tbuckley/cabot-search huggingface dataset:
Abstract PS15-13: Safe margins for delineation of left anterior descending artery (LAD) using cardiac-gated CT-scan (CG-CT) in left side breast cancer patients
Authors: Eliot Nicolas, Nadjoua Khalifa, Sabrina Bouhroum, Cyril Laporte, Youlia Kirova
Journal: Cancer Research (2021)

Abstract Background: Cardiac toxicity after breast cancer (BC) radiotherapy (RT) is partly due to the large radiation doses to coronary arteries. The left anterior descending artery (LAD) is particularly exposed. A first step in achieving robustly proven dose constraints to the LAD during treatment planning is homogeneous delineation based on guidelines. LAD delineation can be problematic due to heart movements.Purpose/Objective(s): The aim of the study was to establish a safety margin for delineation of the LAD in BC patients.Materials/Methods: We studied 45 left-sided BC patients who had an indication for adjuvant radiotherapy between 2015 and 2018. They all underwent cardiac-gated computed tomography scan (CG-CT), as well as planning CT scans (P-CT) with or without contrast agents, to assess LAD diameter and movements. CG-CT was performed while monitoring the cardiac cycle. Acquisition was launched immediately after contrast injection (arterial sequence), with deep inspiration breath hold and use of a beta-receptor blocking agent. By manually reviewing each scan, the LAD positions and diameter were defined at 20 different phases of the cardiac cycle at 5 different sites: ostium, circumflex (Cx) bifurcation (bfc), first diagonal (D1) bfc, second diagonal (D2) bfc and apex (right coronary anastomosis). Next step is to introduce it in softwear of automatic delineation to improve the atlas of cardiac structures.Results: Movement of the LAD is maximal at the ostium, then constant overall even when far from its origin. The diameter decreases with the distance from ostium: 4.9 mm (OS), 3.9 mm (Cx), 3.5 mm (D2) and 3.1 mm (D2).Conclusion: We suggest using a safety delineation margin consisting of a cylinder with a diameter of 10 mm surrounding the LAD. These findings must be validated in independent series of patients treated for BC. Citation Format: Eliot Nicolas, Nadjoua Khalifa, Sabrina Bouhroum, Cyril Laporte, Youlia Kirova. Safe margins for delineation of left anterior descending artery (LAD) using cardiac-gated CT-scan (CG-CT) in left side breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-13.
Abstract 16530: High Use of Oral Anticoagulation in Eligible Patients Discharged With Heart Failure and Atrial Fibrillation Irrespective of Ejection Fraction: Insights From the AHA Get With The Guidelines- Atrial Fibrillation Program
Authors: Nancy Luo, Haolin Xu, Hani Jneid, Gregg C Fonarow, Renato D Lopes, Christopher B Granger, Anne B Curtis, Andrea M Russo, William R Lewis, Jonathan P Piccini, Robert J Mentz, Sana M Al-Khatib
Journal: Circulation (2017)

Background: Prior studies have shown underuse of oral anticoagulation (OAC) for stroke prophylaxis in patients with atrial fibrillation (AF) and heart failure (HF). The use of OAC in the era of dir...
Contents of US Food and Drug Administration Refuse-to-File Letters for New Drug Applications and Efficacy Supplements and Their Public Disclosure by Applicants
Authors: Harinder Singh Chahal, Sanjana Mukherjee, Daniel W. Sigelman, Robert Temple
Journal: JAMA Internal Medicine (2021)

