tbuckley/cabot-search huggingface dataset:
Predicting protocol completion in randomized clinical trials (RCTs): The occurrence of adverse events in the first treatment cycle.
Authors: Gillian Gresham, Miriam Nuno, Steven Piantadosi
Journal: Journal of Clinical Oncology (2015)

e17700 Background: Patients may not complete treatment protocol due to treatment intolerance or occurrence of severe or prolonged adverse events (AEs). It was of interest to evaluate the effect of timing and severity of AEs on completion of protocol. Methods: Data from a phase 3, randomized clinical trial of lung cancer patients were used as a case example. The primary outcome of interest was protocol completion defined as a subject’s successful completion of all treatment cycles. AEs were summarized by the highest grade (NCI CTCAE v.3) experienced within each cycle on a 1-5 severity scale. The association between AE severity and treatment cycle was explored in ordinal regression models accounting for correlated repeated measurements. The association between the first treatment cycle and toxicity severity was subsequently fit in a logistic regression model adjusting for potential confounders. Results: There were 642 patients included in the analysis and a total of 187 different AEs spanning 24 organ systems. Baseline characteristics were similar across treatment groups. The mean number of cycles was 3.3 (SD: 1.17). Treatment cycle was significantly associated with toxicity severity where patients were more likely to experience severe toxicities in cycle 1 (C1) (p < 0.0001). The impact of AE severity on protocol completion in the first treatment cycle was then evaluated in multivariable analysis (Table). An increase in AE severity resulted in significantly reduced odds of completing treatment protocol (p-trend < 0.0001). Conclusions: AEs in cycle 1 play a pivotal role in protocol completion. The occurrence of more serious AEs early in treatment strongly diminish the probability of completing assigned therapy. Careful attention to toxicities and possible intervention during C1 will increase the likelihood of patients receiving a full course of treatment. Severity Grade Odds Ratio 95% CI p-value Mild 0-1 Reference - - - Moderate 2 0.39 0.22 0.71 0.002 Severe 3 0.28 0.16 0.51 < 0.0001 Life-threatening/death 4-5 0.17 0.09 0.31 < 0.0001
Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic
Authors: Sarah Tomkovich, Christine M. Dejea, Kathryn Winglee, Julia L. Drewes, Liam Chung, Franck Housseau, Jillian L. Pope, Josee Gauthier, Xiaolun Sun, Marcus Mühlbauer, Xiuli Liu, Payam Fathi, Robert A. Anders, Sepideh Besharati, Ernesto Perez-Chanona, Ye Yang, Hua Ding, Xinqun Wu, Shaoguang Wu, James R. White, Raad Z. Gharaibeh, Anthony A. Fodor, Hao Wang, Drew M. Pardoll, Christian Jobin, Cynthia L. Sears
Journal: Journal of Clinical Investigation (2019)

Mucus-invasive bacterial biofilms are identified on the colon mucosa of approximately 50% of colorectal cancer (CRC) patients and approximately 13% of healthy subjects. Here, we test the hypothesis that human colon biofilms comprise microbial communities that are carcinogenic in CRC mouse models. Homogenates of human biofilm-positive colon mucosa were prepared from tumor patients (tumor and paired normal tissues from surgical resections) or biofilm-positive biopsies from healthy individuals undergoing screening colonoscopy; homogenates of biofilm-negative colon biopsies from healthy individuals undergoing screening colonoscopy served as controls. After 12 weeks, biofilm-positive, but not biofilm-negative, human colon mucosal homogenates induced colon tumor formation in 3 mouse colon tumor models (germ-free ApcMinΔ850/+;Il10-/- or ApcMinΔ850/+ and specific pathogen-free ApcMinΔ716/+ mice). Remarkably, biofilm-positive communities from healthy colonoscopy biopsies induced colon inflammation and tumors similarly to biofilm-positive tumor tissues. By 1 week, biofilm-positive human tumor homogenates, but not healthy biopsies, displayed consistent bacterial mucus invasion and biofilm formation in mouse colons. 16S rRNA gene sequencing and RNA-Seq analyses identified compositional and functional microbiota differences between mice colonized with biofilm-positive and biofilm-negative communities. These results suggest human colon mucosal biofilms, whether from tumor hosts or healthy individuals undergoing screening colonoscopy, are carcinogenic in murine models of CRC.
Obesity and metastatic castration resistant prostate cancer: Results from the control arms of ASCENT2, MAINSAL and VENICE trials.
Authors: Alberto Martini, Nikhil Waingankar, Nicholas M Brown, John P. Sfakianos, Ashutosh Tewari, Matthew Galsky
Journal: Journal of Clinical Oncology (2019)

