tbuckley/cabot-search huggingface dataset:
Therapeutic effect of local Interleukin-15 with radiotherapy in breast cancer.
Authors: Elena Garcia Martinez, Karsten A Pilones, Joseph Aryankalayil, Silvia Formenti, Sandra Demaria
Journal: Journal of Clinical Oncology (2017)

158 Background: Interleukin (IL)-15 is a key regulator of T cell homeostasis with activity in cancer and a favorable toxicity profile compared to IL-2. IL-15 stimulates the proliferation and effector differentiation of CD8 + T cells, and the proliferation and activation of natural killer (NK) cells. We observed IL-15 upregulation by gene arrays in radiotherapy (RT)-treated TSA mouse breast cancer, suggesting that it may play a role in RT-induced anti-tumor immunity. However, the upregulation was modest prompting us to test the hypothesis that administration of IL-15 may enhance in situ vaccination by RT. Methods: BALB/c mice with established poorly immunogenic TSA tumors were sham-treated, treated with tumor-targeted RT (8GyX3 days), IL-15 given peri-tumorally (2 ug/mouse/day for 10 days) starting on the first day of RT, and RT+IL-15, and monitored for tumor growth and survival. Tumor infiltrating lymphocytes (TIL) were analyzed by flow cytometry and immunostaining. In some experiments, Batf3 -/- mice were used as tumor recipient. Results: IL-15 by itself was ineffective, but it significantly increased tumor control by RT (p=0.0007, RT versus RT+IL-15) leading to complete responses in 50% of the mice, most of them durable. Analysis of TILs showed significantly increased NK cells (CD45 + CD3 - DX5 + ) in tumors treated with RT+IL-15 (p&lt;0.0004 versus sham-treated; p&lt;0.02 versus RT). NK cells were also more activated as indicated by expression of CD122 and CD137. Depletion of NK cells completely abrogated the therapeutic effect of the combination, while CD8 T cell depletion reduced tumor control and rate of complete regression. Interestingly, Batf3-/- mice, which lack CD103+ DCs, showed reduced response to RT+IL-15 compared to WT mice. Conclusions: Data suggest that local IL-15 with RT is an effective strategy to induce anti-tumor immunity to poorly immunogenic breast cancer. NK cells are critical mediators of the response, and may act by both killing tumor cells and promoting priming of CD8 T cells. Experiments are ongoing to determine the mechanisms of durable complete responses. &lt;footer&gt;Acknowledgments: IL-15 was provided by NCI BRB. Garcia-Martinez E was supported by GEICAM grant.&lt;/footer&gt;
Concordance of Non–Low-Risk Disease Among Pairs of Brothers With Prostate Cancer
Authors: Fredrik Jansson, Linda Drevin, Thomas Frisell, Pär Stattin, Ola Bratt, Olof Akre
Journal: Journal of Clinical Oncology (2018)

Purpose Prostate cancer among first-degree relatives is a strong risk factor for diagnosis of prostate cancer, and the contribution of heritable factors in prostate cancer etiology is high. We investigated how the concordance of non-low-risk prostate cancer among brothers is affected by their genetic relation. Methods We identified 4,262 pairs of brothers with prostate cancer in the Prostate Cancer Database Sweden. Their cancers were categorized as low risk (Gleason score ≤ 6; clinical stage T1-2, Nx/N0, Mx/M0; and prostate-specific antigen ≤ 10 ng/mL) or non-low risk. The odds ratio (OR) for concordance of non-low-risk cancer was calculated with logistic regression for the different types of fraternity (monozygotic twins, dizygotic twins, full brothers, and half-brothers) Results Among monozygotic twins who both were diagnosed with prostate cancer, the OR for both brothers being in the non-low-risk category was 3.82 (95% CI, 0.99 to 16.72) after adjusting for age and year of diagnosis. Among full brothers, the corresponding adjusted OR was 1.21 (95% CI, 1.04 to 1.39). When the analysis was restricted to brothers who both were diagnosed within 4 years, the results were similar. Conclusion Non-low-risk prostate cancer has a heritable pattern suggesting shared genetic factors, with the highest concordance among monozygotic twins. Our results suggest that a man whose brother has been diagnosed with a non-low-risk prostate cancer is at a clinically relevant increased risk of developing an aggressive prostate cancer himself.
MVA-5T4 immunotherapy and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): An open-label, randomized phase I/II trial.
Authors: Martin Scurr, Tom Pembroke, Richard Adams, Daniel Blount, Alison Brewster, Sarah Gwynne, Richard Harrop, Robert Jones, Robert Hills, Awen Gallimore, Andrew Godkin
Journal: Journal of Clinical Oncology (2017)

