tbuckley/cabot-search huggingface dataset:
Association Between US Norepinephrine Shortage and Mortality Among Patients With Septic Shock
Authors: Emily Vail, Hayley B. Gershengorn, May Hua, Allan J. Walkey, Gordon Rubenfeld, Hannah Wunsch
Journal: JAMA (2017)

<h3>Importance</h3> Drug shortages in the United States are common, but their effect on patient care and outcomes has rarely been reported. <h3>Objective</h3> To assess changes to patient care and outcomes associated with a 2011 national shortage of norepinephrine, the first-line vasopressor for septic shock. <h3>Design, Setting, and Participants</h3> Retrospective cohort study of 26 US hospitals in the Premier Healthcare Database with a baseline rate of norepinephrine use of at least 60% for patients with septic shock. The cohort included adults with septic shock admitted to study hospitals between July 1, 2008, and June 30, 2013 (n = 27 835). <h3>Exposures</h3> Hospital-level norepinephrine shortage was defined as any quarterly (3-month) interval in 2011 during which the hospital rate of norepinephrine use decreased by more than 20% from baseline. <h3>Main Outcomes and Measures</h3> Use of alternative vasopressors was assessed and a multilevel mixed-effects logistic regression model was used to evaluate the association between admission to a hospital during a norepinephrine shortage quarter and in-hospital mortality. <h3>Results</h3> Among 27 835 patients (median age, 69 years [interquartile range, 57-79 years]; 47.0% women) with septic shock in 26 hospitals that demonstrated at least 1 quarter of norepinephrine shortage in 2011, norepinephrine use among cohort patients declined from 77.0% (95% CI, 76.2%-77.8%) of patients before the shortage to a low of 55.7% (95% CI, 52.0%-58.4%) in the second quarter of 2011; phenylephrine was the most frequently used alternative vasopressor during this time (baseline, 36.2% [95% CI, 35.3%-37.1%]; maximum, 54.4% [95% CI, 51.8%-57.2%]). Compared with hospital admission with septic shock during quarters of normal use, hospital admission during quarters of shortage was associated with an increased rate of in-hospital mortality (9283 of 25 874 patients [35.9%] vs 777 of 1961 patients [39.6%], respectively; absolute risk increase = 3.7% [95% CI, 1.5%-6.0%]; adjusted odds ratio = 1.15 [95% CI, 1.01-1.30];<i>P</i> = .03). <h3>Conclusions and Relevance</h3> Among patients with septic shock in US hospitals affected by the 2011 norepinephrine shortage, the most commonly administered alternative vasopressor was phenylephrine. Patients admitted to these hospitals during times of shortage had higher in-hospital mortality.
Correlation of the maximum standardized uptake value for f-18 fluorodeoxyglucose with molecular subtype and survival in advanced breast cancer.
Authors: Zhen Jia, Xi-Chun Hu, Yingjian Zhang, Min Zhou, Biyun Wang, Zhong Hua Wang, Yongping Zhang
Journal: Journal of Clinical Oncology (2012)

10567 Background: Tumor glucose metabolism correlates with tumor biology and clinical outcome of breast cancer patients. This prospective cohort study was to explore correlations of 18 F-FDG uptake, a surrogate for glucose metabolism, with molecular subtypes in women with advanced breast cancer. Methods: Patients diagnosed as advanced breast cancer were enrolled in the study. PET/CT was performed and the Maximum Standardized Uptake Value (SUVmax) of each lesion was documented as baseline, so was clinical and treatment information. Diagnosis of malignant nature of a lesion was confirmed by pathology or further follow-up. Patients who had got a progressive disease in the efficacy assessment were assigned new treatments as per-institutional guidelines. Results: 244 patients met the criteria and were all put into this analysis. Independent factors for influencing SUVmax value included luminal subtype (p= 0.002), triple-negative subtype (p&lt;0.001), ER status (p= 0.028), Her-2 status (p&lt;0.001), and CEA level (p&lt;0.001). A higher SUVmax was significantly associated with poorer median PFS (6.9 vs. 8.1 months, p=0.040) and OS (13.8 vs. 16.9 months, p=0.003). Cox Regression analysis showed that SUVmax value, previous treatments, subsequent treatments and treatment efficacy were four independent prognostic factors for PFS, while age, menopausal status, disease free interval, 4 subtypes, previous treatments, number of metastatic sites, SUVmax value and subsequent treatment efficacy were independent prognostic factors for OS. Conclusions: 18 F-FDG uptake correlates with molecular subtypes in women with advanced breast cancer. Baseline SUVmax is an independent prognostic factor for survival of patients with advanced breast cancer, especially those with luminal subtypes.
Untapped Potential of Observational Research to Inform Clinical Decision Making: American Society of Clinical Oncology Research Statement
Authors: Kala Visvanathan, Laura A. Levit, Derek Raghavan, Clifford A. Hudis, Sandra Wong, Amylou Dueck, Gary H. Lyman
Journal: Journal of Clinical Oncology (2017)