287 Background: Previous findings regarding the correlation between body mass index (BMI) and survival in patients with prostate cancer are conflicting and may be disease-state dependent. We aimed to test whether BMI among patients with metastatic prostate cancer (mCRPC) is associated with overall survival (OS) and cancer-specific mortality (CSM). Methods: We identified 1577 patients with mCRPC from the control arms of 3 randomized trials. The role of BMI was investigated both as a continuous and categorical variable ( &lt; 20 vs. 20-25 vs. 25-30 vs. &gt; 30 km/m2). A BMI &gt; 30 kg/m2 was considered obese. Analyses were adjusted for age, PSA, ECOG, # of metastasis and prior treatment. A Cox semi-proportional hazard model was used to predict OS, whereas the competing risks regression was used for predicting cancer-specific mortality (CSM). Results: The median (IQR) age for the patient population was 69 (63,74) years with a median (IQR) BMI of 28 (25-31) kg/m 2 . Of the 1577 patients included, 655 had died during follow-up (median follow-up for survivors = 12 months). BMI emerged as a protective factor for OS both as a continuous variable (HR: 0.96; 95% CI: 0.94, 0.99; p = 0.015) and as a categorical variable (obesity: HR: 0.71, 95% CI: 0.53, 0.96; p = 0.027). The effect BMI on CSM was confirmed both as a continuous (SHR: 0.94; 95% CI: 0.91, 0.98; p = 0.002) and as a categorical variable (obesity SHR: 0.65; 95% CI: 0.45, 0.93; p = 0.018). No interaction was detected between the BMI categories and docetaxel dose. Conclusions: Obesity, compared with lower weight categories, is associated with improved CSM and OS in mCRPC treated with docetaxel. The mechanistic basis for this observation warrants further study.
Abstract MP68: Effects of Macronutrients on Serum Short Chain Fatty Acids (SCFA): Results From the Optimal Macro-Nutrient Intake to Prevent Heart Disease (OmniHeart) Trial
Authors: Noel T Mueller
Journal: Circulation (2019)

Introduction: Emerging evidence links greater concentrations of serum SCFA, derived from microbial fermentation of indigestible fiber in the colon, with better cardiometabolic health. The OmniHeart trial tested the effects of 3 diets that differed in % kcal of carbohydrate, protein, and unsaturated fat; each diet was high in fiber (~30g/day) and isocaloric. Hypothesis: All 3 diets, being high in fiber, would increase SCFAs, but there will be differences between diets. Methods: The OmniHeart trial is a randomized crossover trial that enrolled 158 men and women, aged 30 years or older, with systolic blood pressure 120–159 mm Hg, diastolic blood pressure &lt; 100 mm Hg. Participants consumed each of 3 different isocaloric diets for 6 weeks in random order: a carbohydrate (CARB)-rich diet (similar to DASH); a protein (PROT)-rich diet with protein predominantly from plant sources; and a diet rich in monounsaturated fat (UNSAT). Fasting serum was collected from participants at baseline, while they consumed their own diet, and at the end of each diet intervention period. SCFAs were measured in stored serum with LC-MS/MS (Metabolon Method TAM148)and normalized by log transformation. We fitted a linear regression model using generalized estimating equations to examine mean change in log-transformed SCFAs from baseline in each diet and between diets. Results: Compared to baseline diet, all 3 diets increased acetic acid; CARB and UNSAT diets decreased propionic acid; and the PROT diet increased butyric acid ( Figure 1, top panels ). PROT increased acetic acid more than CARB, but no differently than UNSAT. PROT increased propionic acid compared to both CARB and UNSAT ( Figure 1, bottom panels ). Conclusion: All 3 high-fiber OmniHeart diets affected microbiota-derived serum SCFA concentrations with some notable differences between diets. Future research is needed to determine whether changes in SCFA mediate the relationship of dietary change and cardiometabolic disease risk factors.
Abstract P207: Frequent but Not Infrequent Potato Consumption is Associated With a Higher Risk of Coronary Artery Disease: the Million Veteran Program
Authors: Vijaykumar Bodar, Yuk-Lam Ho, Rachel Ward, Kelly Cho, David Gagnon, Michael Gaziano, Luc Djousse’
Journal: Circulation (2019)

