatment were related to 1) change in negative symptoms, 2) extrapyramidal symptom profile, 3) effect on prolactin levels, and 4) response rate.Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenic psychopathology, with a substantially more favorable safety profile, than haloperidol. It meets several of the criteria for a novel atypical antipsychotic agent.
Abstract 1525: Atrial Rhythm Acutely Modulates Connexin43 Expression and Phosphorylation State in Human Atrial Fibrillation
Authors: Rashmi Ram, Mary L Ruehr, Beth S Bunnell, A M Gillinov, David R Van Wagoner
Journal: Circulation (2008)

Background: Adjacent areas of heterogenous conduction in the atria form a substrate for atrial fibrillation (AF). Connexin proteins (Cx) underlie conduction between myocytes; conduction is modulated by connexin expression and phosphorylation. Here we tested the hypothesis that left atrial (LA) expression and/or phosphorylation of Cx43 is distinctly regulated by atrial rhythm. Methods: Cx43 expression and phosphorylation was evaluated in LA tissue homogenates from 3 groups: cardiac surgery patients with history of AF presenting for surgery in AF (AFAF, n=8); history of AF but in sinus rhythm (AFSR, n=8); patients with no history of AF (CTL, n=8). Groups were matched for age, LA size, EF (&gt;50%), CAD, valve disease, and hypertension. Results: Western blot analysis revealed increased total Cx43 expression (t-Cx43) in AFAF (2.03±0.38) compared to AFSR (0.85±0.15, p=0.01) and SR (0.98±0.16, p=0.02) groups. Blots re-probed with an antibody detecting non-phosphorylated Cx43 at S368 (Np-Cx43) revealed a significant decrease in the Np-Cx43/t-Cx43 ratio, indicating increased S368 phosphorylation in the AFAF group (by 23% in AFAF vs. AFSR, p=0.046; by 12% in AFAF vs. CTL, p=0.051). Subcellular compartmentation of t-Cx43 was assessed in 3 samples per group using tissue fractionation and immunoblotting. Cytoskeletal t-Cx43 levels were increased in AFAF vs. AFSR and vs. CTL, ANOVA, p=0.016); t-Cx43 expression was not different between groups in membrane, cytoplasmic or nuclear fractions. Confocal microscopy revealed greater Cx43 lateralization in both AF groups compared to CTL. Conclusion: Our results (increased Cx43 expression and phosphorylation) suggest that AF rhythm at the time of surgery , more than the history of AF, has a distinct impact on LA Cx43 remodeling. Further the dynamic increase restricted to the cytoskeletal compartment suggests that cytoskeletal changes in AF may modulate connexin trafficking to the cell surface. This may affect the anisotropic properties of atrial conduction. Additional electrophysiological studies are needed to determine the functional contribution of lateralized Cx. Our study provides the first evidence linking acute rhythm status with regulation of Cx43 expression and phosphorylation in human atria.
Trade-offs associated with axillary lymph node dissection: Implications of the eligibility versus enrollment in ACOSOG Z0011.
Authors: Monica Shalini Krishnan, Abram Recht, Jennifer Ruth Bellon, Rinaa S. Punglia
Journal: Journal of Clinical Oncology (2012)

6022 Background: Results from ACOSOG Z0011 suggest axillary lymph node dissection (ALND) may not be necessary for patients following positive sentinel lymph node biopsy (SLNB). Concerns have been raised regarding generalizability of this trial, given the low-risk patient population. It is uncertain whether a subgroup who would have been eligible for ACOSOG Z0011 but were not adequately represented in the study may still benefit from ALND. Methods: We constructed a decision analysis using a Monte Carlo model to simulate axillary recurrence risk, lymphedema, and quality of life of women aged 45, 55 and 75 y/o with Stage II cancers following breast conserving surgery (BCS) with positive SLNB who were then treated with ALND and whole-breast radiation (BRT) or BRT alone. Women were divided into two risk groups based on the Memorial Sloan-Kettering Cancer Center non-sentinel lymph node (NSLN) nomogram: those with risk of residual nodal involvement of 30-60% (high risk); and those with risk less than 30% (low risk, similar to the Z0011 patients). Probabilities and utilities for health states were derived from prior studies. Results: BRT alone resulted in improved quality-adjusted life expectancy (QALE) in the low-risk group, while ALND with BRT resulted in improved QALE in the high-risk group. Overall survival (OS) was similar at 5 years with both treatment strategies in both groups but was superior with ALND at 20 years in the high risk group (Table). Differences in outcomes decreased with increasing age. In the low-risk group, sensitivity analysis showed BRT alone is preferred unless the axillary recurrence risk with BRT is greater than 1.6% or the lymphedema risk with ALND is less than 10%. In the high-risk group, ALND with BRT is the preferred strategy unless the axillary recurrence risk with BRT is less than 2.3%. Conclusions: Patients who would have been eligible for ACOSOG Z0011 but are at higher risk of having residual nodal disease following BCS and positive SLNB may benefit from ALND plus BRT rather than BRT alone. [Table: see text]