tbuckley/cabot-search huggingface dataset:
Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti–PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer
Authors: Canan Kasikara, Viralkumar Davra, David Calianese, Ke Geng, Thomas E. Spires, Michael Quigley, Michael Wichroski, Ganapathy Sriram, Lucia Suarez-Lopez, Michael B. Yaffe, Sergei V. Kotenko, Mariana S. De Lorenzo, Raymond B. Birge
Journal: Cancer Research (2019)

Abstract Tyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS→TAM receptor→PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti–PD-1 alone or in combination. Tyro3, Axl, and Mertk were differentially expressed on multiple cell subtypes in the tumor microenvironment. Although monotherapeutic administration of either pan-TAM kinase inhibitor (BMS-777607) or anti–PD-1 mAb therapy showed partial antitumor activity, combined treatment of BMS-777607 with anti–PD-1 significantly decreased tumor growth and incidence of lung metastasis. Moreover, combined treatment with BMS-777607 and anti–PD-1 showed increased infiltration of immune stimulatory T cells versus either monotherapy treatment alone. RNA NanoString profiling showed enhanced infiltration of antitumor effector T cells and a skewed immunogenic immune profile. Proinflammatory cytokines increased with combinational treatment. Together, these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti–PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy. Significance: These findings show that pan-inhibition of TAM receptors in combination with anti–PD-1 may have clinical value as cancer therapeutics to promote an inflammatory tumor microenvironment and improve host antitumor immunity.
Late toxicity described using patient reported outcomes measures (PROMS) in men treated with salvage radiation following primary high intensity focal ultrasound (HIFU) for localized prostate cancer.
Authors: Reena Davda, Clement Orczyk, Mark Prentice, Aylin Sarova, Manit Arya, Hashim Ahmed, Mark Emberton, Caroline Moore, Anita Mitra, Heather Ann Payne
Journal: Journal of Clinical Oncology (2019)

131 Background: In primary treatment of localised prostate cancer, minimally invasive ablative therapies such as HIFU aim to achieve cancer control whilst offering a potentially favourable toxicity profile. At 5 years median follow up, 12% of patients treated with focal HIFU require salvage therapy. PROMS using Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC‐CP) provide a validated and clinically relevant tool to assess and quantify side effects from pelvic radiotherapy. There is limited data on late toxicity using PROMs with salvage radiotherapy in this setting. Methods: Retrospective analysis from prospectively collected data of 28 patients who received salvage radiotherapy at our institution 2010-2018 was performed. Late bowel and urinary toxicity measured by EPIC-CP is reported. Results: Gleason score at diagnosis: 3+3 4/28; 3+4 22/28; 4+3 2/28. HIFU treatment received: focal: 9/28; whole gland: 6/28; focal and redo focal: 7/28; focal and redo whole gland: 1/28; whole gland and redo: 5/28. All patients had mpMRI and biopsy proven recurrence with median PSA 6.6 ng/ml (0.57- 30.89). Median age at radiation was 67 years (55-80). Patients received 74 Gy to the prostate and 4 patients received additional pelvic lymph node irradiation. Three men received conformal radiotherapy (multiphase technique) and 25 arcing intensity modulated radiotherapy with hormone therapy as per risk stratification. Cumulative incidence of toxicity is reported at median follow-up of 43 months (7-99). Overall urinary function: no problem 8/28; very small problem 4/28; small problem 7/28; moderate problem 5/28; big problem 4/28 Urinary Incontinence Symptom Score: 2.5/12 (0-12) Urinary Irritation /Obstructive Symptom Score: 3.1/12 (0-12) Bowel Symptom Score: 3.5/12 (0-11) Biochemical relapse has occurred in 2/28 patients. Conclusions: Functional and oncological outcomes for a greater number of patients treated with minimally invasive ablative therapies followed by salvage radiation are required, however this data suggests radiation is a well-tolerated and effective salvage option following primary HIFU.
Continuous portal triad clamping in hepatectomy for primary liver cancer with chronic liver disease: A prospective controlled study.
Authors: Yi Wang, Wei Wang, Ruiliang Ge, Lei Yuan, Yanfu Sun, Gongtian Wei
Journal: Journal of Clinical Oncology (2015)

