tbuckley/cabot-search huggingface dataset:
Advancing Healthcare Reform: The American Heart Association’s 2020 Statement of Principles for Adequate, Accessible, and Affordable Health Care: A Presidential Advisory From the American Heart Association
Authors: John J. Warner, Ivor J. Benjamin, Keith Churchwell, Grace Firestone, Timothy J. Gardner, Janay C. Johnson, Jackie Ng-Osorio, Carlos J. Rodriguez, Lynn Todman, Kristine Yaffe, Clyde W. Yancy, Robert A. Harrington
Journal: Circulation (2020)

The mission of the American Heart Association is to be a relentless force for a world of longer, healthier lives. The American Heart Association has consistently prioritized the needs and perspective of the patient in taking positions on healthcare reform while recognizing the importance of biomedical research, providers, and healthcare delivery systems in advancing the care of patients and the prevention of disease. The American Heart Association's vision for healthcare reform describes the foundational changes needed for the health system to serve the best interests of patients and to achieve health care and coverage that are adequate, accessible, and affordable for everyone living in the United States. The American Heart Association is committed to advancing the dialogue around healthcare reform and has prepared this updated statement of our principles, placed in the context of the advances in coverage and care that have occurred after the passage of the Affordable Care Act, the rapidly changing landscape of healthcare delivery systems, and our evolving recognition that efforts to prevent cardiovascular disease can have synergistic benefit in preventing other diseases and improving overall well-being. These updated principles focus on expanding access to affordable health care and coverage; enhancing the availability of evidence-based preventive services; eliminating disparities that limit the availability and equitable delivery of health care; strengthening the public health infrastructure to respond to social determinants of health; prioritizing and accelerating investments in biomedical research; and growing a diverse, culturally competent health and healthcare workforce prepared to meet the challenges of delivering high-value health care.
Regorafenib dose escalation therapy for patients with refractory metastatic colorectal cancer (RECC Study).
Authors: Masato Nakamura, Takeshi Yamada, Shun Ishiyama, Masanobu Enomoto, Hajime Yokomizo, Chihiro Kosugi, Hiromichi Sonoda, Kei Ishimaru, Keiichiro Ishibashi, Hidekazu Kuramochi, Keijiro Nozawa, Ryo Ohta, Makoto Takahashi, Hiroshi Yoshida, Yojiro Hashiguchi, Keiji Hirata, Kenji Katsumata, Hideyuki Ishida, Keiji Koda, Kazuhiro Sakamoto
Journal: Journal of Clinical Oncology (2020)

116 Background: Regorafenib, a multi-kinase inhibitor, significantly improved overall survival in previously treated metastatic colorectal cancer (mCRC) patients in the phase 3 CORRECT trial. Despite its significant benefits, various toxicities such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited regorafenib use. The toxicities occur soon after treatment initiation, typically within the first cycle, and later improve. Although the standard daily dose of regorafenib is 160 mg, physicians have adopted various dosing regimens in clinical practice, indicating the need to optimize the dosing strategy to maintain the antitumor benefits. The ReDOS study demonstrated the effectiveness of a weekly dose-escalating strategy (WDES) of regorafenib starting with a lower daily dose. We conducted the phase II RECC study to evaluate the safety and efficacy of WDES for regorafenib in an Asian population. Methods: Patients with sufficient organ function who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3 if no severe drug-related toxicities were observed. The primary endpoint was progression-free survival (PFS) and secondary endpoints were time to treatment failure (TTF), response rate (RR), overall survival (OS), and safety. Tumor response and progression were assessed radiologically every 8 weeks. Results: From March 2017 to November 2018, 57 eligible patients were enrolled and all started regorafenib at 80 mg/day. Thirty-five patients (61%) were subsequently escalated to 120 mg/day and 16 (28%) to 160 mg/day. Forty patients (70.2%) finished Cycle 2 at 8 weeks. Only 8 patients (14%) discontinued treatment because of adverse events. The median PFS was 1.9 months, RR was 0%, and disease control rate was 32%. The most frequent adverse event ≥grade 3 was hypertension (17.5%), followed by HFSR (14%). No treatment-related deaths occurred. Conclusions: Regorafenib dose escalation was well tolerated with PFS similar to that reported in the CORRECT study, indicating that WDES may represent an option for regorafenib administration. Clinical trial information: UMIN000028933.
Real-world treatment attrition rates in advanced esophagogastric cancer.
Authors: Erica S Tsang, Howard John Lim, Daniel John Renouf, Janine Marie Davies, Jonathan M. Loree, Sharlene Gill
Journal: Journal of Clinical Oncology (2020)