<h3>Importance</h3> Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts “filing reviews” to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance. Why the FDA issues RTF letters and how often the letters and their contents are made publicly available are unknown. <h3>Objectives</h3> To quantitatively analyze the FDA’s reasons for issuing RTF letters and assess the public transparency of RTF letters and their contents. <h3>Design and Setting</h3> This cross-sectional study analyzes RTF letters issued in response to new drug applications and efficacy supplements (applications for new indications or patient populations for already approved drugs) submitted to the FDA between January 1, 2008, and December 31, 2017. Statistical analysis was conducted in July 2019. <h3>Main Outcomes and Measures</h3> Two types of information were extracted and cataloged from RTF letters: (1) the reasons why the FDA refused to file applications and (2) the FDA comments that, while not a basis for RTF letters, conveyed important information to applicants. The extent to which applicants publicly disclosed the FDA’s refusal reasons were also assessed. <h3>Results</h3> The study included 103 RTF letters containing a total of 644 identified FDA refusal reasons. Among the 2475 applications that the FDA received during the study time frame, 98 (4.0%) received RTF letters. Overall, 84.5% (544 of 644) of the refusal reasons were for scientific deficiencies; most reasons were related to drug efficacy and safety (196 [30.4%]) and drug quality (125 [19.4%]). The remaining 15.5% of refusal reasons (100 of 644) were for application organization deficiencies or legal issues. A total of 26.2% of the RTF letters (27 of 103) identified presubmission advice from the FDA that applicants did not follow; the most frequently ignored advice was related to clinical trial design (33.3% [9 of 27]), followed by product chemistry and manufacturing (25.9% [7 of 27]). Applicants publicly disclosed the existence of 16 of 103 RTF letters (15.5%); however, only 5.4% of applicant-disclosed reasons (35 of 644) matched the refusal reasons that the FDA had provided in the RTF letters. <h3>Conclusions and Relevance</h3> This cross-sectional study found that the FDA refused to file applications for substantive reasons related to quality, safety, and efficacy, and applicants’ disclosure of those reasons was incomplete. This work sheds light on the FDA’s regulatory decision-making processes and the RTF reasons that could delay availability of therapies to patients.
Abstract PS17-39: Inhibition of acetate metabolism enhances host anti-tumor immunity
Authors: Katelyn Miller, Zachary T. Schug
Journal: Cancer Research (2021)

Abstract Acquired resistance to anti-cancer therapy is an enormous challenge. One of the main factors contributing to therapy resistance is tumor hypoxia. The stress imposed by tumor hypoxia forces cancer cells to adapt in order to survive. These metabolically adapted cancer cells are often more invasive, more malignant, and more drug resistant. As a result, the cancer cells that emerge from hypoxic tumor regions are more likely to cause patient relapse. There is therefore a critical need to understand the mechanisms that promote the survival of cancer cells in stressful tumor microenvironments. We previously showed that the enzyme acetyl-CoA synthetase 2 (ACSS2) supports cancer cell metabolism in hypoxic and nutrient-depleted environments. ACSS2 endows cancer cells with the ability to use acetate as an alternative nutrient source to drive acetyl-CoA biosynthesis during stress and genetic silencing of ACSS2 inhibits human breast tumor growth in xenograft models. Given the important role of acetate metabolism in breast cancer we expanded upon our studies by using immunocompetent hosts and syngeneic mouse tumor models. Our results revealed a previously unknown role of ACSS2 in modulating host anti-tumor immunity. We found that ACSS2 deficient tumors are unable to grow when host immunity is intact. Depletion of host immunity (T cells) using genetic or pharmacological models rescues the growth of ACSS2 deficient tumors. Pharmacological inhibition of ACSS2 in tumors in vivo displayed gene signatures associated immune infiltration and activation within the tumor microenvironment. Moreover, ACSS2 deficient breast cancer cell lines show a marked susceptibility to T cell killing in vitro. Our current research demonstrates a novel role for acetate metabolism in supporting tumor extrinsic modulation of host anti-tumor immunity. Since activation of acetate metabolism via ACSS2 is a near universal hallmark of metabolically stressed cancer cells, targeting acetate metabolism represents an unrealized opportunity with significant upside for improving current therapeutic modalities in breast cancer. Citation Format: Katelyn Miller, Zachary T. Schug. Inhibition of acetate metabolism enhances host anti-tumor immunity [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-39.
Response Rates to Anti–PD-1 Immunotherapy in Microsatellite-Stable Solid Tumors With 10 or More Mutations per Megabase
Authors: Cristina Valero, Mark Lee, Douglas Hoen, Ahmet Zehir, Michael F. Berger, Venkatraman E. Seshan, Timothy A. Chan, Luc G. T. Morris
Journal: JAMA Oncology (2021)

