tbuckley/cabot-search huggingface dataset:
Effects of Non-Linear or Linear Aerobic Training (AT) Dosing Regimens on Impaired Cardiovascular (CV) Function in Patients with Operable Breast Cancer: A Randomized Controlled Trial (RCT).
Authors: Jessica Scott, Samantha M. Thomas, James Emmett Herndon, Jeffrey M. Peppercorn, Pamela S. Douglas, Michel Khouri, Chau T. Dang, Anthony Francis Yu, Diane Catalina, Cristi Ciolino, Catherine Capaci, Meghan Michalski, Neil Derek Eves, Lee Jones
Journal: Journal of Clinical Oncology (2019)

541 Background: Breast cancer therapy causes marked impairments in CV function predisposing to elevated risk of CV morbidity. We investigated the effects of two AT dosing regimens on CV function in post-treatment patients with operable breast cancer. Methods: In a three-arm, parallel-group RCT, 174 post-menopausal patients (2.8 years post primary adjuvant therapy) with impaired age/sex-matched peak oxygen consumption (VO 2 peak) were randomized to: (1) conventional linear AT (uniform dose-intensity / session), (2) nonlinear AT (variable dose-intensity / session), or (3) stretching (attention control). AT consisted of 64 supervised treadmill walking sessions delivered four times weekly at either ~70% VO 2 peak for 40 mins/session (linear) or 55% to 100% VO 2 peak for 20-45 mins/session (nonlinear) for 16 consecutive weeks. Stretching was matched to AT on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO 2 peak. Secondary end points were other markers of CV risk profile (biochemical CV risk profile, cardiac function, body composition), patient-reported outcomes (PROs), tolerability (e.g., relative dose intensity), and safety. All analyses followed the intention-to-treat principle. Results: Rates of lost-to-follow were &lt; 10% in all arms. Relative dose intensity of AT was 73% ± 27% and 80% ± 21% in linear and nonlinear arms, respectively. No serious adverse events were observed. In adjusted analysis, compared to control, VO 2 peak (ml O 2 . kg -1. min -1 ) increased 0.7 (± 0.3) ml O 2 . kg -1. min -1 (p = 0.06) and 0.8 (± 0.4) ml O 2 . kg -1. min -1 (p = 0.02) in linear and nonlinear AT, respectively. Rates of VO 2 peak improvement greater than the technical error of measurement (i.e., ≥1.32ml O 2 . kg -1. min -1 ) were 33% and 39% in linear and nonlinear AT (p = 0.03), respectively. Both AT regimens were associated with improvements in several secondary CV end points but only nonlinear AT improved PROs compared with control (all p’s &lt; 0.05). There were no differences between the two AT regimens. Conclusion: AT significantly improves CV function and PROs in post-treatment breast cancer patients. The efficacy-tolerability ratio favors the non-linear regimen over the conventional linear prescription approach. Clinical trial information: NCT01186367.
DNA damage repair (DDR) gene alterations as a predictive biomarker for response to platinum-containing chemotherapy in advanced biliary tract cancer (BTC).
Authors: Heejung Chae, Changhoon Yoo, Deokhoon Kim, Jae Ho Jeong, Heung-Moon Chang, Kyu-Pyo Kim, Baek-Yeol Ryoo
Journal: Journal of Clinical Oncology (2019)

4078 Background: Although many studies using whole-exome sequencing or targeted sequencing have reported the molecular profile of BTC, its clinical implications remains unclear. In this study, we assessed a predictive role of DDR gene mutations in advanced BTC patients treated with platinum-containing regimen. Methods: Eighty-eight patients with pathologically-confirmed BTC who received first-line gemcitabine-cisplatin combination (n = 69) or fluoropyrimidine-oxaliplatin combination (n = 19) were included in this analysis. Targeted exome sequencing was performed using Foundation Medicine T7 assay or in-house OncoPanel AMC. Germline or somatic mutations in ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, MLH1, MSH2, MSH6, MRE11A, NBN, PALB2, PMS2, RAD50, RAD51, RAD51C, RAD51D, and XRCC2 were classified as DDR gene mutations. Data regarding baseline characteristics and treatment outcomes were retrospectively obtained from medical records. Results: The median age was 62 years (range, 25-78), with male comprising 64.8% (n = 57). By primary tumor site, 21 patients with GBC (23.9%), 44 with ICC (50.0%) and 23 with ECC (26.1%) were included. Most patients received palliative chemotherapy for their initially metastatic (50.0%) or recurred (44.3%) disease; the rest 5.7% had locally advanced disease. The median PFS and OS of overall patients were 7.1 and 16.1 months, respectively with median follow-up duration of 20.2 months. DDR gene mutations were found in 63.5% of patients. BRCA2 (18.2%) was most frequently mutated, followed by ATM (13.6%), and ATR (8.0%). DDR gene mutations were significantly associated with prolonged PFS (presence vs. absence; median, 6.9 vs. 5.7 months; P = 0.013) and OS (median, 21.0 vs. 13.3 months, P = 0.009). The impact of DDR gene mutations remained significant in multivariate analyses for PFS that included other prognostic factors (hazard ratio, 0.51; P = 0.009), but not for OS. Conclusions: The presence of DDR gene mutations might be a promising predictive biomarker for response to platinum-based chemotherapies in advanced BTC. Future investigation using novel agents targeting DDR gene alteration in BTC are warranted.
The Role of Brain Barriers in Maintaining Brain Vitamin Levels
Authors: Kendra A. Tiani, Patrick J. Stover, Martha S. Field
Journal: Annual Review of Nutrition (2019)

