tbuckley/cabot-search huggingface dataset:
Validation of the Glasgow Microenvironment Score in patients with colon cancer: A pathology-based prognostic tool.
Authors: Peter G Alexander, Antonia K. Roseweir, Kathryn AF Pennel, Hester Catharina Van Wyk, Arfon GMT Powell, Campbell SD Roxburgh, Paul G. Horgan, Joanne Edwards, Donald C. McMillan, James Hugh Park
Journal: Journal of Clinical Oncology (2020)

206 Background: The Glasgow Microenvironment Score (GMS), comprised of assessment of the tumour inflammatory cell infiltrate (using Klintrup-Mäkinen (KM) grade) and tumour-associated stroma (TSP), has been reported as a stage-independent prognostic score in patients with colorectal cancer. The present study aims to validate the GMS and examines its prognostic utility in the context of stage and MMR status. Methods: Patients who had undergone resection of stage I-III colon cancer were included ( n= 495). GMS was scored by combining KM and TSP as follows: high KM scores 0; low KM with low TSP scores 1; low KM and high TSP scores 2. Cancer specific (CSS) and overall survival (OS) were primary endpoints. Subgroup analysis was performed to assess the utility of GMS according to TNM, venous invasion and MMR status. Results: There were 30% of patients with GMS 0, 56% with GMS 1 and 14% with GMS 2. Five-year survival for GMS 0, 1 and 2 across the whole cohort were 89%, 74% and 66%, respectively. GMS was associated with age, mode of presentation, TNM, venous invasion and MMR status. On multivariate analysis, GMS was independently associated with CSS (HR 1.35, 95% CI: 1.02-1.79, p= 0.04) and OS (HR 1.23, 95% CI: 1.02-1.48, p= 0.03); this was independent of emergency presentation ( p&lt; 0.01), T-stage ( p= 0.03) and N-stage ( p&lt; 0.001) for CSS. Subgroup analysis found that GMS was able to stratify CSS regardless of node-negative or node-positive disease (both p&lt; 0.01), venous invasion ( p&lt; 0.05), elective presentation ( p&lt; 0.01) and MMR-proficient tumours ( p&lt; 0.001), although it was not able to stratify emergency presentation ( n= 154) or MMR-deficient disease ( n= 102) due to small sample size. Universally, the prognosis for GMS 0 was good, but was poor for GMS 2. The prognosis for GMS 1 varied depending on MMR and nodal status. Conclusions: This study validates the use of the GMS as an independent prognostic pathology-based tool for stratification of colon cancer. It could be readily applied to routine clinical practice and may be used to aid decision making regarding adjuvant treatments in colorectal cancer. It should be further validated in prospective randomised trials.
BCL-2 antagonism sensitizes cytotoxic T cell–resistant HIV reservoirs to elimination ex vivo
Authors: Yanqin Ren, Szu Han Huang, Shabnum Patel, Winiffer D. Conce Alberto, Dean Magat, Dughan Ahimovic, Amanda B. Macedo, Ryan Durga, Dora Chan, Elizabeth Zale, Talia M. Mota, Ronald Truong, Thomas Rohwetter, Chase D. McCann, Colin M. Kovacs, Erika Benko, Avery Wimpelberg, Christopher Cannon, W. David Hardy, Alberto Bosque, Catherine M. Bollard, R. Brad Jones
Journal: Journal of Clinical Investigation (2020)

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4+ T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets in ex vivo CD4+ T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.
Human leukocyte antigen expression in paired primary lung lesions and brain metastases in non-small cell lung cancer.
Authors: Jarrett Failing, Marie-Christine Aubry, Aaron Scott Mansfield
Journal: Journal of Clinical Oncology (2020)