In June 2020, the US Food and Drug Administration approved the anti-programmed cell death 1 drug pembrolizumab for patients with malignant solid tumors of any histologic type with high tumor mutational burden (TMB; ≥10 mutations per megabase). The predictive value of this universal cutoff for high TMB is not well understood.To examine the performance of a universal definition of high TMB in an independent cohort of patients with solid tumors treated with immune checkpoint inhibitors.This retrospective cohort study included 1678 patients at a single cancer referral center treated with immune checkpoint inhibitors from January 1, 2015, to December 31, 2018. Patients had 16 different cancer types and were treated with anti-programmed cell death 1 or programmed cell death ligand-1 immunotherapy. Tumors underwent next-generation sequencing.At least 1 dose of immune checkpoint inhibitors.Best overall response to immune checkpoint inhibitor therapy. The hypothesis tested was formulated after data collection and prior to analysis.Of 1678 patients, 924 (55%) were male, and the median age was 64 years (interquartile range, 55-71 years). Using the universal cutoff of 10 mutations per megabase, 416 tumors (25%) were categorized as having high TMB. Across cancer types, the proportion of TMB-high tumors ranged from 0% of kidney cancers to 53% of melanomas (113 of 214). Tumors categorized as TMB-high had higher response rates compared with TMB-low tumors in only 11 of 16 cancer types. In the entire cohort, response rates increased with higher cutoffs for TMB-high categorization, reaching 41% (169 of 416) for TMB more than 10 and 56% (90 of 161) for TMB more than 18, the highest TMB decile. Response rates also increased with TMB percentile within cancer type. Using cancer-specific cutoffs, 457 tumors (27%) were categorized as TMB-high. Response rates within cancer type ranged from 4% for pancreatic cancer (1 of 26) to 70% for melanoma (46 of 66). Cancer-specific cutoffs were associated with numerically higher response rates for TMB-high compared with TMB-low tumors in 14 of 16 cancer types.The data from this cohort study validate the finding of generally higher response rates following immune checkpoint inhibitor therapy for tumors with TMB of 10 or more mutations per megabase, across multiple cancer types. However, the predictive value of a universal numerical threshold for TMB-high was limited, owing to variability across cancer types and unclear associations with survival outcomes. Further investigation will help define cancer type-specific TMB cutoffs to guide decision-making.
Emerging Lessons From COVID-19 for the US Clinical Research Enterprise
Authors: Derek C. Angus, Anthony C. Gordon, Howard Bauchner
Journal: JAMA (2021)

Perrine Janiaud, PhD; Cathrine Axfors, MD, PhD; Andreas M. Schmitt, MD; Viktoria Gloy, PhD; Fahim Ebrahimi, MD, MSc; Matthias Hepprich, MD; Emily R. Smith, ScD, MPH; Noah A. Haber, ScD; Nina Khanna, MD; David Moher, PhD; Steven N. Goodman, MD, PhD; John P. A. Ioannidis, MD, DSc; Lars G. Hemkens, MD, MPH
Pronociceptive Roles of Schwann Cell–Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy
Authors: Madoka Koyanagi, Satoshi Imai, Mayuna Matsumoto, Yoko Iguma, Nobuko Kawaguchi-Sakita, Takeshi Kotake, Yuki Iwamitsu, Mpumelelo Ntogwa, Ren Hiraiwa, Kazuki Nagayasu, Mamiko Saigo, Takashi Ogihara, Atsushi Yonezawa, Tomohiro Omura, Shunsaku Nakagawa, Takayuki Nakagawa, Kazuo Matsubara
Journal: Cancer Research (2021)