It is increasingly recognized that tissue-specific nutrient deficiencies can exist in the absence of whole-body deficiency and that these deficiencies may result from disease or disease-related physiological processes. Brain and central nervous system tissues require adequate nutrient levels to function. Many nutrients are concentrated in the cerebrospinal fluid relative to the serum in healthy individuals, and other nutrients resist depletion in the presence of whole-body nutrient depletion. The endothelial, epithelial, and arachnoid brain barriers work in concert to selectively transport, concentrate, and maintain levels of the specific nutrients required by the brain while also blocking the passage of blood-borne toxins and pathogens to brain and central nervous system tissues. These barriers preserve nutrient levels within the brain and actively concentrate nutrients within the cerebrospinal fluid and brain. The roles of physical and energetic barriers, including the blood-brain and blood-nerve barriers, in maintaining brain nutrient levels in health and disease are discussed.
Association of genetic variations within the T-cell costimulatory LIGHT gene with outcome in stage II and III colon cancer.
Authors: Martin D. Berger, Shu Cao, Inti Zlobec, Yuji Miyamoto, Mitsukuni Suenaga, Diana L. Hanna, Shivani Soni, Alberto Puccini, Ryuma Tokunaga, Madiha Naseem, Francesca Battaglin, Wu Zhang, Alessandro Lugli, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

2633 Background: T-cell activation plays a key role in maintaining an effective host immunity and antitumor control. Targeting costimulatory immune checkpoint proteins can lead to increased antitumor immunity. We hypothesize, that variations in genes encoding for T-cell activation molecules may predict outcome in stage II and III colon cancer patients. Methods: The impact of 4 functional single nucleotide polymorphisms (SNPs) within the LIGHT, ICOS, CD80 and GITR genes on time to recurrence and overall survival was evaluated in 209 patients with stage II and III colon cancer. Genomic DNA was extracted from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: median age = 70y (19-91); female/male ratio = 41.6% / 58.4%; 111 patients had stage II, and 98 stage III colon cancer. The LIGHT rs3760746 SNP showed significant association with recurrence rate in the overall population. Patients harboring any G allele had a lower 3-years recurrence rate compared to those with a A/A genotype (16% vs 30%) in both univariate (HR 0.53, 95% Confidence intervall (CI) 0.29-0.96, p = 0.033) and multivariate analyses (HR 0.52, 95% CI 0.29-0.95, p = 0.034). This trend was most evident among patients with stage III colon cancer. Here again, G allele carriers had both a lower 3-years recurrence and a longer 5-years overall survival rate compared to those having a A/A genotype (21% vs 40% and 77% vs 43%) in both univariate (HR 0.42, 95% CI 0.19-0.90, p = 0.021 and HR 0.51, 95% CI 0.25-1.03, p = 0.046) and multivariate analyses (HR 0.43, 95% CI 0.20-0.93, p = 0.033 and HR 0.30, 95% CI 0.14-0.65, p = 0.002). Conclusions: Our results provide the first evidence that polymorphisms within the T-cell costimulatory LIGHT gene might serve as prognostic markers in patients with stage II and III colon cancer. Targeting LIGHT might be a promising approach to further optimize treatment options and to improve outcome of colon cancer patients in the adjuvant setting.
Measuring phospho-MET by multiplex immunofluorescence to aid in selection of patients with MET activation in tumors.
Authors: Tony Navas, Apurva K. Srivastava, Jeevan P Govindharajulu, Yvonne A. Evrard, Susanne Borgel, John Carter, Li Chen, Biswajit Das, Raymond Divelbiss, Chris Karlovich, Rajesh Patidar, Marianne Radzyminski, Jesse Stottlemyer, Paul M. Williams, Melinda G. Hollingshead, Donald Bottaro, James H. Doroshow, Ralph E. Parchment
Journal: Journal of Clinical Oncology (2019)

