tbuckley/cabot-search huggingface dataset:
Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
Authors: Zachary S Buchwald, Tahseen H Nasti, Judong Lee, Christiane S Eberhardt, Andreas Wieland, Se Jin Im, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K Khan
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response. Methods We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells. Results We show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8 + T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8 + T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8 + T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8 + and stem-like CD8 + T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8 + T-cells and stem-like CD8 + T-cells in both the irradiated and unirradiated tumor. Conclusions These correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8 + T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.
Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis
Authors: Andrea B Apolo, John A Ellerton, Jeffrey R Infante, Manish Agrawal, Michael S Gordon, Raid Aljumaily, Theodore Gourdin, Luc Dirix, Keun-Wook Lee, Matthew H Taylor, Patrick Schöffski, Ding Wang, Alain Ravaud, Juliane Manitz, Gregory Pennock, Mary Ruisi, James L Gulley, Manish R Patel
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma. Methods Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome. Results 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24–43), and median treatment duration was 2.8 months (range 0.5–42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses. Conclusions After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.
Reporting of results should be standardised
Authors: D A Fitzmaurice, F D R Hobbs
Journal: BMJ (1996)

Sialylation of tumor cells is involved in various aspects of their malignancy (proliferation, motility, invasion, and metastasis); however, its effect on the process of immunoediting that affects tumor cell immunogenicity has not been studied. We have shown that in mice with impaired immunoediting, such as in IL-1α<sup>−/−</sup> and IFNγ<sup>−/−</sup> mice, 3-methylcholanthrene–induced fibrosarcoma cells are immunogenic and concomitantly bear low levels of surface sialylation, whereas tumor cells derived from wild type mice are nonimmunogenic and bear higher levels of surface sialylation. To study immune mechanisms whose interaction with tumor cells involves surface sialic acid residues, we used highly sialylated 3-methylcholanthrene–induced nonimmunogenic fibrosarcoma cell lines from wild type mice, which were treated with sialidase to mimic immunogenic tumor cell variants. In vivo and in vitro experiments revealed that desialylation of tumor cells reduced their growth and induced cytotoxicity by NK cells. Moreover, sialidase-treated tumor cells better activated NK cells for IFN-γ secretion. The NKG2D-activating receptor on NK cells was shown to be involved in interactions with desialylated ligands on tumor cells, the nature of which is still not known. Thus, the degree of sialylation on tumor cells, which is selected during the process of immunoediting, has possibly evolved as an important mechanism of tumor cells with low intrinsic immunogenicity or select for tumor cells that can evade the immune system or subvert its function. When immunoediting is impaired, such as in IFN-γ<sup>−/−</sup> and IL-1α<sup>−/−</sup> mice, the overt tumor consists of desialylayed tumor cells that interact better with immunosurveillance cells.
Utility of Restricted Mean Survival Time Analysis for Heart Failure Clinical Trial Evaluation and Interpretation
Authors: Carlotta Perego, Marco Sbolli, Claudia Specchia, Mona Fiuzat, Zachary R. McCaw, Marco Metra, Chiara Oriecuia, Giulia Peveri, Lee-Jen Wei, Christopher M. O’Connor, Mitchell A. Psotka
Journal: JACC Heart Failure (2020)