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3−/− mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell–derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN. Significance: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.
Considering the Importance of Context for Ethical Practice on Reimbursement, Compensation and Incentives for Volunteers in Human Infection Controlled Studies
Authors: Primus Che Chi, Esther Owino, Irene Jao, Vicki Marsh, Dorcas Kamuya
Journal: The American Journal of Bioethics (2021)

The proposed framework by Lynch et al. (2021) for promoting ethical forms of payment in Human Infection Controlled Studies (HICS) in general and SARS-Cov-2 HICS in particular is an important contri...
Abstract PS6-53: Higher clinical lymph node stage predicts worse survival in patients with breast cancer who achieve a pathologic complete response after neoadjuvant chemotherapy
Authors: Li-Yun Xie, Kun Wang, Yan-Xia Shi, Hai-Lu Chen, Jian-Hao Huang, Yang-Hang Fan, Si-Qi Qiu, Zhi-Yong Wu
Journal: Cancer Research (2021)

Abstract Background: Despite patients with breast cancer who achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) generally demonstrate improved survival, some of these patients will develop breast cancer recurrence. Identification of factors associated with recurrence in patients with pCR after NAC would be helpful to optimize treatment strategies in breast cancer. In this study, we aim to particularly explore the factors associated with the prognosis of this patient population.Methods: Data of patients from three tertiary hospitals and treated with NAC between 2005 and 2019 were retrospectively collected. A pCR was defined as no invasive tumor in the breast and no tumor in the lymph node (ypT0/is, ypN0). Factors associated with pCR were analyzed using univariable and multivariable logistic regression analyses. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. The prognostic value of clinicopathological factors regarding DFS and OS were determined by univariable and multivariable Cox regression analyses.Results: A total of 897 patients were used for the analysis, including 287 patients with a pCR and 610 patients without pCR. Clinical TNM stage, histological grade, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, Ki67, molecular subtype, NAC regimen and NAC cycles were associated with pCR status, with TNM stage and molecular subtype as independent predictors of pCR. Patients with a pCR had a superior DFS (pCR vs non-pCR, hazard ratio [HR] 0.26 (95% confidence interval [CI] 0.15-0.45, P&amp;lt;0.001) and OS (pCR vs non-pCR, hazard ratio [HR] 0.13 (95% confidence interval [CI] 0.05-0.35, P&amp;lt;0.001). In patients with pCR, clinical T stage, N stage and TNM stage were associated with DFS and OS, with higher N stage as an independent predictor of a worse DFS and OS.Conclusions:Clinical N stage of breast cancer is an independent predictor of worse DFS and OS in patients with a pCR after NAC. Possible this could support treatment escalation in this patient population in the future. Citation Format: Li-Yun Xie, Kun Wang, Yan-Xia Shi, Hai-Lu Chen, Jian-Hao Huang, Yang-Hang Fan, Si-Qi Qiu, Zhi-Yong Wu. Higher clinical lymph node stage predicts worse survival in patients with breast cancer who achieve a pathologic complete response after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-53.
Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer.
Authors: S Nowinski, W Cross, M Mossner, G Cresswell, A Banerjee, M Williams, Baker A-M., B Lu, C Kimberley, H Davis, N Matthews, M M Lacle, Tomlinson Ipm., M Jansen, A Watson, C Barnes, N A Wright, J Bridgewater, M Rodriguez-Justo, H Kocher, S J Leedham, A Sottoriva, T A Graham
Journal: Cancer Research (2020)
Management of Dyspnea in Advanced Cancer: ASCO Guideline
Authors: David Hui, Kari Bohlke, Ting Bao, Toby C. Campbell, Patrick J. Coyne, David C. Currow, Arjun Gupta, Aliza L. Leiser, Masanori Mori, Stefano Nava, Lynn F. Reinke, Eric J. Roeland, Carole Seigel, Declan Walsh, Margaret L. Campbell
Journal: Journal of Clinical Oncology (2021)

