tbuckley/cabot-search huggingface dataset:
Statistical issues and recommendations for noninferiority trials in oncology: A systematic review.
Authors: S. Tanaka, Y. Kinjo, Y. Kataoka, S. Matsumoto, K. Yoshimura, S. Teramukai
Journal: Journal of Clinical Oncology (2011)

e13073 Background: This systematic review aims to provide an overview of previously published noninferiority (NI) trials in cancer with a special emphasis on methodological issues. Methods: We identified citations of randomized trials assessing NI of antineoplastic treatments by a computerized and manual search in October 2010 and reviewed for inclusion criteria. Data were extracted independently by 2 of 3 authors. Results: We identified 72 articles. An increasing trend was observed (4.9 articles per year between 2001 and 2007, 12.7 articles per year between 2008 and 2010). Quality of reporting in recent published articles was moderately improved after 2008 when the CONSORT was extended to NI trials (p<0.01). NI margins were used in 68 trials (94%, 17 trials used the fixed margin method, 5 trials used the effect retention method, 1 trial used both, 45 trials did not specify the method). Overall, variability in the resulting sizes of margins was small and margins were set to be no larger than the assured effect of active control. There was no trial that took uncertainty in historical data into consideration of the NI margin explicitly. Four trials had a plan of switching from superiority to NI. Five trials conducted a post hoc NI analysis. Conclusions: Statistical considerations in NI trials are less well established than in superiority trials and future methodological researches are needed. Practical recommendations were presented in the table. Design An NI margin should be specified prior to sample size calculation. Design The fixed margin and effect retention methods can be chosen according to objective of the trial. The objective would be to prove absence of a clinically relevant difference or that the experimental treatment has an effect greater than zero. Design A best estimate of the effect of active control, ideally from a meta-analysis, is necessary. It is not recommended to conduct an NI trial in cancers with limited evidence. Potential uncertainty in historical evidence should be examined carefully. Reporting Justification for an NI margin should be reported with reference to historical data in addition to the items in the CONSORT checklist. General It is advisable to follow guidelines from regulatory authorities.
The Opioid Rotation Ratio (ORR) from transdermal fentanyl (TDF) to strong opioids in cancer patients.
Authors: Akhila Sunkepally Reddy, Sriram Yennu, Suresh K. Reddy, Jimin Wu, Diane D Liu, Eduardo Bruera
Journal: Journal of Clinical Oncology (2015)

182 Background: Despite being the most frequently prescribed strong opioid by oncologists, there is a lack of knowledge of the accurate the opioid rotation ratio (ORR) from transdermal fentanyl (TDF) to other strong opioids in cancer patients. Opioid rotation (OR) from TDF to other strong opioids is performed very frequently in cancer patients for uncontrolled pain or opioid induced neurotoxicity (OIN). The aim of our study was to determine the ORR of TDF to other strong opioids, as measured by morphine equivalent daily dose (MEDD). Methods: In this ad hoc analysis, we reviewed 2471 consecutive patient visits to the supportive care center of a tertiary cancer center in 2008 for an OR from TDF to other strong opioids by a palliative medicine specialist. Information regarding demographics, Edmonton Symptom Assessment Scale (ESAS), and MEDD were collected in patients who followed-up within 6 weeks. Linear regression analysis was used to estimate the ORR between TDF dose and net MEDD (MEDD after OR minus MEDD of breakthrough opioid used along with TDF before OR). Successful OR was defined as 2-point or 30% reduction in pain score and continuation of the new opioid at follow up. Results: 47/2471 patients underwent OR from TDF to other opioids and followed-up within 6 weeks. The median age was 54 years, 53% were male, and 77% had advanced cancer. The median time between OR and follow up was 14 days. Uncontrolled pain (83%) followed by OIN (15%) were the most frequent reasons for OR and 77% had a successful OR with significant improvement in ESAS pain and symptom distress scores. In patients with OR and no worsening of pain at follow-up (n = 41), the median ORR (range) from TDF mg/day to net MEDD was 100 (12.5-217), TDF mcg/hour to net MEDD was 2.4 (0.3-5.2), and correlation of TDF dose to net MEDD was .60 (P &lt; 0.0001). Conclusions: The median ORR from TDF mg/day to MEDD is 100 and from TDF mcg/hour to MEDD is 2.4. Further validation studies are needed.
Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes
Authors: Bart L. Scott, Marcelo C. Pasquini, Brent R. Logan, Juan Wu, Steven M. Devine, David L. Porter, Richard T. Maziarz, Erica D. Warlick, Hugo F. Fernandez, Edwin P. Alyea, Mehdi Hamadani, Asad Bashey, Sergio Giralt, Nancy L. Geller, Eric Leifer, Jennifer Le-Rademacher, Adam M. Mendizabal, Mary M. Horowitz, H. Joachim Deeg, Mitchell E. Horwitz
Journal: Journal of Clinical Oncology (2017)