3131 Background: Currently, patient selection criteria for clinical testing of MET inhibitors are limited. Robust studies selecting patients based on MET protein expression, MET gene amplification, or mutations have not met their efficacy goals. Development of microscopy-based assays to quantify levels of phospho-MET (pMET) in tumors has been hampered by poor antibody specificity. Here, we present the development and validation of a robust, highly specific multiplex immunofluorescence assay (IFA) that measures pY1235-MET and total MET in tumor tissue. Methods: This assay utilizes antibodies to pY1235-MET (NCI-23111), total MET (D1C2), and plasma membrane (PM) marker Na + /K + -ATPase, each conjugated to a different Alexa Fluor dye. We used tumor tissue from crizotinib-treated SNU5 xenograft models to demonstrate pY1235-MET assay fitness-for-purpose and cross-platform assay concordance with our validated pMET ELISA. In addition, this IFA was validated by phospho-peptide competition using custom tissue microarrays (TMA) derived from patients with colorectal carcinoma (CRC). Finally, we developed quantitative algorithms to assess pY1235 MET levels in the plasma membrane and nucleus using PM and DAPI masks, respectively. Patient-derived xenograft models (PDX) were obtained from NCI’s Patient-Derived Models Repository (www.pdmr.cancer.gov). Results: The prevalence of high pY1235-MET expression in CRC patient specimens was greater than expected; of the 64 TMA cores evaluated, 29 (45%) and 19 (29%) had high pY1235-MET and total MET levels, respectively, as defined by mean marker area of ≥ 30 μm 2 /cell. To address the potential utility of pY1235-MET as a diagnostic biomarker, we examined 15 CRC PDX models by pMET ELISA and IFA. Two CRC tumor models were positive for pY1235-MET expression in both assays. The pY1235-MET IFA results and gene expression data were used to select PDX models for ongoing preclinical trials of potent MET inhibitors. Conclusions: This novel pY1235-MET IFA will enable clinicians to address the utility of activated MET as a biomarker for patient selection and/or prediction of response in clinical trials of MET inhibitors. Funded by NCI Contract No. HHSN261200800001E.
Symptoms and characteristics of cancer patient visits to an emergency room.
Authors: Michael Gallaway, Nimi Idaikkadar
Journal: Journal of Clinical Oncology (2019)

e18306 Background: Cancer patients are increasingly likely to visit an emergency department (ED) for acute care compared to the general population. Cancer patients who visit the ED often have long wait times, increased exposure to infection, and lesser quality treatment. The Centers for Medicare &amp; Medicaid Services (CMS) is encouraging efforts to decrease survivor acute care visits. The purpose of this study was to examine cancer-related ED visits using a national population-based sample to understand why they are seeking care in an ED. Methods: A retrospective cohort study of U.S. patients who visited EDs between June 1, 2017 and May 31, 2018 was conducted using the National Syndromic Surveillance Program (NSSP) BioSense Platform. Cancer patients were identified using International Classification of Diseases, 10 th Revision (ICD-10) codes for any cancer type and specifically for cancers of the bladder, female breast, cervix, colon and rectum, kidney, liver, lung, ovary, pancreas, prostate, or uterus. Symptoms were identified using syndromic definitions and key-word queries. Significance testing (p-value ≤0.01), was used to assess differences in the prevalence of symptoms by cancer type. Results: There were 97 million visits to EDs during the study period, 710,297 (0.8%) were among cancer survivors. Slightly more were female (50.1%) than male (49.5%); more were aged 65 or older (53.6%) than 18-64 (1.4-35.3%). The most common symptoms were pain (19%), gastrointestinal (14%), respiratory (12%), neurologic (5%), fever (5%), and injury (4%). Prevalence of symptoms differed significantly by cancer type. Some symptoms were higher among those with specific cancer types compared to all cancers in aggregate: pain (cervical, liver, pancreas); gastrointestinal (pancreas, liver, colorectal); respiratory (lung); neurologic (liver, lung), fever (pancreas, liver), injury (prostate), and bleeding (colorectal, liver). Conclusions: Use of NSSP data enabled a descriptive characterization of more than half of the U.S. ED visits among cancer patients. These comprehensive findings inform best practices to reduce unplanned acute care and help inform possible modifications in treatment and care protocols among survivors of specific cancers.
FDA analysis: Demographic trends in bladder and renal cancer trials.
Authors: Laura L Fernandes, Zhantao Lin, Lola A. Fashoyin-Aje, Shenghui Tang, Rajeshwari Sridhara, Richard Pazdur
Journal: Journal of Clinical Oncology (2019)