This study sought to demonstrate the statistical and utilitarian properties of restricted mean survival time (RMST) and restricted mean time lost (RMTL) for assessing treatments for heart failure (HF) with reduced ejection fraction. Although the hazard ratio (HR) is the most commonly used measure to quantify treatment effects in HF clinical trials, HRs may be difficult to interpret and require the proportional hazards assumption to be valid. RMST and RMTL are intuitive summaries of groupwise survival that measure treatment effects without model assumptions. Patient time-to-event data were reconstructed from published landmark HF clinical trial Kaplan-Meier curves. We estimated RMST differences (ΔRMSTs) and RMTL ratios between treatment groups for primary and secondary outcomes, and compared test statistics and effect sizes with proportional hazards models. We fit Weibull estimations to extrapolate trial data to 5 years of treatment. Using RMSTs and RMTLs yielded similar statistical conclusions as HR analysis for a compendium of 16 HF clinical trials including 48,581 patients. RMTL ratios approximated HRs for each trial, but ΔRMSTs provided absolute effect sizes unavailable with HRs. For instance, spironolactone added 2.2 months of life over 34 months of treatment, and dapagliflozin added 0.3 months of life over 24 months of treatment. When normalized to 5-years follow-up with Weibull estimation, spironolactone and dapagliflozin added 6.0 months and 1.8 months of life for patients, respectively. Statistically, RMST and RMTL perform similarly to proportional hazards modeling but may help patients by providing clinically relevant intuitive estimates of treatment effects without prohibitive assumptions.
Long-Term Outcomes After Infective Endocarditis After Transcatheter Aortic Valve Replacement
Authors: David del Val, Axel Linke, Mohamed Abdel-Wahab, Azeem Latib, Nikolaj Ihlemann, Marina Urena, Kim Won-Keun, Oliver Husser, Howard C. Herrmann, Luis Nombela-Franco, Asim N. Cheema, Hervé Le Breton, Stefan Stortecky, Antonio L. Bartorelli, Jan Malte Sinning, Ignacio Amat-Santos, Antonio Munoz-Garcia, Stamatios Lerakis, Enrique Gutiérrez-Ibanez, Martin Landt, Didier Tchetche, Luca Testa, Helene Eltchaninoff, Ugolino Livi, Juan Carlos Castillo, Tarun Chakravarty, John G. Webb, Marco Barbanti, Susheel Kodali, Fabio S. de Brito, Henrique Barbosa Ribeiro, Antonio Miceli, Claudia Fiorina, Guglielmo Mario Actis Dato, Francesco Rosato, Vicenç Serra, Jean-Bernard Masson, Harindra C. Wijeysundera, Jose A. Mangione, Maria-Cristina Ferreira, Valter Correa Lima, Alexandre Siciliano Colafranceschi, Alexandre Abizaid, Marcos Antonio Marino, Vinicius Esteves, Julio C.M. Andrea, Dominique Himbert, Costanza Pellegrini, Vincent Auffret, Paolo Olivares, Fabian Nietlispach, Thomas Pilgrim, Eric Durand, John Lisko, Raj Makkar, Abdullah Alkhodair, Lars Søndergaard, Norman Mangner, Lisa Crusius, David Holzhey, Ander Regueiro, Josep Rodés-Cabau
Journal: Circulation (2020)
Using the Risk Assessment Index to predict mortality and quality of life in breast and gynecologic cancer patients.
Authors: Ellen Ormond, Jeffrey Borrebach, Stefanie C Altieri Dunn, Andrew Bilderback, G J. Van Londen, Daniel Hall
Journal: Journal of Clinical Oncology (2020)

239 Background: Cancer patients vary considerably in health status making it challenging to evaluate the risk of complications from cancer treatment. To aid oncologists in identifying patients with highest risk for adverse outcomes, we investigated the Risk Assessment Index (RAI), a validated tool used to assess frailty in patients prior to elective surgery. We assessed whether the RAI could serve to predict mortality, hospital utilization, and quality of life in cancer patients. Methods: Participants were breast and gynecological cancer patients treated at UPMC Magee Women’s Cancer Center who completed the RAI between July 2016 and December 2017. Patients completed patient reported outcomes (PROs) during each visit including the Short Form (SF)-12, Edmonton Symptom Assessment, anxiety and depression screens, and MD Anderson Symptom Inventory (MDASI) and were analyzed up to 180 days from the RAI date. Mortality was assessed at 90, 180, and 365-day intervals, and hospital utilization was assessed within 90-days of RAI. Results: There were 1,764 unique breast and gynecological cancer patients. Significant correlations between the RAI and mortality were observed for both groups with frail patients having higher rates of mortality at each interval. Frailty was associated with higher rates of hospitalization compared to non-frail patients (31% vs 20%, p = 0.05 &amp; 50% vs 34%, p = 0.02 for breast and gynecologic patients, respectively). Frailty correlated with fair/poor ratings on the SF-12 for breast and gynecologic patients (r = 0.13, p = 0.01; r = 0.37 p &lt; 0.001, respectively). On the Edmonton, frailty correlated with lower ratings of well-being in breast cancer patients (r = 0.11, p = 0.012) and higher symptom burden in gynecological patients (r = 0.23, p = 0.01). No correlations were observed between the RAI and anxiety or depression. For gynecologic patients, there were significant correlations between the RAI and MDASI with frail patients having higher rates of pain, fatigue, appetite, diarrhea, and memory. Conclusions: We demonstrated that the RAI is correlated with mortality, self-reported quality of life, and hospitalizations in breast and gynecologic cancer patients. Using this tool to risk-stratify patients may help to guide shared decision-making discussions and provide appropriate treatment and/or supportive services for this vulnerable population.
Stakeholder feedback at four ePRO-naïve healthcare institutions about the need, effectiveness, and barriers to usage of a fully EHR-integrated ePRO tool.
Authors: Deborah Schrag, Raymond U. Osarogiagbon, Sandra L. Wong, Hannah Hazard, Jessica J Bian, Don S. Dizon, Christine Cronin, Michael J. Hassett
Journal: Journal of Clinical Oncology (2020)