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.
The genomic heritage of metastatic axillary lymph node tumors in breast cancer
Authors: T. E. Becker, R. E. Ellsworth, D. L. Ellsworth, B. Deyarmin, J. A. Hooke, C. D. Shriver
Journal: Journal of Clinical Oncology (2005)

9515 Background It remains unknown whether the primary mode of lymph node metastasis in breast cancer is sequential through the lymphatic chain, or if each node is individually seeded by the primary tumor (i.e. the Halsteadian versus Fisher hypothesis of tumor metastasis). Current theories vary and are based on a limited amount of clinical evidence without supportive molecular data. In this novel analysis, primary breast and metastatic axillary lymph node carcinomas were examined for global patterns of allelic imbalance (AI) to determine the timing and pattern of nodal metastatic tumor dispersion. Methods Patients enrolled in the Clinical Breast Care Project with node-positive breast cancer (n=25) involving multiple axillary lymph nodes (mean=4; range 2–7) were selected. DNA was extracted from pure populations of tumor cells obtained by laser capture microdissection. Referent DNA was obtained from blood or disease-free skin samples. A panel of 52 microsatellite markers from 26 commonly deleted regions in breast cancer was used to assess AI, which was determined by the peak height ratio (≤0.35) between alleles from tumor and referent samples. Student’s t-tests were performed to compare data sets, and global patterns of AI were investigated. Results A significantly higher level of AI was detected in the primary breast (36%) than the lymph node (26%) tumors (p<0.05). Across all chromosomal regions examined, AI was significantly more frequent in the breast primary, compared to metastatic lymph node tumors, at 3p14.1, 7q31.1-q31.31, 11p15, and 11q23.3 (p<0.05), with no regions showing significantly more AI in the lymph node metastases than in the breast primary tumors. Global clustering analysis investigating for similarities among the lymph nodes revealed a high variability in their patterns of AI, suggesting independent origins. Conclusion Multiple metastatic lymph node tumors from the same patient exhibit highly divergent patterns of AI. Primary breast carcinomas may acquire metastatic potential early in development and individual metastatic tumor cells that successfully metastasize to the axillary lymph nodes appear to originate primarily independent of each other from different cell lineages within the primary tumor. No significant financial relationships to disclose.
Real-world treatment patterns, health care resource utilization (HRU), and costs among patients with Waldenstrom macroglobulinemia (WM) initiating therapy.
Authors: Brad Schenkel, Lorie Ellis, Stephanie Korrer, Stacey DaCosta Byfield
Journal: Journal of Clinical Oncology (2016)

17 Background: WM is a rare, indolent B-cell lymphoma with 1000 to 1500 new cases diagnosed annually in the US. The disease is incurable with current therapy. Prior to January 2015 when ibrutinib was approved by the US FDA for WM, there were no therapies approved in this indication. This study describes initial systemic anti-cancer therapy (SACT) and HRU among WM patients (pts). Methods: A retrospective study using a large, national US claims database from 1/2007-10/2013 was conducted. Adult WM pts ( ≥ 2 claims for WM) with ≥ 1 claim for SACT were identified; the first SACT claim date was the index date. Pts were required to have a WM diagnosis within 3 months (m) prior to the index date and be continuously enrolled (CE) in the health plan for 12m pre- and ≥ 6m post-index date. Pregnant pts and those with SACT in the pre-index period were excluded. The first line of therapy (LOT1) period was examined; the LOT started at index date and the regimen included all drugs received within 60 days. The LOT ended at the earliest of, start of a new drug, ≥ 60-day gap in receipt of initial drug regimen, death or CE end. All-cause HRU and costs during LOT1 were examined. Results: There were 161 WM pts identified. 66% of pts were ≥ 65 yrs (mean age 69), 55% were male, and by insurance type, 49% were Medicare Advantage pts vs. 51% commercially insured. Mean total follow-up time was 23m, and mean duration of LOT1 was 4.7m. The top 4 most common LOT1 regimens accounted for 71% of patients: Rituximab (R) only (39%); bortezomib+ R (14%); bendamustine+ R (9%) and cyclophosphamide+ R (9%). No other regimens identified accounted for more than 4% of pts. Overall, 96% and 81% of pts had ≥ 1 office or hospital outpatient visit with mean per patient per month (PPPM) visits of 3.55 (standard deviation, SD = 2.41) and 2.60 (SD = 3.06), respectively. Approximately 25% and 21% had ≥ 1 ER visit or inpatient stay with mean PPPM visits of 0.11 (SD = 0.24) and 0.06 (SD = 0.16), respectively. Total mean PPPM healthcare costs during LOT1 was $13,589 (SD = $13,404). Conclusions: HRU and costs were high among WM pts initiating SACT. Future studies should examine whether differences in LOT1 regimen choice are associated with differences in cost and outcomes.
Optimizing the CD34+ Cell Dose for Allogeneic Transplantation.
Authors: J. Mehta, Andrew M Evens, J. Altman, O. Frankfurt, Martin Tallman, L. Gordon, S. Williams, J. Winter, J. Krishnamurthy, S. Duffey, V. Singh, R. Meagher, S. Singhal
Journal: Blood (2008)
Effect of metformin on survival in pancreatic ductal adenocarcinoma.
Authors: Sunil Amin, Grace Mhango, Jenny J Lin, Anne Aronson, Paolo Boffetta, Juan P. Wisnivesky, Aimee Lucas
Journal: Journal of Clinical Oncology (2016)