PURPOSE To provide guidance on the clinical management of dyspnea in adult patients with advanced cancer. METHODS ASCO convened an Expert Panel to review the evidence and formulate recommendations. An Agency for Healthcare Research and Quality (AHRQ) systematic review provided the evidence base for nonpharmacologic and pharmacologic interventions to alleviate dyspnea. The review included randomized controlled trials (RCTs) and observational studies with a concurrent comparison group published through early May 2020. The ASCO Expert Panel also wished to address dyspnea assessment, management of underlying conditions, and palliative care referrals, and for these questions, an additional systematic review identified RCTs, systematic reviews, and guidelines published through July 2020. RESULTS The AHRQ systematic review included 48 RCTs and two retrospective cohort studies. Lung cancer and mesothelioma were the most commonly addressed types of cancer. Nonpharmacologic interventions such as fans provided some relief from breathlessness. Support for pharmacologic interventions was limited. A meta-analysis of specialty breathlessness services reported improvements in distress because of dyspnea. RECOMMENDATIONS A hierarchical approach to dyspnea management is recommended, beginning with dyspnea assessment, ascertainment and management of potentially reversible causes, and referral to an interdisciplinary palliative care team. Nonpharmacologic interventions that may be offered to relieve dyspnea include airflow interventions (eg, a fan directed at the cheek), standard supplemental oxygen for patients with hypoxemia, and other psychoeducational, self-management, or complementary approaches. For patients who derive inadequate relief from nonpharmacologic interventions, systemic opioids should be offered. Other pharmacologic interventions, such as corticosteroids and benzodiazepines, are also discussed. Additional information is available at www.asco.org/supportive-care-guidelines .
BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting
Authors: Noa Dagan, Noam Barda, Eldad Kepten, Oren Miron, Shay Perchik, Mark A Katz, Miguel A Hernán, Marc Lipsitch, Ben Reis, Ran D Balicer
Journal: New England Journal of Medicine (2021)

BackgroundAs mass vaccination campaigns against coronavirus disease 2019 (Covid-19) commence worldwide, vaccine effectiveness needs to be assessed for a range of outcomes across diverse populations in a noncontrolled setting. In this study, data from Israel's largest health care organization were used to evaluate the effectiveness of the BNT162b2 mRNA vaccine.MethodsAll persons who were newly vaccinated during the period from December 20, 2020, to February 1, 2021, were matched to unvaccinated controls in a 1:1 ratio according to demographic and clinical characteristics. Study outcomes included documented infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), symptomatic Covid-19, Covid-19–related hospitalization, severe illness, and death. We estimated vaccine effectiveness for each outcome as one minus the risk ratio, using the Kaplan–Meier estimator.ResultsEach study group included 596,618 persons. Estimated vaccine effectiveness for the study outcomes at days 14 through 20 after the first dose and at 7 or more days after the second dose was as follows: for documented infection, 46% (95% confidence interval [CI], 40 to 51) and 92% (95% CI, 88 to 95); for symptomatic Covid-19, 57% (95% CI, 50 to 63) and 94% (95% CI, 87 to 98); for hospitalization, 74% (95% CI, 56 to 86) and 87% (95% CI, 55 to 100); and for severe disease, 62% (95% CI, 39 to 80) and 92% (95% CI, 75 to 100), respectively. Estimated effectiveness in preventing death from Covid-19 was 72% (95% CI, 19 to 100) for days 14 through 20 after the first dose. Estimated effectiveness in specific subpopulations assessed for documented infection and symptomatic Covid-19 was consistent across age groups, with potentially slightly lower effectiveness in persons with multiple coexisting conditions.ConclusionsThis study in a nationwide mass vaccination setting suggests that the BNT162b2 mRNA vaccine is effective for a wide range of Covid-19–related outcomes, a finding consistent with that of the randomized trial.