154 Background: Current immunotherapies including checkpoint inhibitors and vaccines for advanced colorectal cancer (CRC) have been largely ineffective. We hypothesized that combining an MVA-based vaccine targeting the tumor-associated antigen 5T4 (TroVax) with low-dose cyclophosphamide to deplete Foxp3 + regulatory T-cells (Tregs), could improve immunological responses and patient outcomes. Methods: In this open-label phase I/II clinical trial, TaCTiCC (TroVax and Cyclophosphamide Treatment in Colorectal Cancer) 53 patients with inoperable metastatic CRC were randomized to receive either no treatment (group 1, n=8), metronomic low-dose CPM (50mg B.D. during treatment weeks 1&amp;3; group 2, n=9), TroVax only (6 i.m. injections weeks 4 to 16, group 3, n=18), or low-dose CPM followed by TroVax (group 4, n=18). The primary endpoint was boosted anti-5T4 responses at week 7, as measured by increased T-cell and antibody responses; secondary endpoints included progression-free (PFS)/overall survival (OS), and anti-5T4 responses over the trial period. Results: CPM depleted Tregs in 21/27 patients during treatment week 3 (p=0.0045), resulting in significantly prolonged PFS amongst groups 2&amp;4 over group 1 (5.0 vs. 2.5 months, HR=0.17 95% CI 0.048-0.62, p=0.0072). TroVax induced a &gt;2-fold increase in anti-5T4 immune responses in 15/36 group 3&amp;4 patients; these patients experienced significantly prolonged median PFS (6.5 vs. 2.4 months, HR 0.31 95% CI 0.14-0.65, p=0.0022) and OS (20 vs. 12 months, HR=0.37 95% CI 0.17-0.82, p=0.014). Combination of CPM &amp; TroVax was not significantly superior. The primary endpoint at a single timepoint was not met since CPM-induced responses declined by week 7, and TroVax-induced responses were greatest at weeks 10-16. No serious adverse events were reported. Conclusions: Both CPM and TroVax induced highly beneficial anti-tumor immune responses resulting in significantly prolonged survival of end-stage CRC patients without toxicity. This is the first study to show a clear benefit of immunotherapy in advanced CRC, and suggests this approach may be superior (and less toxic) to continuous palliative chemotherapy in these patients. Clinical trial information: 54669986.
Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity
Authors: Hyun Cheol Roh, Linus T.Y. Tsai, Mengle Shao, Danielle Tenen, Yachen Shen, Manju Kumari, Anna Lyubetskaya, Christopher Jacobs, Brian Dawes, Rana K. Gupta, Evan D. Rosen
Journal: Cell Metabolism (2018)
Social Worker–Aided Palliative Care Intervention in High-risk Patients With Heart Failure (SWAP-HF)
Authors: Arden E. O’Donnell, Kristen G. Schaefer, Lynne W. Stevenson, Kristen DeVoe, Kayley Walsh, Mandeep R. Mehra, Akshay S. Desai
Journal: JAMA Cardiology (2018)