383 Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal. Diabetes mellitus (DM) is both a risk factor for and a sequela of PDAC. Metformin, a commonly prescribed biguanide oral hypoglycemic used for the treatment of type II DM, has been found to have a chemo-protective role in PDAC in some in-vitro and human-based studies; conflicting literature exists regarding its potential role as a therapeutic agent. We investigated whether metformin use prior to PDAC diagnosis is associated with improved survival of patients with DM. Methods: We used the Surveillance, Epidemiology, and End-Results (SEER) linked Medicare database to identify diabetic patients with PDAC diagnosed between 2007-2011. Information regarding use of anti-hyperglycemic drugs prior to cancer diagnosis was extracted from Part D claims. The diabetic severity comorbidity index (DCSI) was used to control for DM severity. Logistic regression was used to calculate propensity scores for metformin use based on each patient’s sociodemographic characteristics, diabetic severity, and co-morbidity status. Inverse propensity weighted Cox Proportional-Hazard Models were subsequently used to assess the association between metformin use and overall survival adjusting for measured confounders. Results: We identified 1916 patients with PDAC and a diagnosis of DM on hypoglycemic medications at least one year prior to cancer diagnosis. Of these, 1098 (57.3%) were treated with metformin and 818 (42.7%) with other DM medications. Mean survival for those on metformin was 5.5 months compared with 4.2 months for those not on metformin (p &lt; 0.01). After adjusting for confounders, patients on metformin had a 12% decreased risk of mortality compared to patients on other medications (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.81-0.96, P &lt;.01). In stratified analysis, differences persisted for those with Charlson score 0-1 vs &gt; 2, DCSI 0-1 vs &gt; 2, and for those treated with insulin vs other hypoglycemic medications (p &lt; 0.01 for all). Conclusions: Metformin is associated with increased survival among diabetics with PDAC. If confirmed in prospective study, these results suggest a possible role for metformin use in diabetics with PDAC.
Quality assurance governance and implementation in cancer pathology: A national survey of Canada.
Authors: Gunita Mitera, John Srigley, Laurette Geldenhuys, Martin Trotter, Fergall Magee, Esther Ravinsky, Meg McLachlin, Diponkar Banerjee, Bernard Têtu, Beverley Carter, Tarek Rahmeh, Rosemary Henderson
Journal: Journal of Clinical Oncology (2013)

73 Background: Robust quality assurance (QA) programs incorporating both technical and interpretive aspects of QA are integral to accurate pathology diagnosis and quality of care a cancer patient receives. Programs and governance addressing technical pathology quality have been well developed in Canada and internationally. The extent of interpretive pathology QA implementation across Canada remains unknown. The objective of this study was to document the current landscape for pathology QA in Canada. Methods: An environmental scan was conducted to determine the types and extent of current large institution and provincial-level pathology QA programs in place across Canada. An electronic survey was administered to key stakeholders and senior decision makers in cancer pathology. Targeted interviews were conducted with pathology leaders in each province to verify survey results, deliberate and resolve ambiguous responses. Results were presented to all survey respondents as a feedback mechanism. Results: 9/10 provinces currently have a professional group representing pathologists. 10/10 provinces currently have a technical QA program. Of these, 2/10 provinces are governed through Accreditation Canada, 3/10 provinces are governed through the Ontario Laboratory Accreditation Program and the remaining 5/10 provinces are governed by separate provincially-led programs. For interpretive pathology QA, 2/10 provinces have a coordinated provincial interpretive QA program, 5/10 provinces do not have provincial coordination, and have plans to implement one, and 3/10 provinces do not have a provincially coordinated interpretive QA program in place, nor are they planning to develop one. Conclusions: This is the first study to document the provincial landscape for pathology QA in Canada. Large pan-Canadian variations remain for level of integration and future plans to develop and integrate interpretive pathology QA programs within provinces. Next steps should include the development of a pan-Canadian recommendations framework for interpretive pathology QA to help guide senior decision-makers in implementing such quality programs provincially.
Could a healthy diet attenuate COPD risk in smokers?
Authors: Raphaëlle Varraso, Seif O Shaheen
Journal: Thorax (2017)