e19301 Background: Over the last decade, multiple agents have demonstrated efficacy for advanced esophagogastric cancer (EGC). Despite the availability of later lines of therapy, there remains limited real-world data about the treatment attrition rates between lines of therapy. We sought to characterize the use and attrition rates between lines of therapy for patients with advanced EGC. Methods: We identified patients who received at least one cycle of chemotherapy for advanced EGC between July 1, 2017 and July 31, 2018 across 6 regional centers in British Columbia (BC), Canada. Clinicopathologic, treatment, and outcomes data were extracted by chart review. Patients who continued on treatment were censored at the date of last contact. Results: Of 245 patients who received at least one line of therapy, median age was 65.7 years (IQR 58.2-72.3) and 186 (76%) were male, ECOG PS 0/1 (80%), gastric vs. GEJ (36% vs. 64%). Histologies included adenocarcinoma (78%), squamous cell carcinoma (8%), and signet ring (14%), with 31% HER2 positive. 72% presented with de novo disease, and 25% had received previous chemoradiation. There was a high level of treatment attrition, with patients receiving only one line of therapy (n = 122, 50%), two lines (n = 83, 34%), three lines (n = 34, 14%), and four lines (n = 6, 2%). Kaplan-Meier survival analysis demonstrated improved survival with increasing lines of therapy (median overall survival 7.7 vs. 16.6 vs. 22.8 vs. 40.4 months, p&lt; 0.05). On multivariable Cox regression, improved survival was associated with better baseline ECOG and increased lines of therapy ( p&lt; 0.05). Conclusions: The steep attrition rates between therapies highlight the unmet need for more efficacious earlier-line treatment options for patients with advanced EGC. [Table: see text]
Caspases in Cell Death, Inflammation, and Pyroptosis
Authors: Sannula Kesavardhana, R.K. Subbarao Malireddi, Thirumala-Devi Kanneganti
Journal: Annual Review of Immunology (2020)

Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D-induced pyroptosis.
Tissue levels of steroid hormones and their receptors, prolactin, and SHBG in patients with gastric cancer.
Authors: Oleg Ivanovich Kit, Elena M. Frantsiyants, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Nikolay S. Samoylenko
Journal: Journal of Clinical Oncology (2020)

448 Background: Hormones and their receptors are important effectors providing interconnection between the primary tumor and metastatic niches. The aim of the study was to determine levels of steroid hormones and their receptors, prolactin (PRL) and SSBG in tissues of gastric cancer (GC), omentum and peritoneum. Methods: Levels of steroid hormones and their receptors, PRL and SSBG were determined by ELISA in tissues of primary tumors, omentum and peritoneum in main groups: 1 (M 0 ) – GC T 3-4 а N 0-3 M 0 (n = 24) and 2 (M 1 ) – GC T 3-4 а N 0-3 M 1 (n = 21); in tissues of the stomach, omentum and peritoneum – in the control group (non-cancer patients, n = 17). Results: In GC (М 1 ), estradiol was reduced in primary tumors, omentum and peritoneum by 4.2, 4.0 and 8.6 times, respectively; increased levels of free testosterone (by 18.9, 2.0 and 2.8 times) and PRL (by 8.0, 7.6 and 1.7 times) were observed (p &lt; 0.05). GC (М 0 ) was characterized by high levels of estrogen receptors (ER) α – by 1.2 times (p &lt; 0.05), progesterone (PR) – by 3.5 times and SSBG – by 1.4 times (p &lt; 0.05); tissues of the omentum and peritoneum showed increased levels of ERα – by 2.4 and 3.9 times, ERβ – by 1.5 (p &lt; 0.05) and 2.5 times, РR – by 2.2 and 1.5 times (p &lt; 0.05). GC (М 1 ) had low ERα levels. Conclusions: Decreased levels of estradiol, together with elevated levels of free testosterone and prolactin, in tumor tissues can be considered marking for peritoneal metastases. Correlation between the content of these hormones in the omentum and peritoneum and the presence of metastasis in the organs confirms the “seed and soil” principle.
Feasibility of endoscopic resection in gastric gastrointestinal stromal tumor.
Authors: Yuri Kim, Hwoon-Yong Jung, Do Hoon Kim, Jeong Hoon Lee, Kee Don Choi, Ji Yong Ahn, Hee Kyong Na, Young Soo Park
Journal: Journal of Clinical Oncology (2020)