ASCO believes that high-quality observational studies can advance evidence-based practice for cancer care and are complementary to randomized controlled trials (RCTs). Observational studies can generate hypotheses by evaluating novel exposures or biomarkers and by revealing patterns of care and relationships that might not otherwise be discovered. Researchers can then test these hypotheses in RCTs. Observational studies can also answer or inform questions that either have not been or cannot be answered by RCTs. In addition, observational studies can be used for postmarketing surveillance of new cancer treatments, particularly in vulnerable populations. The incorporation of observational research as part of clinical decision making is consistent with the position of many leading institutions. ASCO identified five overarching recommendations to enhance the role of observational research in clinical decision making: (1) improve the quality of electronic health data available for research, (2) improve interoperability and the exchange of electronic health information, (3) ensure the use of rigorous observational research methodologies, (4) promote transparent reporting of observational research studies, and (5) protect patient privacy.
Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with pazopanib after progression on other targeted therapies (TT): A single-institution experience.
Authors: Marc Ryan Matrana, Aditya V. Shetty, Bradley J. Atkinson, Lianchun Xiao, Paul G. Corn, Randall E. Millikan, Eric Jonasch, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2012)

4615 Background: Pazopanib is an approved multi-tyrosine kinase inhibitor that prolongs progression-free survival (PFS) compared to placebo in treatment-naive and cytokine-refractory mRCC. Outcomes and safety data on its use after TT are limited. Methods: We retrospectively reviewed pts with mRCC who received salvage pazopanib between 11/09-11/11. Kaplan-Meier method was used to estimate survival outcomes. PFS was calculated from start of pazopanib until progressive disease (PD) or death. Univariable and multivariable Cox proportional hazards models were fitted to evaluate associations of PFS with covariables. Results: 114 consecutive pts met inclusion criteria (median age 62.6 years, 66% males, 83% clear cell). All pts had PD after other TT (median # of prior TT 2, range 1-5; median time on prior TT 23.3 mos). 79% of pts had PD on sunitinib, 39% on sorafenib, 19% on temsirolimus, 59% on everolimus, and 23% on bevacizumab. 25% received prior chemotherapy and 16% received prior cytokines in addition to TT. 87% had prior nephrectomy. 11% had favorable-risk, 68% intermediate-risk, and 21% poor-risk per MSKCC criteria. 85 events (PD or death) occurred. Median OS was 17 mos (95% CI: 10.3-NA). Median PFS was 6.4 mos (95% CI: 4.5-9.5). By multivariable analysis, PFS was associated with male gender (HR=0.433, 95%CI: 0.269-0.696; p=0.0006), # of metastatic sites (HR=1.252; 95%CI: 1.04-1.503; p=0.016), hypertension exacerbation (HR=0.378; CI: 0.175-0.813; p=0.0128) and PS 2+ vs.0-1 (HR=2.067; CI: 1.243-3.437; p=0.0052). 58% discontinued pazopanib due to PD, 12% died of PD on treatment, and 11% discontinued pazopanib due to adverse events (AEs), mostly GI complaints or fatigue. There were no treatment related deaths. Common AEs included: fatigue (44%), diarrhea (29%), nausea/vomiting (15%), anorexia (14%), hypertension exacerbation (11%), hypothyroidism (11%), hand-foot skin reaction (9%), and increase LFTs (4%). 86% of AEs were grade 1/2. Conclusions: In this retrospective study, pazopanib demonstrated efficacy in mRCC following PD with other TT. AEs were mild/moderate and manageable.
Use of the National Heart, Lung, and Blood Institute Data Repository
Authors: Sean A. Coady, George A. Mensah, Elizabeth L. Wagner, Miriam E. Goldfarb, Denise M. Hitchcock, Carol A. Giffen
Journal: New England Journal of Medicine (2017)