Let food be thy medicine and medicine be thy food.Hippocrates

The predominant risk factor for COPD in high-income countries is cigarette smoking,1 but not all smokers develop COPD.2 It has been hypothesised that a diet rich in antioxidants may counteract the deleterious oxidant effects of smoking and hence prevent COPD.3 Although most studies that have linked dietary antioxidant foods and nutrients to COPD have been cross-sectional,3 a few cohort studies have also reported associations between higher intake and a slower decline of lung function or a lower incidence of COPD.4–7

In Thorax ,8 using longitudinal data from 44 335 men in the Cohort of Swedish Men, Kaluza et al investigated the association between total fruit and vegetable consumption and incident COPD, according to smoking habits. COPD was ascertained through patient and death registers. Briefly, after adjustment for several potential confounders, they reported a negative and significant association between fruit and vegetable intake and the risk of COPD. This finding is consistent with a large number of cross-sectional studies, and with a few longitudinal studies investigating the role of fruit and vegetable intake in the aetiology of COPD-related outcomes. Addressing the potential modifying effect of smoking on the diet-COPD association could help to clarify the potential causal role of diet. The authors reported a significant interaction between smoking and dietary intake of antioxidant-rich fruits and vegetables on the risk of COPD, and showed that the beneficial dietary associations were restricted to ex-smokers and current smokers. These results are in agreement …
Comprehensive genomic profiling of neuroendocrine carcinoma of the prostate.
Authors: Sumanta K. Pal, Matthew I. Milowsky, Julia Andrea Elvin, Siraj Mahamed Ali, Jean H. Hoffman-Censits, Jo-Anne Vergilio, James Suh, Badar Mian, Hugh A.G. Fisher, Tipu Nazeer, Vincent A. Miller, Philip J. Stephens, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2016)

187 Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.
Addressing distress in head and neck cancer patients: A quality improvement project.
Authors: Natalie Riblet, Karen Skalla, Alison Peterson, Auden McClure, Karen Homa, Thomas H. Davis
Journal: Journal of Clinical Oncology (2012)

43 Background: To better address the emotional needs of cancer patients by improving mental health care in Head and Neck Cancer (HNC) Medical oncology at Norris Cotton Cancer Center, Lebanon, NH, through implementing an evidence-based process for identifying and managing psychological distress. Methods: Using quality improvement methods, mental health care in HNC Medical Oncology was evaluated and revised November 2010 through April 2012. In January 2011, a two-component intervention was put into routine care including 1) the validated National Comprehensive Cancer Network (NCCN) distress thermometer (DT) and 2) a treatment decision algorithm. A licensed nursing assistant administered the DT and providers reviewed results as part of the clinical exam. Heightened distress was defined as a score of ≥ 4. Screening processes were improved through Plan-Do-Study-Act (PDSA) cycles. Results: Prior to January 2011, identification of distress was based on provider’s clinical assessment. Of 104 patients seen between November 2010 and January 2011, 25% (26) were diagnosed with psychological problems. Cause-effect diagraming suggested that lack of a formalized process for distress assessment contributed to missed diagnoses. Providers were unfamiliar with mental health resources. As reported in Psycho-Oncology 21(Suppl. 1): 51(2012) after implementing process changes, bi-weekly distress screening rates rose from 0% to 38% between January and July 2011. With additional PDSA cycles, these rates increased to 74% between October 2011 and April 2012. Similar to proposed benchmarks, 84% (47) of newly diagnosed patients (56) were assessed for distress. Furthermore, of 138 unique patients seen, 71% (98) were screened for distress and 47% (46) of these had heightened distress. Providers addressed the needs of all those identified. Improvement was attributed to the empowerment of staff and participation of senior leadership. Barriers included a heavy reliance on the presence of trained staff. Conclusions: Quality improvement methods can be applied to the cancer setting in order to create systems of care, which more reliably identify and address distress. Teams, however, must be invested in the work and receive support from senior leadership.