Background: Potato consumption is highly prevalent all around the world. Previous studies have reported a positive association of potato intake with hypertension and diabetes due to high glycemic load. However, data are scarce on potato consumption and risk of coronary artery disease (CAD). Hypothesis: We hypothesized that potato consumption is positively associated with risk of CAD. Method: We prospectively studied 148,671 participants from Million Veteran Program(MVP). We used a Willett food frequency questionnaire to assess consumption of baked, boiled, and mashed potatoes. The incidence of CAD was assessed through electronic health record. We used Cox Proportional hazard model to compute the hazard ratio and 95% confidence interval (95% CI) for CAD events across categories of potato intake. Results: The average age of men was 64 years ( SD = 12) and 90 % were men. A total of 6,309 new cases of CAD occurred during mean follow up of 2.7 ± 1.4 y. Median potato consumption was 1 cup/week. The crude incidence of CAD from lowest to highest categories of potato consumption was 14.1, 15.0, 15.2, 16.1, and 18.9 per 1000 person-years, respectively. Hazard ratios ( 95% CIs) of CAD were 1.00 ( reference), 1.01 (0.92-1.11), 1.02 ( 0.93-1.11), 1.04 (0.95 - 1.15), and 1.21 (1.07-1.36) for potato intake of &lt;1 cup/month, 1-3 cups/month, 1 cup/week, 2-4 cups/week, and 5+ cups/week respectively, adjusting for age, gender, race, body mass index (BMI), alcohol consumption, exercise, smoking, overall diet quality, and education (P for linear trend = 0.01). The observed relation of potato consumption with CAD was not modified by age, BMI, gender, and ethnicity. In a sensitivity analysis, exclusion of CAD events occurred during the first year did not alter the findings. Conclusion: Frequent (5+ cups/week) but not infrequent potato consumption was associated with a higher risk of CAD among MVP participants.
Abstract P069: Longitudinal Associations Between Metabolic Status, Insulin Clearance, and Insulin Sensitivity: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) Cohort
Authors: Zhila Semnani-Azad, Ravi Retnakaran, Stewart B Harris, Bernard Zinman, Anthony J Hanley
Journal: Circulation (2019)

Metabolically healthy obese individuals (MHO) are those with obesity but normal metabolic profiles. The relationship of MHO to type 2 diabetes mellitus (T2DM) risk is unclear. Limited data are available on metabolic status and declining insulin clearance (IC) and insulin sensitivity (IS), which are well-documented features in the pathogenesis of T2DM. Objective: To assess longitudinal changes in IC and IS among metabolically healthy and unhealthy obese and non-obese participants. Hypothesis: Longitudinal declines in IC and IS will be greater among participants classified as metabolically unhealthy and/or obese compared to metabolically healthy non-obese (MHN). Methods: Adults ≥30 years old at-risk for T2DM in PROMISE had three assessments over 6 years (n=558). Obesity was classified as BMI ≥30 kg/m 2 . Baseline metabolic parameters, including blood pressure, TAG, HDL, fasting glucose, waist circumference, and medication use, were used to determine metabolic status. Metabolically healthy status was defined as the presence of &lt;3 metabolic abnormalities. Values from oral glucose tolerance tests at each visit were used to calculate Matsuda insulin sensitivity index (ISI), and the ratios of fasting C-peptide-to-insulin (IC FASTING ) and areas-under-the-curve of C-peptide-to-insulin (IC AUC ). Generalized estimating equations (GEE) evaluated the association of baseline metabolic status with longitudinal changes in IC and IS, adjusting for covariates. Results: The multivariate GEE model showed that MHO and MUO had greater declines in IC and IS over time compared to MHN ( Figure , both p&lt;0.01). Metabolically unhealthy non-obese (MUN) had a longitudinal decline in IC FASTING but not IC AUC compared to MHN, and a more modest relative decline in IS. Conclusions: Compared to MHN, presence of a metabolically unhealthy and/or obese phenotype negatively impacted IC and IS over time. The more pronounced declines in IC in MUO and MHO may reflect a compensatory response to the poorer IS in these groups.
Expression and functional relevance of long non-coding RNAs in acute myeloid leukemia stem cells
Authors: Marius Bill, Dimitrios Papaioannou, Malith Karunasiri, Jessica Kohlschmidt, Felice Pepe, Christopher J. Walker, Allison E. Walker, Zachary Brannan, Aparna Pathmanathan, Xiaoli Zhang, Krzysztof Mrózek, Allison LaRocco, Stefano Volinia, Clara D. Bloomfield, Ramiro Garzon, Adrienne M. Dorrance
Journal: Leukemia (2019)
Long-term Somatic Disease Risk in Adult Danish Cancer Survivors
Authors: Trille Kristina Kjaer, Elisabeth Anne Wreford Andersen, Jeanette Falck Winther, Pernille Envold Bidstrup, Michael Borre, Henrik Møller, Signe Benzon Larsen, Christoffer Johansen, Susanne Oksbjerg Dalton
Journal: JAMA Oncology (2019)