822 Background: Endoscopic resection (ER) can be applied for small SETs of stomach. GISTs can be diagnosed pathologically after resection. Initially we used ESD. Submucosal tunneling endoscopic resection (STER) was introduced for overcoming limitations of ESD. However, STER was very difficult to apply for gastric lesions. We developed new ER method, clip-assisted surgical endoscopy (CASE, Jung's method). In this study, we evaluate the feasibility of ER for GISTs and compared 3 ER methods. Methods: Medical records of 53 patients who diagnosed GISTs after ER for SETs from 2005 to 2019 were reviewed retrospectively. Average age was 60.0 ± 10.6 years. ESD, STER and CASE were performed for 23, 5, and 25 patients, respectively. Clinical characteristics, procedure times, and outcomes of each endoscopic technique were analyzed. Results: Average pathological size of GIST was 2.1 cm. 94.3% proved to be very low risk of malignant potential. Location of SETs were different; ESD applied mainly for body lesions, STER tried for fundus lesions, CASE also mainly for fundus and high body lesions. Overall R0 and R1 resection rate was 62.3%, and 35.8%. There are 34 patients who had complications after the procedure (21 micro-perforation, 12 macro-perforation, 1 bleeding), but perforation would be a part of ER procedure for SETs. In ESD, some macro-perforations was a reason for surgical conversion. Four patients (2 ESD, 1 STER, 1 CASE) underwent surgical conversion during ER. STER had the longest procedure time (50.3, 95.2 and 40.7 min, P = 0.018). After development of CASE procedure, we can reduce procedure time and on-site surgical conversion. R0 resection rate was highest in CASE. No R1 resected patients were recurrent so far. Conclusions: ER seems to be safe and effective therapeutic options for removing small gastric GISTs. Using CASE (Jung's method), ER would be more comfortable especially in the fundus lesions.
Evaluating maintenance therapies in advanced oesophago-gastric adenocarcinoma (OGA): Interim analysis and biomarker results from the PLATFORM study.
Authors: David Cunningham, Caroline Yean Kit Fong, Clare Peckitt, Gayathri Anandappa, Michael Davidson, Bijal Patel, Andrea Turner, Ruwaida Begum, Catherine Cafferkey, Katharina von Loga, Marlon Rebelatto, Russell D. Petty, Madeleine Hewish, Tom Roques, Fareeda Y. Coxon, Carys Morgan, Jonathan Wadsley, Tom Waddell, Naureen Starling, Ian Chau
Journal: Journal of Clinical Oncology (2020)

282 Background: Advanced OGA patients (pts) are treated with platinum-based 1 st line chemotherapy but the role of maintenance therapy once disease control is obtained is unknown. Methods: PLATFORM is a prospective, open-label, adaptive phase II trial assessing maintenance therapy in OGA. HER2 negative pts with advanced OGA achieving response or stable disease on completion of 1 st line platinum-based chemotherapy were initially randomised to surveillance (A1), capecitabine (A2) and durvalumab (A3). Rucaparib (A4) and capecitabine+ramucirumab (A5) were subsequently added as part of adaptive design. Primary endpoint is progression-free survival with target recruitment of 154pts/arm. A pre-planned futility interim analysis (IA) is triggered when 61 pts/arm are recruited and evaluable using 12-week progression-free rate (PFR). Individual arms will continue accrual if the upper limit of 1-sided 95% CI difference is &gt; 0 when compared to A1. Biomarker analyses of A1 and A3 IA patients include: PDL1 as tumour and immune cell combined proportion (TIP), multiplex IHC of tumour infiltrating lymphocytes (TILs), TMB and MSI status by whole exome sequencing. Results: To date, 1053 pts have registered prior to or during 1 st line therapy and 356 pts randomised. Primary attrition was due to disease progression. Baseline demographics in the IA population (arms A1 to A3, n = 183) were male (81%); median age 65 yrs; metastatic disease (92%); oesophageal (40%), OG junction (28%) and gastric (32%) primary. 12-week PFR were A1: 51% (95%CI: 38-64%); A2: 52% (95%CI: 40-65%); A3: 49% (95%CI: 36-62%). PFR differences to arm A1 were A2: 1.6% (95%CI: -13.2 to 16.5%); A3: -1.6% (95%CI: -16.5 to 13.3%). In A1, PFR was 53% vs 43% in PDL1 TIP &lt; 10% and ≥10% respectively. In A3, PFR was 51% vs 100% in PDL1 TIP &lt; 10% and ≥10% respectively. 3 pts in A3 had partial response; none were seen in A1 and A2. Density of TILs subsets, TMB and MSI data will be presented. Conclusions: PLATFORM IA did not indicate futility in maintenance capecitabine or durvalumab compared to surveillance in advanced OGA and will continue to target accrual. Incremental radiological responses were observed with maintenance durvalumab only. Clinical trial information: NCT02678182.
Homologous recombination deficiency (HRD) by BROCA-HR and survival outcomes after surgery for patients (pts) with pancreatic adenocarcinoma (PC): A single institution experience.
Authors: Amy E. Chang, David Bing Zhen, Marc Radke, Kelsey K. Baker, Andrew L. Coveler, Kit Man Wong, Venu Gopal Pillarisetty, Mary Weber Redman, Elizabeth Swisher, E. Gabriela Chiorean
Journal: Journal of Clinical Oncology (2020)