43 Background: Human leukocyte antigens (HLA) are crucial for cytotoxic T cell responses to cancer. Loss of HLA expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors we have observed discordant responses between brain metastases and extracranial disease and reported on differential PD-L1 expression and clonal T cell infiltration between paired primary lung lesions and brain metastases. In this project we sought to evaluate whether HLA expression was retained in metastatic NSCLC. Methods: Adult patients with paired primary NSCLC and brain metastases were identified from our institution’s tissue registry. HLA-A cell membrane expression on tumor cells was determined by immunohistochemistry with an anti-HLA-A antibody. Tumors with greater than 10% HLA expression were considered positive. Agreement statistics (κ) and Fisher’s exact test were used for analysis. Results: 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%)(κ = 0.57, 95% CI 0.35-0.79)(p = 0.0001). There was no significant difference in the time between the primary tumor and brain metastasis resections in patients with HLA expression disagreement compared to those with HLA expression agreement. None of the patients received immune checkpoint inhibitors for treatment of these lesions. Conclusions: We found significant differences in HLA-A expression on tumor cells in nearly one quarter of paired primary lung cancers and brain metastases. Differences in HLA expression may help explain the discrepancies in response to immune checkpoint inhibitors at different sites of disease and warrants further study.
APG101_CD_002: A phase II, randomized, open-label, multicenter study of weekly APG101 plus reirradiation versus reirradiation in the treatment of patients with recurrent glioblastoma.
Authors: Martin Bendszus, Jürgen Debus, Wolfgang Wick, Grigory Kobyakov, Tobias Martens, Oliver Heese, Josef Pichler, Roger Stupp, Claudia Kunz, Harald Fricke
Journal: Journal of Clinical Oncology (2012)

2034 Background: Preclinical data indicate antiinvasive activity of APG101, an intravenous CD95 ligand-binding fusion protein, as well as synergistic activity together with radiotherapy in glioblastoma. Methods: Patients with recurrent glioblastoma after prior standard radiochemotherapy with temozolomide (± 1 second-line chemotherapy) were considered for re-irradiation provided a tumor diameter 1-4 cm and time since the end radiotherapy ≥ 8 months. Patients were randomized 1:2 between radiotherapy (36 Gy; 5 times 2 Gy per week) or radiotherapy plus APG101 at 400 mg weekly flat dose to be continued until progression. Radiotherapy plans were centrally evaluated. Primary endpoint was 6-months progression free survival (PFS-6). MRIs were performed every 6-weeks and centrally read. Sample size of the investigational treatment arm according to a two-stage design of Simon required 55 patients. A control arm of 28 patients was implemented to validate the assumptions on PFS-6 in a cohort of patients treated with reirradiation alone. Results: Between 12/09 and 09/11, 84 pts in 25 centers were randomized and treated, preliminary data of the current report are available on 71 patients (49 APG01 + irradiation, 22 irradiation alone). Median age was 57 years, median KPS 90%. The maximal tumor diameter was ≤ 2-5 cm in 34 patients and &gt; 2.5 cm in 37 patients. No SUSARs have to be reported. Nine patients achieved PFS-6 in the APG101 arm and none in the radiotherapy arm. Conclusions: APG101_CD_002 is the first trial evaluating CD95-mediated pathway inhibition as a therapeutic strategy. This trial is also the prospective trial on reirradiation in glioblastoma. Side effects of the combination were minimal, and treatment could be delivered as planned. The experimental arm met the primary endpoint. The approach to block rather than stimulate the CD95 system is breaking a paradigm. Our data suggest that CD95 inhibition by APG101 should be evaluated in the management of newly diagnosed glioblastoma in combination with standard radiochemotherapy. Further molecular data and updated results will be presented.
PORTICO: First Randomized Controlled Trial of Vasomodulator Therapy in Portopulmonary Hypertension
Authors: Sarah Raevens, Michael B. Fallon
Journal: Hepatology (2020)

Raevens, Sarah M.D., Ph.D.; Fallon, Michael B. M.D.Editor(s): Corey, Kathleen E.3; Malhi, Harmeet4 Author Information
Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes
Authors: Paola Maffi, Torbjörn Lundgren, Gunnar Tufveson, Ehab Rafael, James A.M. Shaw, Aaron Liew, Frantisek Saudek, Piotr Witkowski, Karolina Golab, Federico Bertuzzi, Bengt Gustafsson, Luisa Daffonchio, Pier Adelchi Ruffini, Lorenzo Piemonti, Rita Nano, Alessia Mercalli, Vito Lampasona, Paola Magistretti, Valeria Sordi, Secchi Antonio, Barbara Antonioli, Marta Galuzzi, Marta Cecilia Tosca, Luciano De Carlis, Giacomo Colussi, Olle Korsgren, Helena Pollard
Journal: Diabetes Care (2020)

Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control.The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression.In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.
Comparing the accuracy of EUS and CT in staging of esophageal cancer.
Authors: Hyun Ik Shim, Dong Ho Lee, Jae Ho Cho, Cheol Min Shin, Hyuk Yoon, Young Soo Park, Nayoung Kim
Journal: Journal of Clinical Oncology (2020)

286 Background: Endoscopic ultrasound (EUS) is a suitable device for staging of esophageal cancers. However, chest computed tomography (CT) has traditionally been the standard diagnostic modality for malignancies. This study aimed was to compare the accuracies of EUS and chest CT in T and N staging of esophageal cancers. Methods: We retrospectively analyzed 149 patients who had undergone EUS examination and 275 patients who had undergone chest CT before cancer surgery. The inclusion criteria were: 1) patients diagnosed with esophageal cancer on biopsy, 2) patients who had undergone EUS examination or chest CT before cancer surgery, and 3) patients who underwent cancer surgery at the Seoul National University Bundang Hospital from May 2003 to December 2018. We determined the accuracy of T and N staging on EUS examination and chest CT with the biopsy specimens. Results: The overall accuracies of EUS examination and chest CT were 72.5% (108/149) and 68.7% (189/275), respectively, for T staging ( p = 0.487) and 64.4% (96/149) and 61.5% (169/275), respectively, for N staging, which was not statistically different ( p = 0.596). For the substaging, the accuracy of EUS examination was not statistically different than that of chest CT for the T, N stage. Conclusions: EUS examination is not superior to chest CT for diagnosing T stage in esophageal cancers, whereas chest CT is not superior to EUS examination for diagnosing N stage in esophageal cancers. EUS examination and chest CT are not satisfactory for diagnosing T, N stage in esophageal cancers. Futher study is needed for accurate T, N stage diagnosis in esophageal cancer.
Enhancing Private Sector Health System Preparedness for 21st-Century Health Threats
Authors: Donald M. Berwick, Kenneth Shine
Journal: JAMA (2020)

Not since the threat of global nuclear war first emerged has humankind faced the risks of potential disasters at the scale that the 21st century now brings.Climate change, international terrorism, pandemics, and cyberwarfare are only some of the ways in which injury, morbidity, and mortalitycanspreadrapidlytomillionsofpeople.Ebola,astragic as it has been, is but a small example of what could occur if,forinstance,anuclearblastwentoffinNewYork,sealevel surges flooded Florida, or the electric grid went down in a health emergency.The current coronavirus epidemic in Chinahascreatedamajorinternationalpublichealththreat, led to the full or partial quarantine of nearly 45 million people, and interrupted commerce in many cities. 1 These threats may come in 2 distinct forms.One is a challenge to capacity-a surge of demand for, for instance, trauma care, burn care, or treatment of an infectious agent at a scale far beyond any currently familiar level of mass casualty.Many local care systems are prepared to manage surges of demand of some size. 2 But what if, instead of a few dozen or a few hundred affected individuals, the sudden need were to provide care for thousands or tens of thousands?A second form of threat is a disaster paired with the simultaneous destruction of basic infrastructure, such as a sustainedfailureoftheelectricalgridduetocybersabotage.How would mass casualties be managed if the power went out for many days, gasoline and water pumps no longer worked, and the communication system disappeared?How ready is the US health care system for such 21st-century threats?And how could the nation become more prepared?This was the topic of a series of expert meetings and public workshops titled "Enhancing Private Sector Preparedness for 21st Century Health Threats" between May and October 2019, hosted by the National Academies of Sciences, Engineering, and Medicine (NASEM), and sponsored by the Health and Human Services Assistant Secretary for Preparedness and Response (ASPR).The goal of these meetings was to identify ways to strengthen health care preparedness, levers to incentivize the health care sector, and approaches to activate private sector supporters. Balancing Regional and National ApproachesParticipantsconcurredthattheUShealthsystemisnotcurrentlypreparedforsuchthreats,and,furthermore,thatthe scale of these challenges is far too large for any immediate, comprehensive,nationalsolutions.Progressmustbemade stepwise, building systemic preparedness over time.A logical first step would be to develop and implement efforts to prepare for specific threats at a manageable scale in defined regions of the country, and thereafter to secure a much longer-term set of commitments
Assisted dying: BMA surveys its members for first time
Authors: Abi Rimmer
Journal: BMJ (2020)