e15165 Background: In partial hepatectomy for primary liver cancer (PLC), portal triad clamping (PTC) is an efficient tool to minimize bleeding during parenchymal transection. Currently, most surgeons use intermittent PTC (IPTC) to attenuate the ischemic-reperfusion (IR) injury when anticipated clamping times are longer than 30 min. However, IPTC is associated with drawback of additional bleeding during reperfusion. To evaluate the potential risk of IR insult and intraoperative blood loss, we designed a prospective controlled trial comparing continuous PTC (CPTC) exceeding 30 minutes with IPTC in patients with CLD who were operated on for PLC. Methods: Between June 2011 and May 2013, patients with CLD undergoing hepatectomy for PLC were candidates for the study. They were assigned to two surgical teams utilizing different clamping strategies. In the CPTC group clamping was maintained until cut surface hemostasis had been archived, whereas clamping for 15 min was followed by 5 min of declamping in the IPTC group. Only those with total clamping period exceeding 30 min (including 30 min) were reviewed. The type of operative procedure, operative time, estimated blood loss (EBL), blood transfusion and postoperative liver function were observed and compared between the two groups. The study protocol was approved by the Ethics Committee of our institution. Results: There were 69 patients in CPTC group with clamping period ranging between 30 to 50 min and 73 patients in IPTC group with the same range of total clamping period. The baseline characteristics of patients, the types of hepatectomy and total clamping times were not significantly differed between the two groups. There were no operative deaths or postoperative liver failure in either group. Comparing with those in the IPTC group, the patients in the CPTC group had lower EBL (P < 0.001), lower transfusion requirement (P < 0.001) and, surprisingly, significantly less alteration in postoperative liver function. Conclusions: In complex liver resections where PTC longer than 30 min is required, continuous clamping up to 50 min is safe even in the diseased liver, and intermittent clamping strategy is not necessary as it only results in higher blood loss.
Abstract P317: Bidirectional Associations Between Accelerometer-Measured Sedentary Time, Physical Activity, and Weight Over 10 Years in the CARDIA Study
Authors: Bethany Barone Gibbs, David Aaby, Juned Siddique, Jared Reis, Kara Whitaker, Barbara Sternfeld, Kelley Pettee Gabriel
Journal: Circulation (2019)

Introduction: Though a pattern of high sedentary time (ST) with low light-intensity (LPA) and moderate-to-vigorous intensity PA (MVPA) is associated with weight gain, other data suggest excess weight may precede this behavioral profile in the causal pathway. Objective: To investigate bidirectional associations between activity patterns and weight over 10 years. Methods: Analysis included 886 CARDIA participants (aged 38-50 years, 62% female, 38% black) with weight and accelerometry (≥4 d with ≥10 hr/d) at the year 20 (ActiGraph 7164; 2005-6) and year 30 (ActiGraph wGT3X-BT; 2015-6) exams. Accelerometer data were harmonized and expressed as counts per minute (cpm) and time-dependent (min/d) intensity categories (ST, LPA, MVPA). Linear regression models were constructed to estimate adjusted associations of baseline (Y20) activity with 10-y change in weight and vice versa. Model 2 further adjusted for concurrent 10-y change in the independent variable. When intensity categories were the independent variables, regression coefficients estimated the effect of replacing ST with LPA or MVPA, adjusted for accelerometer wear time. Results: Over the 10-y follow-up, weight increased by a mean 2.55 ± 8.05 kg; mean total activity (cpm) decreased by -50 ± 153 cpm. Higher baseline cpm and MVPA were associated with a reduced 10-y weight gain (Model 1); further adjustment for concurrent changes in activity (Model 2) strengthened associations such that both baseline LPA and MVPA were each related to reduced 10-y weight gain ( Table ). Conversely, higher baseline weight was associated with unfavorable changes in activity profile such that ST increased and cpm, LPA, and MVPA decreased over the 10-y follow-up (Model 1); results were similar after adjustment for concurrent weight change (Model 2; Table ). Conclusions: Poor activity profiles and body weight were bidirectionally related. Interventions that work simultaneously to replace ST with LPA and MVPA while also using other methods to address excess weight may be optimal.
Cell-free DNA analysis in renal cell carcinoma: Comparison with tumor sequencing and correlation with response to therapy.
Authors: Lana Hamieh, Amin Nassar, Kathryn Lasseter, Barbara Ogorek, Rana R. McKay, Aaron Thorner, Anwesha Nag, Gwo-Shu Mary Lee, Rupal Satish Bhatt, Mark Pomerantz, Matthew L Freedman, David J. Kwiatkowski, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2019)