Palliative care considerations are typically introduced late in the disease trajectory of patients with advanced heart failure (HF), and access to specialty-level palliative care may be limited.To determine if early initiation of goals of care conversations by a palliative care-trained social worker would improve prognostic understanding, elicit advanced care preferences, and influence care plans for high-risk patients discharged after HF hospitalization.This prospective, randomized clinical trial of a social worker-led palliative care intervention vs usual care analyzed patients recently hospitalized for management of acute HF who had risk factors for poor prognosis. Analyses were conducted by intention to treat.Key components of the social worker-led intervention included a structured evaluation of prognostic understanding, end-of-life preferences, symptom burden, and quality of life with routine review by a palliative care physician; communication of this information to treating clinicians; and longitudinal follow-up in the ambulatory setting.Percentage of patients with physician-level documentation of advanced care preferences and the degree of alignment between patient and cardiologist expectations of prognosis at 6 months.The study population (N = 50) had a mean (SD) age of 72 (11) years and had a mean (SD) left ventricular ejection fraction of 0.33 (13). Of 50 patients, 41 (82%) had been hospitalized more than once for HF management within 12 months of enrollment. At enrollment, treating physicians anticipated death within a year for 32 patients (64%), but 42 patients (84%) predicted their life expectancy to be longer than 5 years. At 6 months, more patients in the intervention group than in the control group had physician-level documentation of advanced care preferences in the electronic health record (17 [65%] vs 8 [33%]; χ2 = 5.1; P = .02). Surviving patients allocated to intervention were also more likely to revise their baseline prognostic assessment in a direction consistent with the physician's assessment (15 [94%] vs 4 [26%]; χ2 = 14.7; P < .001). Among the 31 survivors at 6 months, there was no measured difference between groups in depression, anxiety, or quality-of-life scores.Patients at high risk for mortality from HF frequently overestimate their life expectancy. Without an adverse impact on quality of life, prognostic understanding and patient-physician communication regarding goals of care may be enhanced by a focused, social worker-led palliative care intervention that begins in the hospital and continues in the outpatient setting.clinicaltrials.gov Identifier: NCT02805712.
Healthy controls in nonalcoholic fatty liver disease management: A biomedical research perspective
Authors: Saumya Pandey
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: The recently published article by Takyar et al. strongly suggests that nonalcoholic fatty liver disease (NAFLD) has emerged as a major public health problem in ethnically disparate population(s) in the postgenomic era.1 Healthy volunteers (disease‐free controls) are indeed essential and/or critical for stringent, robust, and reliable biomedical research worldwide, including the Western world as well as the Asian Pacific region with a significant proportion of NAFLD patients.2 The cross‐sectional study's overall quality could have been enhanced with more meaningful interpretation of data if the investigators had maintained homogeneity in case and control numbers (3,160 subjects/149 trials: 101 noninterventional, 33 interventional, and 15 vaccine trials) and incorporated age‐matched controls; a major study strength is the stratified/subgroup analysis in females and males with relevant statistical adjustments for clinical covariates/parameters (phosphorylated nuclear factor, alanine aminotransferase cut‐off titers ≥20 for women or ≥31 for men and body mass index >25). Written informed consent is a core tenet of bioethics in good‐practice research; healthy controls/volunteers and NAFLD cases in clinical trials should be explained the rationale of participation in the study by organizing a one‐to‐one interview and/or counseling/awareness lecture session. I wish to add that successful strategies utilizing meaningful participation of age‐matched, healthy, disease‐free controls of same ethnicity in a population‐based disease management clinical research study protocol(s) are warranted in the near future so as to provide a broad‐spectral public health research model in terms of a cost‐effective, patient‐friendly, timeline‐based global collaborative environment with pooled samples of diverse genetic landscapes. One of the major challenges in the hepatology research field is the relative paucity of clinically relevant predictive and prognostic biomarkers to identify and accordingly stratify susceptible individuals at risk of developing NAFLD; this demerit/drawback can be significantly diminished by recruiting age‐matched, healthy controls of the same ethnicity as NAFLD cases so that the possibility of population admixture is ruled out. Furthermore, selective or combined use of different molecular computed tomography/magnetic resonance imaging diagnostic modalities in liver imaging (elastography, iron/fat deposition) is a promising strategy for monitoring liver‐tissue–specific aberrations in disease progression in asymptomatic versus symptomatic study subjects.4 Targeting interrelated biochemical/metabolic pathways, especially transmembrane receptors and drug metabolizing enzymes/transporters, may be efficacious in unraveling the cellular/molecular mechanisms in NAFLD pathogenesis.
Tumor mutational load in gynecological and breast cancer.
Authors: Filipa Lynce, Joanne Xiu, Elias Obeid, Antoinette R. Tan, Zoran Gatalica, Claudine Isaacs, Paula Raffin Pohlmann
Journal: Journal of Clinical Oncology (2017)