For the first time, the BMA is asking its members what position it should take on assisted dying. The results of the survey will be made available to BMA members ahead of this year’s annual representative meeting (ARM) in June. They will inform a debate and a vote at the meeting regarding the BMA’s policy position.

Since 2006 the BMA has opposed assisted dying in all forms.1 Its policy says that neither physician assisted suicide nor voluntary euthanasia should be made legal in the UK. In 2016, representatives at the association’s ARM rejected a motion calling on the BMA to adopt a neutral position.2

The BMA defines physician assisted dying as …
Molecular profiling for precision cancer therapies
Authors: Eoghan R. Malone, Marc Oliva, Peter J. B. Sabatini, Tracy L. Stockley, Lillian L. Siu
Journal: Genome Medicine (2020)

Abstract The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics.
Workforce: leaders urge NHS to publish delayed plan as soon as possible
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The NHS should release a full and costed version of its long promised workforce plan as soon as possible or risk undermining efforts to boost doctor numbers, medical leaders have urged.

The interim people plan for the NHS in England was released last June,1 and a full plan with more detailed funding and policy commitments was promised by the end of 2019, after the government’s spending review.

The plan has since been delayed, although the NHS said in its …
Phase II trial of trifluridine/tipiracil and irinotecan for the treatment of advanced refractory biliary tract cancer.
Authors: Hao Xie, Mitesh J. Borad, Daniel H. Ahn, Tanios S. Bekaii-Saab, Nguyen H. Tran, Zhaohui Jin, Henry C. Pitot, Lucas J. Huebner, Qian Shi, Jaclynn Wessling, Lori M. Durgin, Minetta C. Liu, Tara L. Hogenson, William J Phillips, Martin Fernandez-Zapico, Steven R Alberts, Amit Mahipal
Journal: Journal of Clinical Oncology (2020)

TPS594 Background: Effective treatment options are very limited for patients with advanced refractory biliary tract cancer (BTC). Fluoropyrimidine-based chemotherapy regimen such as 5-fluorouracil and irinotecan are frequently utilized for these patients after first-line therapy despite lack of FDA approval. Trifluridine/tipiracil (FTD/TPI) is a novel oral nucleoside with antitumor activity in both fluoropyrimidine sensitive and resistant tumors due to its unique mechanisms of action. Given early toxicity and efficacy data from our previous study on single-agent trifluridine/tipiracil (FTD/TPI) in advanced BTC, the clinical evaluation of its combination with irinotecan represents a rational approach for the treatment of advanced refractory BTC. Methods: This is a single-arm phase II trial with a two-stage design to assess the efficacy of trifluridine/tipiracil (FTD/TPI) and irinotecan in advanced refractory BTC. Key eligibility criteria include histologically confirmed advanced, unresectable BTC who have progressed on at least one line of systemic therapy and have measurable disease per RECIST v1.1. Target accrual is 25. Treatment includes trifluridine/tipiracil (FTD/TPI) 25 mg/m 2 on days 1-5 and irinotecan 180 mg/m 2 on day 1 in 14-day cycles. Patients will be evaluated for response every 4 cycles and in the absence of disease progression, therapy may be given up to 2 years. The primary end point is the progression-free survival rate at 16 weeks. Secondary endpoints include overall response rate, disease control rate, progression-free survival, overall survival, and incidence of adverse events. Correlative biomarker studies include evaluations of circulating tumor DNA and circulating tumor cells at baseline, after 4 cycles and at progression; and development of patient-derived tumor organoids from pre-treatment biopsies for parallel treatments. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc. Clinical trial information: NCT 04072445.