e18144 Background: Many publications report under representation of minorities in certain subgroups, which may limit the generalizability of clinical trial (CT) results. This analysis, investigates and reports enrollment trends in CTs submitted between 2006-2017 in support of marketing applications for drugs indicated for the treatment of urothelial (UC) and renal cancer carcinoma (RCC), and compares them to incidence rates of these diseases by Surveillance, Epidemiology, and End Results (SEER) registry and the US census bureau. Methods: We identified all marketing applications for the treatment of UC and RCC that provided the primary evidence of safety and efficacy and aggregated the demographic data across trials and disease. Using these two pooled datasets, we compared the patient proportions enrolled in each of the race, sex and age categories to the corresponding rates in US cancer population estimated based on the corresponding incidence rates reported by SEER and the US census bureau using a Chi-squared test. Results: The pooled seven UC and 14 RCC CTs provided 2035 and 6757 patients respectively. The results are summarized below for the 939 (46%) UC and 1489 (22%) RCC patients enrolled in the US. Conclusions: Our findings indicate that majority of the patients were enrolled outside of the US. There were lower proportion of Black patients (4% vs 8%), older patients, age ≥ 75 years (30% vs 48%) and males (74% vs 80%) enrolled in UC population in the US. Higher proportions were observed in both White (89% vs 85%) and Asian (4% vs 2%) patients in UC and in White (90% vs 79%) patients in RCC.[Table: see text]
TAXOMET: A French prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC.
Authors: MARC Pujalte Martin, Delphine Borchiellini, Julien Viotti, Aline Guillot, Jean Baptiste Paoli, Dominique Besson, Werner Hilgers, Claude El Kouri, Gerard Cavaglione, Frank Priou, Tifenn Lharidon, Remy Largillier, Jean-Laurent Deville, Benjamin Hoch, Renaud Schiappa, Jean François Tanti, Frederic Bost, Jean-Marc Ferrero
Journal: Journal of Clinical Oncology (2019)

5004 Background: Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective cohort studies suggest a decrease in PC incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in PC preclinical models, with increase apoptosis when added to DOCE. The addition of MET could enhance DOCE efficacy in mCRPC patients (pts). Methods: TAXOMET is a phase II prospective multicentric randomized controlled trial. Non-diabetic mCRPC pts were assigned 1:1 to receive DOCE 75mg/m2 every 21 days + prednisone (P) 5 mg twice a day and either MET 850mg twice a day (arm A) or placebo (arm B), up to 10 cycles. The primary end point was PSA response rate (≥50% decrease). Main secondary endpoints included objective response rate (ORR, according to RECIST v1.1), clinical and biological progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). Comparisons between arm A and B were performed using Chi² test for qualitative data and Log-rank test for survival data. Results: From January 2013 to December 2015, 99 pts were randomized (50 pts in arm A and 49 pts in arm B) in 10 french centers, and 95 pts were evaluable. No difference was observed between arm A and arm B in PSA-response rate (72% in both arms), ORR (28% in both arms), clinical or biological mPFS (7.3 months vs 5.8 months p = 0.848) and mOS (24.2 months (95CI: 17.2 – 33.7) vs 19.7 months (95CI: 14.8 – 36.8), p = 0.53), respectively. There was no difference between arms in adverse events, except a trend for diarrhea to be more common with MET (70% in arm A vs 50% in arm B, p = 0.072), but few grade 3-4 events. There was no difference in QoL according to QLQ-C30 score between the two arms during the treatment period. Conclusions: This is the first prospective randomized controlled trial to evaluate the combination of MET with DOCE+P in mCRPC. The addition of MET has no meaningful clinical benefit in this setting. Clinical trial information: NCT01796028.
Clinical insights for hematological malignancies from an artificial intelligence decision-support tool.
Authors: Miyoung Kim, Jane Snowdon, S Dilhan Weeraratne, Winnie Felix, Lionel Lim, Irene Dankwa-Mullan, Young Kyung Lee, Eunyup Lee, Kibum Jeon, Jee-Soo Lee, Dae Young Zang, Hyo Jung Kim, Ho Young Kim, Boram Han
Journal: Journal of Clinical Oncology (2019)