Long-term health effects of cancer in adult survivors are a major concern; however, it is difficult to differentiate between the consequences of cancer and cancer treatment and those of normal aging or comorbidity.To provide an overview and investigate the temporal pattern of hospitalizations for medically verified incident somatic disease in adult survivors compared with cancer-free comparison people, taking into consideration pretreatment comorbidity and the socioeconomic position of the participants.In this nationwide, population-based cohort-cohort study, 458 646 survivors of the 12 most frequent first primary cancers listed in the Danish Cancer Registry between January 1, 1997, and December 31, 2014, and 2 121 567 matched cancer-free comparison people were identified from the Danish Central Population Registry. Hospitalizations for somatic diseases after cancer diagnosis or study entry were identified from the National Patient Register and stratified according to the 11 main diagnostic groups in the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. A cohort of cancer survivors was formed for each combination of cancer type and diagnostic group, with a corresponding group of cancer-free people, resulting in 132 unique cohorts. Data analysis was performed from September 1, 2017, to January 15, 2018.Risk of hospitalization and the temporal pattern of incidence were analyzed in Cox proportional hazards regression models. Cumulative incidence proportions were calculated by the pseudo-observation method.A total of 2 580 213 people were investigated, of whom 458 646 were cancer survivors (mean [SD] age, 69 [11.6] years; 230 793 [50.3%] male and 227 853 [49.7%] female) and 2 121 567 were comparison people (mean [SD] age, 69 [11.5] years; 1 054 465 [49.7%] male and 1 067 102 [50.3%] female). More cancer survivors vs comparison people had comorbid conditions at the time of cancer diagnosis or study entry (Charlson Comorbidity Index ≥1: 19% vs 13%). Overall, the risk of hospitalizations for somatic diseases was significantly higher for cancer survivors in almost all diagnostic groups (eg, diseases in the nervous system among breast cancer survivors: hazard ratio, 1.20; 95% CI, 1.17-1.22; diseases in the respiratory system in lung cancer survivors: hazard ratio, 5.85; 95% CI, 5.63-6.07; and diseases in blood and blood-forming organs in prostate cancer survivors: hazard ratio, 2.60; 95% CI, 2.50-2.71).The findings suggest that adult survivors of the 12 most common cancers are at significantly higher risk for a broad range of somatic diseases that require hospitalization compared with matched cancer-free comparison people. The results of this study suggest the importance of close, targeted monitoring for new somatic disease during follow-up care of cancer survivors.
Second cancer following radical prostate cancer treatment.
Authors: Bjorg Y Aksnessaether, Arne Solberg, Tor Åge Myklebust, Solveig Roth Hoff, Eva Skovlund, Olbjørn Klepp, Jo-Åsmund Lund
Journal: Journal of Clinical Oncology (2019)

16 Background: We estimated second cancer (SC) risk following radical prostate cancer (PC) treatment and evaluated if the risk was influenced by treatment. Methods: We analyzed data from the Cancer Registry of Norway on all patients with PC (first cancer diagnosis) from 1997-2014. Standardized incidence ratios (SIRs) for SC were calculated. Subdistribution hazard ratios (SHRs) were estimated in treatment groups (prostatectomy (RP) reference). Results: Median follow-up in 24155 radically treated patients was 6 and 4 years in the external beam radiotherapy (EBRT) and RP-groups, respectively. SC-incidence was indifferent from that of the reference population in 24155 radically treated patients, higher following EBRT, SIR 1.06(1.01-1.12), and lower following RP, SIR 0.91(0.84-0.98). EBRT-patients had higher rectal and urinary bladder cancer incidences. Compared to RP, the EBRT-patients had a 38 % higher risk of any SC. Respective figures for rectal, urinary bladder and lung cancer: 72, 38, and 113%. Conclusions: EBRT-patients had a slightly higher SC-incidence than the general population. The rectal and urinary bladder cancer risk should be taken into account in follow-up after EBRT.[Table: see text]
Pre-treatment neutrophil to lymphocyte ratio and platelet to lymphocyte ratio as potential prognostic factors in patients with newly diagnosed ovarian cancer.
Authors: Agnieszka Badora-Rybicka, Elzbieta Nowara
Journal: Journal of Clinical Oncology (2015)