Research on data sharing from clinical trials has focused on elucidating perceptions, barriers, and attitudes among trialists and study participants with respect to sharing data. However, little information exists regarding utilization or associated publication of articles once clinical trial data have been widely shared.We analyzed administrative records of investigator requests for data access, linked publications, and bibliometrics to describe the use of the National Heart, Lung, and Blood Institute data repository.From January 2000 through May 2016, a total of 370 investigators requested data from 1 or more clinical trials. Requests for trial data have been increasing, with 195 investigators (53%) initiating requests during the last 4.4 years of the study period. The predominant reason for requesting data was post hoc secondary analysis of new questions (72%), followed by analytic or statistical approaches to clinical trials (9%) and meta-analyses or pooled study research (7%). Of 172 requests with online project descriptions, only 2 requests were initiated for reanalysis of primary-outcome findings. Data from 88 of 100 available clinical trials were requested at least once, and the median time from repository availability to first request was 235 days. A total of 277 articles were published on the basis of data from 47 trials. Citation metrics from 224 articles indicated that half of the publications have cumulative citations that rank in the top 34% normalized for subject category and year of publication.Demand for trial data for secondary analysis has been increasing. Requesting data for the a priori purpose of reanalysis or verification of original findings was rare.
APACT: A phase 3 randomized, open-label, multicenter trial evaluating the use of adjuvant <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (G) versus G alone in patients (pts) with surgically resected ductal pancreatic adenocarcinoma (PDA).
Authors: Margaret A. Tempero, Dana Backlund Cardin, Andrew Biankin, David Goldstein, Malcolm Moore, Eileen Mary O'Reilly, Philip Agop Philip, Hanno Riess, Teresa Macarulla, Lotus Yung, Xinyu Wei, Brian Lu
Journal: Journal of Clinical Oncology (2014)

TPS4162^ Background: Resection is the only curative treatment for PDA. Adjuvant chemotherapy following resection is associated with improved disease-free survival (DFS), median overall survival (OS), and 5-year survival for pts with resectable PDA. Despite these improvements, recurrence rates are still high, and survival rates remain poor, requiring more effective adjuvant therapies. In the phase 3 MPACT trial, nab-P plus G was manageable and demonstrated superiority to G alone for OS (median 8.5 vs 6.7 months; HR 0.72; 95% CI, 0.617 - 0.835; P < 0.001) and all secondary efficacy endpoints in pts with metastatic PDA [Von Hoff et al. N Engl J Med. 2013]. The current phase 3 trial (APACT) will evaluate the efficacy and safety of nab-P plus G vs G alone as adjuvant chemotherapy in pts with surgically resected PDA. Methods: Approximately 800 eligible pts will be randomized 1:1 (stratified by resection status [R0 vs R1], lymph node status [positive vs negative], and region) to receive nab-P 125 mg/m2 plus G 1000 mg/m2 or G 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle for 6 cycles. Eligibility criteria include histologically confirmed resected PDA with macroscopic complete resection (R0 and R1); surgical staging T 1-3, N0-1, M0; ECOG PS 0 or 1; acceptable hematologic function; and no prior neoadjuvant therapy or radiation for PDA. Pts will be assessed by CT scan every 8 weeks for the first 24 weeks, every 12 weeks for the first 3 years, and every 24 weeks thereafter until disease recurrence for up to 5 years. The primary endpoint is DFS by independent review. Secondary endpoints include: OS and safety. Exploratory endpoints include tumor markers and quality of life by EORTC QLQ-C30 and QLQ-PAN26. One interim analysis for safety and 2 interim analyses for efficacy are planned. This design provides 90% power to detect a hazard ratio of 0.74 for DFS, with a 2-sided 5% significance level, which represents a 36% improvement in median DFS with nab-P plus G vs G alone. Biospecimen collection will be integrated with the trial process to ensure a high yield of material for biomarker discovery. Clinical trial information: NCT01964430.
Analysis of survival in patients with chronic myelogenous leukemia in pre- and post-imatinib era involving comparison of large academic medical center versus national data: The Beaumont experience.
Authors: Cynthia Barbara Aller, Paul Rigo, Ishmael A. Jaiyesimi
Journal: Journal of Clinical Oncology (2013)