655 Background: Massively parallel sequencing (MPS) of circulating-free DNA (cfDNA) is seeing increasing use in multiple cancer types. There is little data on its use in metastatic renal cell carcinoma (mRCC) as a tool for prognostication and disease monitoring. Methods: cfDNA was extracted from 63 blood samples of 40 metastatic RCC patients (pts). Serial samples were obtained in 12 of 40 (30%) pts (median = 1, range = 1-7). cfDNA was used for targeted MPS using a custom bait-set of 27 genes commonly mutated in RCC. Variants observed in at least 3 reads, in both read directions, and at an allele frequency (AF) of ≥0.5% for single nucleotide variants (SNV), or in 2 reads and AF of ≥0.2% for small indels, were candidate variants validated by Sanger sequencing or amplicon MPS (aMPS). All mutations identified in cfDNA were also assessed in matched patient WBC DNA using aMPS and Sanger sequencing. Tumor specimens from 23 pts were also sequenced in parallel using our institutional OncoPanel assay that assesses 275-447 cancer-associated genes and results were compared with those seen in the cfDNA. Results: Thirty-one of 38 (82%) candidate variants were validated in 17 of 40 pts. Ten of those (32%) from 10 pts were also detected in WBC DNA, 3 of which were germline and 7 were at low mosaic frequency and likely reflected clonal hematopoiesis (CH). The remaining 21 variants validated in cfDNA were in TP53 (6), PBRM1 (3), SETD2 (3), VHL (2), ATM (2), NF2 (2), PTEN (1), PIK3CA (1), and MTOR (1). Two of 17 (12%) pts without tumor mutation analysis had 4 validated variants seen in cfDNA only. 10 of 23 (43%) pts with tumor mutation analysis had one or more variants seen in both tumor DNA and cfDNA. Three of the 23 had mutations seen only in cfDNA. Pts with any mutation in cfDNA (n = 14) had a significantly shorter overall survival in comparison to those without a finding (p &lt; 0.001). Among 12 pts with serial samples, 5 had cfDNA variants identified. Response to therapy correlated with variant prevalence in all 5, including 2 with significant partial responses. Conclusions: This study suggests that paired tumor–cfDNA analysis has value in the assessment of response to therapy in RCC. Further analysis is proceeding.
Abstract P007: Age and Gender Differences in Response to Repeat Blood Pressure Measurement After Brief Rest Period
Authors: Sarina Sachdev, Hassan Tahir, Landai Nguyen, Bassam Omar, Christopher Malozzi, G. Mustafa Awan, Farnoosh Rahimi
Journal: Circulation (2019)