e16555 Background: Recent studies have shown that the presence of systemic inflammation correlates with worse outcomes in many types of cancers. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been proposed as indicators of systemic inflammatory response. The aim of the study was to assess the prognostic value of pre-treatment NLR and PLR in patients with newly diagnosed ovarian cancer. Methods: We conducted a retrospective analysis of medical documentation of 172 patients with newly diagnosed ovarian cancer, treated in Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch between 2008 and 2012. ROC curves for PFS, EFS and OS prediction were plotted to verify cut-off points for NLR and PLR. Progression free survival (PFS), event free survival (EFS), and overall survival (OS) were analysed for correlation with NLR and PLR using Cox regression model. Results: Patients with pre-treatment NLR as well as PLR greater than or equal to the cut-off point determined by ROC curve analysis achieved significantly shorter PFS (p = 0.0007 and p < 0.0001 respectively), EFS (both, p < 0.0001) and OS (both, p < 0.0001) in comparison to patients with NLR and PLR below the cut-off point. Higher pre-treatment NLR and PLR were associated with worse performance status, higher Ca-125 level and advanced stage of the disease (all, p < 0.0001). In univariate analysis pre-treatment NLR and PLR were negative prognostic factors for PFS (p = 0.0003 and p < 0.0001 respectively), EFS (both, p < 0.0001) and OS (both, p < 0.0001). However, in multivariate analysis independent prognostic factor for PFS were only: clinical stage (p = 0.0001), Ca-125 level (p = 0.0479) and PLR (p = 0.0447). The only independent prognostic factor for EFS was clinical stage (p < 0.0001). Conclusions: Patients with elevated NLR and PLR had significantly worse survival outcomes. In univariate analysis both, NLR and PLR were associated with poor prognosis. However, in multivariate analysis only PLR remained independent prognostic factor (for PFS).
Cost-effectiveness of trastuzumab emtansine (T-DM1) for HER2-positive advanced breast cancer (ABC).
Authors: Quang Anh Le, Yuna Bae
Journal: Journal of Clinical Oncology (2015)

6610 Background: The EMILIA trial demonstrated T-DM1 significantly increased in median profession-free (3.2 months) and overall (5.8 months) survival relative to combination therapy with lapatinib plus capecitabine (LC) in patients with HER2-positive ABC previously treated with trastuzumab and a taxane. We performed an economic analysis of T-DM1 compared to LC and monotherapy with capecitabine (C) from both US payer and societal perspectives. Methods: We developed 4 possible Markov models to compare the projected lifetime costs and outcomes of T-DM1 and LC, and C. Markov models 1 and 2 have four health states (progression-free, response to therapy, disease-progression, and death), and Markov models 3 and 4 have three health states (progression-free, disease-progression, and death). In models 1 and 3, the possibility of death can occur in any health state; while in models 2 and 4, death can only occur in disease-progressing health state. Transition probabilities were estimated from published relevant trials. Six-week cycle time was modeled to follow the assessment time interval in the trials. Direct costs of the therapies, major adverse events, laboratory tests, and disease progression, indirect costs (productivity losses due to morbidity and mortality), and health utilities were obtained from published sources. The models used 3% discount rate and reported in 2014 US dollars. One-way and probabilistic sensitivity analyses were performed in the study. Results: When incorporating both model structural and parameter uncertainty, the resulting incremental cost-effectiveness ratios (ICER) comparing T-DM1 to LC and T-DM1 to C were $172,152 per quality-adjusted life year (QALY) and $126,251/QALY from the US societal perspective, respectively. From the US payer perspective, the ICERs were $205,598/QALY (T-DM1 vs. LC) and $164,628/QALY (T-DM1 vs. C). (See Table) Conclusions: From the US societal perspective, T-DM1 may be cost-effective relative to C. However, T-DM1 is not clearly cost-effective when comparing to LC from both perspectives. Treatment Regimen Lifetime Direct Cost ($) Lifetime Indirect Cost ($) QALYs T-DM1 270,630 27,335 2.04 LC 180,202 42,046 1.60 C 101,966 66,653 1.01