e13023 Background: Next generation sequencing (NGS) in hematological tumors is increasingly shaping clinical treatment decisions at the point of care. While the impact of NGS panels in solid tumors is largely therapeutic, targeted sequencing in hematological tumors can additionally provide diagnostic and prognostic insights. Additional data generated in hematological tumor sequencing makes manual interpretation and annotation of variants tedious and non-scalable. In this study we compared hematological tumor variant interpretation using an artificial intelligence decision-support system, Watsonä for Genomics (WfG), with expert guided manual curation. Methods: Patients with hematological tumors at Hallym University, College of Medicine between December 2017 and December 2018, were sequenced using the 54 gene Illumina TruSight Myeloid Panel. WfG interpreted and annotated all patients’ sequencing results, a subset of which were assessed manually to ascertain concordance. Results: 54 South Korean patients with hematological malignancies were analyzed (23 Acute Myeloid Leukemia, 12 myeloproliferative neoplasm, 5 myelodysplastic syndrome, 5 multiple myeloma and 9 others). Comparison of manual and WfG interpretation of 10 randomly selected cases yielded 90% (9/10) concordance and identification of 9 clinically actionable variants (33%) not found in manual interpretation. In total, WfG identified that 71% (38/54) of all cases had at least one clinically actionable therapeutic alteration (a variant targeted by a US FDA approved drug, off-label drug, or clinical trial). 33% (18/54) of cases had genes that were targeted by a US FDA approved therapy including JAK2, IDH1, IDH2, and FLT3. In cases without therapeutic alterations, WfG identified diagnostic or prognostic insights in an additional 20% (11/54) of patients. 9% (5/54) had no clinically actionable information. Conclusions: WfG variant interpretation correlated well with manually curated expert opinion and identified clinically actionable insights missed by manual interpretation. WfG has obviated the need for labor-intensive manual curation of clinical trials and therapy, enabling our center to exponentially scale our NGS operations.
Phase 1b study of PV-10 and anti-PD-1 in advanced cutaneous melanoma.
Authors: Sanjiv S. Agarwala, Merrick I. Ross, Jonathan S. Zager, Keisuke Shirai, Richard Essner, Bernard Mark Smithers, Victoria Atkinson, Eric Andrew Wachter
Journal: Journal of Clinical Oncology (2019)

9559 Background: PV-10 (rose bengal disodium) is a small molecule oncolytic immunotherapy in development for solid tumors, where intralesional injection can yield immunogenic cell death and tumor-specific reactivity in circulating T cells. It has been administered as a single agent to over 300 cutaneous melanoma patients (pts) in Phase 1-3 testing and under expanded access. Methods: Study PV-10-MM-1201 (NCT02557321) is a Phase 1b/2 study of PV-10 in combination with anti-PD-1 (pembrolizumab) for patients with advanced cutaneous melanoma (Stage IIIB-IV M1c). Patients must have at least 1 injectable lesion and be candidates for pembrolizumab. In Phase 1b pts receive combination treatment q3w for 5 cycles then pembrolizumab alone for up to 24 months; the primary endpoint is safety and tolerability with objective response rate (ORR) and progression free survival (PFS) key secondary endpoints (by RECIST 1.1 after 5 cycles then q12w). Results: Full accrual of the Main Cohort of Phase 1b was reached in April 2018, with an intent-to-treat population of 23 pts (3 IIIC/IIID, 8 M1a, 7 M1b, 5 M1c; median age 70 years, range 28-90). Treatment-Emergent Adverse Events (TEAEs) were consistent with established patterns for each drug, principally Grade 1-2 injection site reactions attributed to PV-10 and Grade 1-3 immune-mediated reactions attributed to pembrolizumab, with no significant overlap or unexpected toxicities: 6 Grade 1-2 TEAEs were attributed to the combination in 6 pts. Response of injected lesions was 77% CR (3% PR) achieved after a median of 3 injections / lesion administered over a median of 4 treatment cycles of PV-10 (range 1-5). Most pts had extensive uninjected tumor burden, and a best overall response of CR was achieved in 9% of pts (1 each M1a and M1b), with 57% of pts achieving PR (including 4 of 5 M1c pts). Response assessment is ongoing; final ORR and PFS data for the Main Cohort will be presented along with correlative T cell data. Conclusions: The primary endpoint for Phase 1b was met, with acceptable safety and tolerability of the combination and no unexpected safety issues identified. Two Phase 1b Expansion Cohorts (24 pts each) have been opened to pts refractory to prior checkpoint inhibition and pts with in-transit or satellite disease. Clinical trial information: NCT02557321.