165 Background: Collecting patient-reported outcomes (PROs) is a proven method to enhance doctor-patient communication and care. With the influx of technology and usage of telehealth services, electronic PROs (ePROS) have become the mainstay for ascertaining how a patient is doing at home. Collection of ePROs is particularly valuable for providers caring for rural and vulnerable populations with limited access to high quality care. A fully EHR-integrated ePRO collection system could help bridge the gap. Methods: To inform the design, function, and deployment of a new EHR-integrated ePRO symptom management system, focus groups with stakeholders were conducted at four institutions caring for largely rural-based populations (Baptist Cancer Center, West Virginia University Cancer Institute, Dartmouth-Hitchcock Medical Center, Maine Medical Center). Sessions were conducted 2 to 3 months prior to the launch of a new ePRO platform and included oncologists, surgeons, practice nurses, tech analysts, operations staff, and institutional leadership. Each group included a 30-minute overview of the new tool followed by a 30-minute discussion with qualitative open-ended questions and clicker-enabled multiple-choice questions. Developed questions utilized the CFIR and RE-AIM implementation frameworks. Results: In total, 134 stakeholders participated from the four institutions. RNs made up nearly half of respondents (47%). 97% of participants felt a new ePRO system would complement existing healthcare initiatives and 64% felt it would be extremely effective/very effective in improving symptom management. Each group was asked to rate the barriers to patient usage of an ePRO system in the home-care setting. Computer literacy (51%) and access to an internet-enabled device (48%) ranked as the highest barriers. Other barriers perceived to be of less significance included privacy, distrust, and limited English-language proficiency. Consequently, two-thirds of respondents felt patients would only be somewhat likely/not so likely to use an ePRO system; one-third felt patients would be likely/extremely likely to utilize the system. Conclusions: From the perspective of stakeholders at four engaged institutions, an integrated ePRO tool is considered a widely acceptable symptom management solution, but uncertainty remains around patient acceptance and uptake. Future research will include post-implementation discussions with stakeholders and evaluation of patient utilization and clinical outcomes.
Should we continue covid-19 suppression measures based on a transmission model that ignored pre-existing human immunity?
Authors: Angela Spelsberg, Ulrich Keil
Journal: BMJ (2020)

Doshi discusses the studies that have shown pre-existing immunity to SARS-CoV-2.[3] Most governments have based their decisions in the covid-19 pandemic on the advice of a limited group of experts, mainly a few virologists and disease modellers. Using earlier transmission models, these experts calculated that an uncontrolled SARS-CoV-2 epidemic would infect about 81% of the UK and the US populations. Assuming an infection fatality rate of 0.9%, they predicted 510 000 (UK) and 2.2 million (US) deaths, …
Abstract PR06: The glutaminase inhibitor CB-839 potentiates antimelanoma activity of standard-of-care targeted therapies and immunotherapies
Authors: Sruthy Varghese, Snigdha Pramanik, Rishika Prasad, Hannah Hodges, Leila Williams, Weiyi Peng, Hussein Tawbi, Vashisht Yennu Nanda
Journal: Cancer Research (2020)

Abstract Nearly all metastatic melanoma patients who respond to targeted therapies will relapse with the disease within a year. Although more durable responses are seen with immune therapies, about half of the melanoma patients do not respond to them, and a significant number of responders eventually relapse. Most relapsed melanomas also exhibit post-treatment resistance to these treatments. Hence, there is a clear and present need to develop therapeutics that counteract resistance associated with relapse. We and others earlier showed that melanomas with elevated mitochondrial activity possess improved cellular rigor and are intrinsically resistant to the antitumor effects of BRAF and MEK inhibitors. In many other instances, melanomas that initially respond to these inhibitors acquire resistance by elevating mitochondrial activity. Mitochondrial activity is elevated in part by increased cellular uptake of glutamine, and its conversion to alpha-ketoglutarate in the TCA cycle, with glutaminase enzyme playing a rate-limiting role. In this study, we show that BRAFV600E-mutant melanomas with intrinsic or acquired resistance to MAPK pathway inhibitors have lower glucose uptake and increased glutamine uptake compared to those that are sensitive. Treatment of these resistant melanomas with single-agent glutaminase inhibitor, CB-839, moderately inhibited their growth. However, a more robust inhibition of their growth was achieved when CB-839 was combined with BRAF and MEK inhibitors. In addition, CB-839 increased the in vivo activity of tumor-infiltrating lymphocytes (TILs) in a mouse vaccine model and also enhanced the proapoptotic effect of human autologous patient-derived TILs on their cognate melanoma cells. Seahorse bioenergetics stress tests showed that CB-839 inhibited mitochondrial OxPhos in tumor cells to a greater extent than in activated TILs. Additional molecular studies are currently in progress. A recent clinical trial in melanoma patients showed that combination treatment with CB-839 and the immune checkpoint blocker, nivolumab, caused an objective response in three melanoma patients who had earlier progressed on treatment with immune checkpoint blockade. Our preclinical results complement this clinical finding and suggest that CB-839 combination could potentiate the efficacy of targeted and immune therapies in refractory melanomas. Citation Format: Sruthy Varghese, Snigdha Pramanik, Rishika Prasad, Hannah Hodges, Leila Williams, Weiyi Peng, Hussein Tawbi, Vashisht Yennu Nanda. The glutaminase inhibitor CB-839 potentiates antimelanoma activity of standard-of-care targeted therapies and immunotherapies [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR06.
An Update on the Incidence and Burden of Diabetic Ketoacidosis in the U.S.
Authors: Kamleshun Ramphul, Jyotsnav Joynauth
Journal: Diabetes Care (2020)