Background: Office-based blood pressure (BP) measurement is a snapshot of a patient’s ambulatory BP, and is subject to variations which may influence management. The objective of this study is to assess the effect of age and gender on repeat BP measurement after a brief rest period in an outpatient cardiology clinic. Methods: Patient charts reviewed in University-based cardiology clinic identified 170 encounters which contained BP re-measurement data due to elevated initial BP of &gt; 130/80 mmHg. BP was measured initially by a nurse, with the patient in a sitting position and the arm resting at the level of the heart. If BP was &gt; 130/80 mmHg, it was repeated by physician after resting the patient for 15 minutes. There were: 86 males (51%); 84 females (49%); 113 (66%) elderly patients ≥ 60 years; 57 (34%) younger patients &lt; 60 years. Results: Allowing 15 minutes of rest resulted in decrease in the systolic BP (SBP) from 153 ± 27 mmHg to 145 ± 27 mmHg (P = 0.003), and decrease in the diastolic BP (DBP) from 87 ± 16 mmHg to 83 ± 15 mmHg (P = 0.04) in the whole patient cohort. The decrease in SBP was 8 mmHg in both males and females (P = NS); while the decrease in DBP was 5 mmHg in males and 2 mmHg in females (P = 0.04). The decrease in SBP was 11 mmHg in the elderly patients compared to 2 mmHg in the younger patients (P = 0.02), while the decrease in DBP was 3 mmHg in the elderly patients compared with 4 mmHg in the younger patients (P = NS). Conclusion: Hypertension is a challenging public health problem. JNC guidelines recommend that prior to BP measurement, persons should be seated quietly for at least 5 minutes in a chair, with feet on the floor, and arm supported at heart level. This resulted in a significant decrease in BP in our patients. In this study we found that, after a brief rest period, males and females decrease SBP to the same extent; males drop DBP greater than females; patients ≥ 60 years of age drop SBP greater than patients &lt; 60 years of age. With a high reported prevalence rates of White-coat hypertension in the elderly, between 15% and 25%, this is a clinically significant observation that reinforces that physicians should remeasure the blood pressure, especially the subset of males and the elderly, in whom a bigger decrement may be detected in blood pressure measurement after a brief rest period.
DNA repair landscape of discordant sibling pairs from hereditary breast cancer families.
Authors: Yongli Ji, Tiffany Rounds, Julie Dragon, Jeffery Bond, Susan Wallace, Joann Sweasy, Marie Wood
Journal: Journal of Clinical Oncology (2015)

1557 Background: DNA repair plays a significant role in carcinogenesis. The aim of this study is to describe the landscape of germline DNA sequence variation among discordant sister pairs (one with and one without breast cancer) from breast cancer families with an emphasis on DNA repair pathways. Methods: Six sister-pairs were identified from a cohort of high-risk women at University of Vermont Cancer Center. To be eligible for inclusion families must have at least 3 cases of breast cancer, 1 diagnosed under age 50. The unaffected sister must be older than the affected sister’s age at diagnosis. Germline DNA was isolated and full exome sequencing was performed for all 12 women. Computational genomics were utilized to identify putative single nucleotide polymorphisms in DNA repair pathway associated genes. Candidate variants were identified based on the quality of the variant call, distribution among sibling pairs, frequency in the general population, and predicted functional consequences. Results: We obtained high-quality exome sequences for each individual. We identified deleterious mutations in several known cancer-associated pathways, including DNA repair. The genetic variants and pathways include (see table): TSC1 (tuberous sclerosis complex) is a tumor suppressor gene; WRN is a member of the RECQ helicase family involved in DNA repair and maintaining genomic stability; PMS2 (postmeiotic segregation increased 2) is involved in mismatch repair;POLQ is a DNA polymerase; POLE is a DNA replicative polymerase. Conclusions: Using 6 discordant sister pairs from high-risk families we were able to obtain high-quality sequences and identify several interesting variants in DNA repair pathways. We have enrolled additional sister pairs and are funded to sequence and analyze 8 additional pairs. Future studies will focus on identification of rare familial variants and understanding the functional significance of identified variants. Variant finding. Gene Variant Findings Rare? Predicted Damaging? TSC1 R37H Het in one case ✓ ✓ WRN M1187V Hets in 2 cases ✓ ✓ WRN C1367R 4/6 cases; p = 0.0625 ≤ 0.3 ✓ PMS2 N335S Het in one case ✓ ✓ POLQ Q1546X Het in one case ✓ Gained stop codon POLE A252V Hets in 2 cases ≤ 0.1 Non- synonymous
Abstract P162: Gout and Risk for Incident Heart Failure, Coronary Heart Disease and Stroke: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Authors: Lisandro D Colantonio, Kenneth G Saag, Jasvinder Singh, Richard Reynolds, Angelo Gaffo, Timothy B Plante, Jeffrey R Curtis, S L Bridges, Emily B Levitan, Ninad Chaudhary, George Howard, Monika M Safford, Paul Muntner, Marguerite R Irvin
Journal: Circulation (2019)