732 Background: 5-7% of PC pts exhibit deleterious germline mutations (MUT) in HR tumor suppressor genes BRCA1 and BRCA2. BROCA-HR is a targeted capture and massively parallel sequencing assay designed to detect all mutation classes including gene rearrangements, copy number variations, and gene aberrations within the Fanconi Anemia-BRCA HR, non-homologous end joining (NHEJ) DNA repair, and DNA mismatch repair pathways. BROCA-HR has been successfully used in breast and ovarian cancer pts for overall prognosis and prediction of response to platinum-based therapies. While BRCA1/2 MUT may confer survival advantage for PC pts if treated with platinum-chemotherapy, the survival impact of HRD is less well defined. Methods: We retrospectively identified 100 consecutive pts who underwent surgical resection for suspected PC at University of Washington Medical Center between 1999 and 2008. Formalin-fixed paraffin embedded resected tumors were sequenced using BROCA-HR. HRD was grouped based on the following deleterious genetic mutations: 1) BRCA1, BRCA2; 2) core HRD: BARD1, BRIP1, RAD51C, RAD51D, PALB2, CDK12, NBN; 3) non-core HRD: ATM, ATR, ATRX, BAP1, BLM, CHEK1/2, ERCC, FANC A/C/D2/E /F/G/L, MRE11, RAD50/51/51B, RIF1, SLX4; 4) HR proficient. Overall survival (OS) was measured from diagnosis until death or last follow-up. Results: 95 pts had histologically confirmed PC, and 81 pts had adequate tumor DNA for analysis. Six pts (7%) had BRCA1/2 MUT (n = 5), or BRCA1 methylation (n = 1), 1 pt (1%) had non-BRCA core HRD ( PALB2 MUT), 7 pts (9%) had non-core HRD: ERCC (2), CHEK2 (2), ATR, RAD51D, and FANCA MUT (1 each). Median OS was: all pts 1.93 yrs (95% C.I. 1.53, 2.16), BRCA1/2 pts 3.09 yrs (95% CI 0.41, 12.21), all core HRD pts 1.21 yrs (95% CI 0.41, 12.21), all core and non-core HRD pts 1.89 yrs (95% CI 0.57, 4.96), HR proficient pts 1.93 yrs (95% CI 1.51, 2.15). There were no OS differences between pts with HRD vs those HR proficient. Conclusions: HRD is common (17%) but does not affect OS for pts with resected PC. Prospective clinical trials should test neo/adjuvant therapies including platinum chemotherapy and PARP inhibitors for pts with HRD.
Surgical clinical treatment of malignant pleural mesothelioma: Retrospective analysis if 15 years
Authors: Ricardo Mingarini Terra, Benoit Bibas, Priscila Berenice Costa, Mauro Federico Tamagno, Teresa Yae Takagaki, Ricardo Beyruti, Gilberto de Castro Junior, Paulo Manuel Pego-Fernandes
Journal: Journal of Thoracic Oncology (2014)
An institutional series of early-onset pancreatic cancer (EOPC): Clinical outcomes and genetic and supportive care referral patterns.
Authors: Kunal C. Kadakia, Sally Jeanne Trufan, Megan Jagosky, William Mills Worrilow, Bradley W. Harrison, Katherine Broyhill, Nicole Lee Gower, Harris Coley, Jimmy J. Hwang, Laura W. Musselwhite, Reza Nazemzadeh, Seungjean Chai, John Stuart Salmon, Edward S. Kim, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2020)