44 Background: Lack of test standardization and conflicting results on PD1 and PD-L1 immunohistochemistry (IHC) assays challenge their use as predictive biomarkers for checkpoint inhibitors. High tumor mutational load (TML) has been linked to therapeutic response with immune checkpoint inhibition in melanoma, lung and colorectal cancer. Herein, we explore association of TML and PD1/PD-L1 expression in gynecological (GC) and breast cancer (BC). As secondary aim we explore the association of TML with BRCA1/2 mutations. Methods: De-identified data from molecular profiling on GC and BC tumors from the CARIS Life Sciences database was analyzed after obtaining IRB approval. TML was defined as the total number of nonsynonymous, somatic mutations per Mb sequenced with a 592-gene panel. PD-1 IHC was tested on Tumor Infiltrating Lymphocytes (TIL) with the cutoff of 1/HPF; PD-L1 expression was measured on tumor cells with the cutoff of 2+, 5%. Biomarker association was tested with ANOVA test (SPSS v23, IBM). Results: As shown in table, cervical (CC) and endometrial cancers (EC) had the highest TML and squamous CC and triple negative BC (TNBC) tumors with highest PD-L1. In EC, MSI-H was associated with higher TML when compared to MSS (20.1 vs. 6.1, p&lt;0.001); 4 POLE-mutated tumors all carried TML (36-678) higher than mean (11.5). TML was not associated with PD1 or PDL1 positivity in any of the diseases. BRCA1/2 mutations were associated with higher mean TML in ovarian cancer (OC) (6.8 vs. 5.4 in wild type, p&lt;0.001) but not in BC (6.3 vs. 6.8 in wild type, p=0.48). Conclusions: In this sample of patients who underwent molecular profiling, there was no association between TML and PD1 or PD-L1 expression. Association between BRCA1/2 tumor mutations and TML in OC is worth exploring. High TML in CC and EC support the development of immunotherapy for these diseases. [Table: see text]
A question of ‘fairness’: Why ethics should factor in the Court of Arbitration for Sport’s decision on the IAAF Hyperandrogenism Regulations
Authors: Silvia Camporesi
Journal: British Journal of Sports Medicine (2018)

The Court of Arbitration for Sport (CAS) in Lausanne, Switzerland, is an international court tasked with settling legal disputes related to sport. This editorial comments on the ongoing Dutee Chand vs Athletics Federation of India (AFI) & International Association of Athletics Federations (IAAF) case1 (see box 1) which pertains to whether there is sufficient evidence to demonstrate a correlation between levels of endogenous testosterone and a competitive advantage in track and field.Box 1 
### Background on Dutee Chand vs AFI & IAAF case

The International Association of Athletics Federations (IAAF) Hyperandrogenism Regulations were in place from 1 May 2011 to 24 July 2015, when they were suspended by the Court of Arbitration for Sport (CAS). The regulations stated that female athletes who naturally produce levels of testosterone higher than 10 nmol/L were not eligible to compete in the female category and would need to take androgen suppressive drugs to resume competition. Dutee Chand, an Indian sprinter, was asked to abide by these Regulations in July 2014 and appealed to the CAS on grounds that the Regulations unfairly discriminated against women who naturally produced higher levels of testosterone. The CAS was not satisfied with the evidence the IAAF provided and …
Exposure-response (E-R) analysis of rilotumumab (R, AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer.
Authors: Min Zhu, Rui Tang, Sameer Doshi, Kelly S. Oliner, Steven Kathman, Per Olsson Gisleskog, Sarita Dubey, Yizhou Jiang, Ross C. Donehower, Timothy Iveson, Elwyn Loh
Journal: Journal of Clinical Oncology (2012)