A recent study by Desai et al. (1) showed that the incidence and economic burden of hospitalizations due to diabetic ketoacidosis (DKA) in the U.S. increased between 2003 and 2014 (1). We sought to understand the most recent impact of the disease in the U.S. using the 2017 National Inpatient Sample (NIS) (www.hcup-us.ahrq.gov/nisoverview.jsp).

A total of 220,340 patients were identified with a primary diagnosis of DKA (61.6 cases of DKA per 10,000 admissions) (Table 1). The incidence of DKA per 10,000 admissions was higher in males (71.2) than females (54.1), and the majority of DKA patients were covered by Medicaid (79,175 patients [36.0%], P < 0.01). Of all DKA patients, 53.3% were of ages 18–44 years. However, a higher incidence per 10,000 admissions was noted in patients of ages 1–17 years. The mean age of patients with DKA was 38.4 years. The total charges among DKA patients in 2017 were $6,757,748,178, with a mean of $30,836.19. The mean length of stay was 3.22 days. A total of 835 deaths were found among DKA patients, with a mortality rate of 0.38%. The overall …
Impact of COVID-19 pandemic on new patient and consult visits at 20 hematology/oncology practices in the ASCO PracticeNET learning network
Authors: Brian Bourbeau, Mou Guharoy, Elizabeth Garrett-Mayer, Stephen Grubbs, Paul Unger, Barbara McAneny, Richard L. Schilsky
Journal: Clinical Cancer Research (2020)

Introduction: During March 2020, as the emergence of COVID-19 began to influence medical and social behaviorsin the United States, oncology practices reported a disruption in normal referral and patient management patterns Participants and staff of ASCO's PracticeNET learning network sought to explore and quantify the impact of thisdisruption through an analysis of patient activity at multiple hematology/oncology practices  Methods: 20 practices submitted their billing data for analysis;practices were located in 14 states and ranged insize from 2 to 29 hematologists/oncologists  From this dataset we analyzed a total of 11,453 new patient and consultvisits (Current Procedural Terminology codes 99201-99205, 99241-99245, 99251-99255, and 99341-99345)performed by hematologists/oncologists from February 9 to April 18, 2020  The number of visits performed fromFebruary 9 to March 14, 2020 was compared to visits performed from March 15 to April 18, 2020  A principaldiagnosis was assigned to each visit following usual coding and billing practices  Results: From February 9 to March 14, practices performed an average of 70 1 (median 55 5) new patient andconsult visits per week  From March 15 to April 19, practices performed an average of 44 5 new patient and consultvisits per week  The average decrease in visits among practices was 35% (95% confidence interval (CI): -42%,-29%)  The decline in visits per practice ranged from -61% to -13%  New patient and consult visits for solidneoplasms decreased by an average of 22% (95% CI: -31%, -13%), visits for blood neoplasms decreased by anaverage of 36% (95% CI: -25%, -47%), and visits for benign hematology and circulatory disorders decreased by anaverage of 44% (95% CI: -53%, -34%)  Conclusions: Oncology practices experienced a decline in new patient and consult visits, first observed in the weekof March 15  New patient and consult visits for blood neoplasms, benign hematology, and circulatory disordersexperienced a greater decline than visits for solid neoplasms  The decrease in activity could be the result ofprioritization of resources or changes in patient behavior in seeking care  Further study is necessary to quantify theimpact of these findings on patient access and outcomes and to monitor recovery efforts