Background: Gout has been associated with a higher risk for coronary heart disease (CHD) and stroke in some but not all prior studies. There are few data available on the risk for incident heart failure associated with gout. Objective: To compare the incidence of heart failure, CHD and stroke among adults with versus without gout. Methods: We used data from 5,499 black and white REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants &gt;65 years of age with Medicare coverage without a history of heart failure, CHD or stroke at baseline in 2003-2007. Gout was defined by (1) ≥1 inpatient claim or ≥2 outpatient or carrier claims on separate days with an ICD-9 diagnosis code for gout (274.x) in Medicare prior to each participant’s baseline study visit, or (2) use of allopurinol, colchicine or probenecid based on a baseline medication inventory. REGARDS study participants were followed through December 31, 2015 for heart failure, CHD, and stroke events, which were adjudicated. Results: Among participants included in the current analysis (mean age 72 years, 45% male, 31% black), 223 (4%) had gout. The incidence of heart failure and CHD was higher, while the incidence of stroke was similar, among participants with versus without gout ( Figure ). After adjustment for sociodemographic and cardiovascular risk factors, hazard ratios comparing participants with versus without gout were 2.41 (95%CI 1.60, 3.64) for heart failure, 1.41 (0.96, 2.07) for CHD and 0.96 (0.58, 1.59) for stroke. There was no statistically significant effect modification by race or gender. In a sensitivity analysis defining gout only based on Medicare diagnosis codes, multivariable-adjusted hazard ratios for heart failure, CHD and stroke associated with gout were 2.25 (95%CI 1.41, 3.59), 1.26 (0.79, 1.99) and 0.83 (0.45, 1.52), respectively. Conclusion: After accounting for sociodemographic and cardiovascular risk factors, gout remains strongly associated with incident heart failure but not with incident CHD or stroke.
An investigation of early discontinuation of temozolomide (TMZ) in patients with glioblastoma.
Authors: Kala Hill, Shan Jiang, Dipen Patel, Kate Worthington
Journal: Journal of Clinical Oncology (2015)

e17769 Background: Discontinuation of oncologic therapy is known to be a multi-factorial phenomenon, with clinical, financial, and other factors being possible contributors. This analysis examines potential variables that may have a significant impact on early discontinuation of TMZ. Methods: Medical and pharmacy claims were analyzed in the IMS Pharmetrics Lifelink Plus database. Adult patients diagnosed with malignant brain cancer (ICD9-CM, 191.XX), treated with TMZ and having undergone brain-related surgery 90 days prior to the first TMZ dose, as well as having had at least 8 months of continuous enrollment post-index, were selected. The index date was defined as the first claim date for TMZ. Early discontinuation was defined as cessation of TMZ prior to 7 treatment cycles. Out-of-pocket (OOP) cost was calculated as the amount allowed minus the amount paid. An MRI within 30 days of TMZ discontinuation was used as a proxy for relapsed/recurrent glioblastoma multiforme (GBM). Early discontinuation was examined using a Cox proportional-hazards model controlling for age, gender, health plan, geographic region, OOP cost, number of claims, co-diagnoses, bevacizumab use and relapsed/recurrent GBM. Since the distribution of cost data is typically truncated and positively skewed, these were analyzed using a generalized linear model (GLM) using a 'gamma' distribution. Results: Among a total of 1131 patients, 394 (35%) discontinued TMZ early. Their mean age was 52.2 years (SD = 10.7) and 44% were female. The mean OOP cost per patient per month was $774 (SD = $2364) for patients discontinuing early, and $498 (SD = $981) for patients completing at least 6 maintenance cycles (p = 0.01). Age, number of claims, number of co-diagnoses, bevacizumab use and relapsed/recurrent GBM were all significant predictors of early discontinuation (p < 0.05) in the Cox proportional-hazards model. In the GLM model, early discontinuers were shown to have a 27% greater monthly OOP cost (p < 0.0002). Conclusions: This investigation demonstrates the importance of specific clinical factors being associated with early discontinuation of TMZ, as well as a meaningful increase in monthly OOP costs for patients that discontinue TMZ early.