e18007 Background: Imatinib mesylate is first-line therapy for chronic myeloid leukemia (CML) since its introduction in May, 2001. Once deadly, CML is now a chronic disorder due to this medication.We sought to analyze the impact on survival in our patient population at Beaumont Health System, a tertiary care facility, versus all hospitals in the United States. Methods: Patients with CML were identified and categorized as pre- or post-2001 when first seen. Analysis of survival in intervals of 12 months in the two groups was done with the Elekta’s National Oncology Data Alliance Database (NODA): 1990-2000 and 2001-2010. Overall 5-year survival results are reported. Results: Analysis of survival was performed on pre- and post-2001 populations in Beaumont patients versus their national counterparts. In the pre-2001 population, 580 patients nationwide and 34 patients from Beaumont were analyzed for a total of 614 patients. In the post-2001 population 1,602 patients nationwide and 122 patients from the Beaumont were analyzed for a total of 1,724 patients. The pre-2001 group nationally showed a survival probability of 28% ± 1.8%, patients in the Beaumont group showed a survival probability of 26% ± 8%. Patients in the post-2001 nationwide group showed a survival probability of 56% ±1.4%, the Beaumont group showed a survival probability of 48% ±5.0%. Both groups showed a significant survival advantage after 2001 in the era of imatinib as first-line therapy for CML. Patients in the national analysis showed a survival advantage of 28% and patients in the Beaumont analysis showed a survival advantage of 22%. Conclusions: This analysis provides evidence for a survival advantage in the post-2001 era of imatinib mesylate therapy a first-line therapy for CML on both a national and our institution level. Differences in numbers of patients analyzed, drug availability, and implementation of molecular monitoring could account for variability of the results. This data supports the revolutionary nature of this medication in the treatment of CML in the United States since 2001.
Phase I and II studies of the decitabine–genistein drug combination in advanced solid tumors.
Authors: Elie Kassouf, Mustapha Ali Tehfe, Marie Florescu, Denis Soulieres, Bernard Lemieux, Jean-Pierre M. Ayoub, Danielle Charpentier, Louise Yelle, Luc Daigneault, Patrick Colin, Richard L. Momparler, Isabelle Plante, Guylaine Lassonde, Michel R Charbonneau, Noel J-M Raynal, Normand Blais
Journal: Journal of Clinical Oncology (2015)

e13556 Background: The combination of epigenetic drug decitabine with genistein, a natural isoflavone, produces synergistic responses in preclinical studies with particular activity shown in lung cancer cell lines. Our phase I dose-escalation study of decitabine with a fixed dose of genistein to treat advanced solid tumor was followed by a phase II study in advanced lung cancer patients. Methods: In phase I, decitabine was administered over 10-hours at increasing doses (60, 120, 240 mg/m2) with continuous administration of genistein 300 mg/day orally. Treatment cycles were repeated every 4 to 6 weeks. The MTD was 120 mg/m2 with neutropenia as DLT. Decitabine at 120 mg/m2 and genistein produced plasma levels of 0.62±0.06 µM and 8.5±5.6 µM, respectively. Results: The drug combination was well tolerated and produced stable disease for more than 6 months (7-14 months) in 5/10 patients. One gastric cancer patient had a 50% reduction in tumor burden after 6 months of therapy. Stable disease was also achieved in patients with desmoplastic small round cell tumor, oncocytic carcinoma, thyroid carcinoma and bladder cancer. The phase II study was focused on nine patients with NSCLC refractory to 3-4 lines of therapy. Eight patients progressed within the first radiologic evaluation at week 6 whereas one patient remains on therapy after 4 cycles of treatment. Grade 3 & 4 treatment-related toxicities were as follows: neutropenia, anemia, febrile neutropenia, and hypertension. Conclusions: Activity of the combination was observed in some patients with tumors of more indolent biology but was modest in the phase II cohort of heavily pretreated NSCLC patients. The efficacy profile observed in this trial suggests that tumors with slower tumor kinetics might benefit more from this type of epigenetic therapy. Clinical trial information: NCT01628471.
Oral low-dose cyclophosphamide, as a second-line agent, in patients with primary docetaxel refractory metastatic castration-resistant prostate cancer (mCRPC).
Authors: Daniela Shapiro, James Thomas Symanowski, Nicholas J. Vogelzang, Oscar B. Goodman
Journal: Journal of Clinical Oncology (2012)