2535 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), the only known MET receptor ligand. In a double-blind, placebo-controlled, phase 2 trial of 121 pts with G/EGJ cancer, R (7.5 or 15 mg/kg) + ECX showed trends for improved overall survival (OS) and progression-free survival (PFS) compared to ECX alone (placebo, P). Methods: E-R analyses were performed using pharmacokinetic (PK), biomarker, efficacy, and safety data. A population PK model was used to evaluate covariate effects (eg, demographics, ECX, and MET status) on R PK and predict individual R exposure (trough steady-state C min [C]). The effect of C on OS/PFS was evaluated with Kaplan-Meier estimates and Cox proportional hazards models. Covariate effects for OS/PFS were evaluated with multivariate analysis. The relationships between adverse events of interest (AEs), lab values, and C were analyzed with descriptive statistics and linear regression models. Results: R showed linear PKs that were unaffected by ECX or MET levels. Pts who received R + ECX were divided into low C (C L ) and high C (C H ) groups by the median C (94 µg/mL). Median PFS was 4.2, 4.5, and 6.9 months in the P, C L , and C H groups; median OS was 8.9, 9.5, and 13.3 months. Improved OS/PFS in C H and improved PFS in C H and C L groups (vs P) were seen after adjusting for baseline covariates. Pts with tumors that expressed high MET levels (MET High : &gt; 50% cells positive) showed greater improvement in OS in the C H vs C L group. No improvement in OS was seen in MET Low pts (C H and C L groups) compared to placebo (see Table). No relationship was seen between R exposure and AEs or lab values. Conclusions: Higher R exposure was associated with improved OS/PFS in MET High pts without increased toxicity, supporting further study of R + ECX in G/EGJ cancer. [Table: see text]
Diagnostic colonoscopy following abnormal FIT results: A quality improvement analysis.
Authors: Trace Heavener, Victoria Jaeger, Kristen Stephenson, Frank McStay, Tommy Sing
Journal: Journal of Clinical Oncology (2018)

568 Background: Published rates of colorectal cancer (CRC) screening with diagnostic colonoscopy after abnormal fecal immunochemical test (FIT) findings have varied substantially from 42% to 83% and median days to follow up colonoscopy have ranged from 41 to 184 days. Although data for lack of follow up exists for urban safety-net hospital systems, Veteran’s Affairs systems, and healthcare systems not located in the southern US to our knowledge no data exists for the Baylor Scott &amp; White Health System (BSWH) which is the largest not-for-profit healthcare system in Texas. Methods: The initial retrospective chart review searched BSWH’s Central Texas division for whom a FIT was ordered during the following dates: June 1, 2014 to June 1, 2016. Eligible patients were between and including 50 and 75 years of age. The search results were manually screened by two resident Internal Medicine physicians. Results: The initial screen produced 232 patients with a positive FIT test. After excluding for testing reasons other than CRC screening, 94 patients were included in the final analysis. Most of those (70/94, 74.47%) received a gastroenterology clinic visit within one year, and most (62/94, 65.96%) received or were offered a colonoscopy. The most common reasons for not completing colonoscopy were patient no-show (14/32, 43.75%) and no documented reason (12/32, 37.5%). Of those receiving a colonoscopy at our institution, median time from positive FIT to colonoscopy was 64 days, a quarter (11/43, 25.58%) waited longer than 6 months, and 22/43 (51.16%) had an abnormal finding. The abnormal findings on colonoscopy included: 3/22 (13.64%) were dysplastic polyps, 13/22 (59.10%) were adenomatous polyps and 6/19 (31.58%) were hyperplastic polyps. Conclusions: Colonoscopy following an abnormal FIT is an important part of preventing and diagnosing CRC. Although fecal based screening tests are more convenient and affordable, it appears that poor follow up is not limited to government and indigent health systems. As one of the largest not-for-profit health systems in the nation, a 65.96% follow up colonoscopy rate after abnormal FIT testing leaves much room for improvement.
Advertising paid and unpaid job roles in sport: an updated position statement from the UK Strength and Conditioning Association
Authors: Chris John Bishop, Peter McKnight, Crofton Alexander, Edward Archer, Richard Hunwicks, Daniel J Cleather
Journal: British Journal of Sports Medicine (2018)

The strength and conditioning (SC this reflected by an increase in UK S&C accredited coaches doubling from ~400 in 2011 to ~800 in 2017. Consequently, the growing interest in S&C has also seen a dramatic increase in internships,1 many of which have been advertised as unpaid.



Figure 1 
Current distribution of SC UKSCA, UK Strength and Conditioning Association.



Whether unpaid internships are legal or not is ambiguous. The government (HM Revenue and Customs in UK) website states that: ‘An intern’s rights depend on their employment status. If an intern is classed as a worker, then they’re normally due the National Minimum Wage’. The definition of a ‘worker’ indicates that a contract is exchanged between the two parties involved. However, if an applicant accepts …
Patient-Derived Organoids Predict Cancer Treatment Response
Authors: Jennifer Abbasi
Journal: JAMA (2018)

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