652 Background: The incidence of EOPC is rising and is associated with substantial implications for affected individuals and their families. Little is known about the extent of physician referrals of these patients (pts) to genetic, supportive care, and hospice services. Methods: Pts with EOPC (≤50 years) were identified using the institutional tumor registry for years 2011-2018 and retrospectively reviewed. Clinical data and rates of referral to supportive, genetic and hospice services were retrieved. Descriptive analyses were performed with 25-75% interquartile ranges (IQR) where appropriate. Overall survival (OS) was assessed using Kaplan-Meier curves and Cox Proportional Hazards modeling. Results: In total, 113 pts with EOPC and a median age of 47 years (range, 28-50) were analyzed. Of these 113 pts, 43% were female, 27% were black, and 45% had metastatic disease at initial presentation. The most commonly administered first line chemotherapy was FOLFIRINOX, with gemcitabine/nab-paclitaxel reserved for the second line. The median OS of pts with metastatic disease was 5.8 compared to 15.8 months for those without metastases. Only 28% of pts were referred to genetic services, and 72% of these underwent genetic testing. Out of the genetically tested pts, pathogenic germline mutations were confirmed for 33%. Of the original 113 pts, 41% received concurrent palliative care, which was provided at a median of 2.4 mos. (IQR, 0.7-6.8) preceding death. The median time between last chemotherapy administered and death was 2 mos. (IQR, 1-4.4), with 23% receiving treatment within the last month of life. Only 55% used hospice services prior to death for a median duration of 0.5 mos. (IQR, 0.2-1.4). Conclusions: Our study suggests that there is a tendency for late utilization of supportive and hospice care in pts with EOPC, possibly due to the desire of both pts and physicians to be more aggressive given the young age. Larger studies are warranted to elucidate barriers to concurrent supportive care, and whether formation of specialized young patient supportive care clinics would aid this situation and to avoid the use of unnecessary chemotherapy near the end of life.
Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors
Authors: Lin Luo, Mateusz C. Ambrozkiewicz, Fritz Benseler, Cui Chen, Emilie Dumontier, Susanne Falkner, Elisabetta Furlanis, Andrea M. Gomez, Naosuke Hoshina, Wei-Hsiang Huang, Mary Anne Hutchison, Yu Itoh-Maruoka, Laura A. Lavery, Wei Li, Tomohiko Maruo, Junko Motohashi, Emily Ling-Lin Pai, Kenneth A. Pelkey, Ariane Pereira, Thomas Philips, Jennifer L. Sinclair, Jeff A. Stogsdill, Lisa Traunmüller, Jiexin Wang, Joke Wortel, Wenjia You, Nashat Abumaria, Kevin T. Beier, Nils Brose, Harold A. Burgess, Constance L. Cepko, Jean-François Cloutier, Cagla Eroglu, Sandra Goebbels, Pascal S. Kaeser, Jeremy N. Kay, Wei Lu, Liqun Luo, Kenji Mandai, Chris J. McBain, Klaus-Armin Nave, Marco A.M. Prado, Vania F. Prado, Jeffrey Rothstein, John L.R. Rubenstein, Gesine Saher, Kenji Sakimura, Joshua R. Sanes, Peter Scheiffele, Yoshimi Takai, Hisashi Umemori, Matthijs Verhage, Michisuke Yuzaki, Huda Yahya Zoghbi, Hiroshi Kawabe, Ann Marie Craig
Journal: Neuron (2020)
Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction (DE/GEJ) cancers.
Authors: Irene S. Yu, Shiru Lucy Liu, Yizhou Zhao, Sally CM Lau, Howard John Lim
Journal: Journal of Clinical Oncology (2020)

452 Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responder (R, ≥ 35% decrease in max SUV) and non-responder (NR, &lt; 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts identified, 52% had pre- and post-induction PETs; 232 pts proceeded to surgery and were included for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p&gt;0.05). Median time from end of treatment to PET was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response (PCR) rates were similar for PET-R vs. PET-NR (14% vs. 13%, p=0.08). The discordance rate between PET vs. pathologic response was 34% (Table). Aborted surgery rate was higher in the PET-NR group (8% vs. 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the two groups (PET-R 31.5 mo vs. PET-NR 36.1 mo, p=0.62). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility and was associated with a significant pathology discordance rate. The role of PET/CT is evolving and the use of post-induction imaging for response assessment and prognostic value may be questionable. [Table: see text]