e15210 Background: Docetaxel is the standard of care for treatment in mCRPC, yet docetaxel resistance is universal, presenting as primary refractoriness or developing after an initial response. While abiraterone and cabazitaxel are FDA approved after docetaxel failure, multiple other agents, including oral low dose cyclophosphamide (OLDC), have also been utilized with some clinical success. We have witnessed several remarkable responses to OLDC and sought to define clinical predictors of such responses. Methods: Twenty-one patients progressing on docetaxel were classified according to initial docetaxel response as either docetaxel non-responsive (DNR) or docetaxel responsive (DR). Patients were classified as DNR if an initial response to docetaxel by prostate specific antigen (PSA) working group-2 and RECIST criteria was absent, or if circulating tumor cells (CTC) numbers remained &gt;5 at all assessed time points. Otherwise patients were classified as DR. All patients initiated OLDC (50-150 mg/day), and subsequent response to OLDC was determined by decrease in CTC, PSA and/or radiologically. Results: Of the DR patients 1/10(10%) responded, while for DNR patients the response rate was 7/11 (63.4%), p= 0.024 between the two groups. The median survival from the date of initial treatment with docetaxel was 84 weeks in initial responders, and 115 weeks in refractory patients (p=0.495). Conclusions: The data suggest that patients who are DNR have higher rates of response to OLDC compared DR patients and may benefit from second line OLDC. A study prospectively evaluating the role of initial response to docetaxel in predicting response to OLDC is warranted, as are additional molecular analyses of DNR patients.
Effect of downregulation of miR-432 on Wnt/β-catenin signaling and human hepatocellular carcinoma proliferation.
Authors: Nan Jiang, Yang Li, Dan-yun Ruan
Journal: Journal of Clinical Oncology (2015)

e15168 Background: Aberrant activation of the Wnt/β-catenin signaling pathway leads to cell proliferation, growth and survival, and promotes the development of various human tumors. This study was undertaken to validate whether the anti-cancer effect of microRNA-432 (miR-432) on hepatocellular carcinoma (HCC) is mediated through regulating Wnt/β-catenin signalling pathways. Methods: The expression levels of miR-432 in HCC tissues and eight HCC cell lines (QGY-7703, Huh7, MHCC97L, Hep3B,HepG2, BEL-7402, MHCC97H, HCCC-9810) were quantified by RT- PCR, QGY-7703 and HepG2 cells were selected for further study. The effect of over-expression and inhibition miR-432 on proliferation of QGY-7703 and HepG2 cells were evaluated using MTT, colony formation assays and FACS respectively. Xenografted tumor model to examine the biological effect of miR-432.The 3'-UTR segments of Wnt/β-catenin pathway (LRP6, TRIM29, and Pygo2 )containing the miR-432 binding sites were amplified by PCR and the luciferase activity in the transfected cells were assayed. Wnt/β-catenin pathway(β-catenin, LRP6,TRIM29 ,Pygo2 ) mRNA and protein level were detected using RT-PCR and Western blotting. Results: The expression of miR-432 was markedly downregulated in HCC cell lines and tissues(P < 0.05), whereas downregulation of miR-432 enhanced the proliferation and tumorigenicity of HCC cells both in vitro and in vivo(P < 0.05). Furthermore, miR-432 directly targeted and suppressed multiple regulators of the Wnt/β-catenin signaling cascade, including LRP6, TRIM29 and Pygo2, which subsequently deactivated Wnt/β-catenin signaling pathway. Finally, miR-432 expression was inversely correlated with the expression of β-catenin(r = -0.688, P = 0.002), LRP6 (r = -0.872, P = 0.007),TRIM29 (r = -0.775, P = 0.004), Pygo2 (r = -0.663, P = 0.014) in clinical HCC samples. Conclusions: These results demonstrated that miR-432 functions as a tumor-suppressive miRNAby suppressing Wnt/β-catenin signaling activation and may represent a therapeutic target for HCC.