tbuckley/cabot-search huggingface dataset:
Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease
Authors: Zhe Lu, Hannelore P. Van Eeckhoutte, Gang Liu, Prema M. Nair, Bernadette Jones, Caitlin M. Gillis, B. Christina Nalkurthi, Fien Verhamme, Tamariche Buyle-Huybrecht, Peter Vandenabeele, Tom Vanden Berghe, Guy G. Brusselle, Jay C. Horvat, James M. Murphy, Peter A. Wark, Ken R. Bracke, Michael Fricker, Philip M. Hansbro
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Necroptosis, mediated by RIPK3 (receptor-interacting protein kinase 3) and MLKL (mixed lineage kinase domain-like), is a form of regulated necrosis that can drive tissue inflammation and destruction; however, its contribution to chronic obstructive pulmonary disease (COPD) pathogenesis is poorly understood. Objectives: To determine the role of necroptosis in COPD. Methods: Total and active (phosphorylated) RIPK3 and MLKL were measured in the lung tissue of patients with COPD and control subjects without COPD. Necroptosis-related mRNA and proteins as well as cell death were examined in lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3-/- and Mlkl-/- mice to acute and chronic CS exposure were compared with those of wild-type mice. The combined inhibition of apoptosis (with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone [qVD-OPh]) and necroptosis (with deletion of Mlkl in mice) was assessed. Measurements and Main Results: The total MLKL protein in the epithelium and macrophages and the pRIPK3 and pMLKL in lung tissue were increased in patients with severe COPD compared with never-smokers or smoker control subjects without COPD. Necroptosis-related mRNA and protein levels were increased in the lungs and macrophages in CS-exposed mice and experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation upon acute CS exposure. Ripk3 deficiency reduced airway inflammation and remodeling as well as the development of emphysematous pathology after chronic CS exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodeling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung-cell death. Conclusions: Necroptosis is induced by CS exposure and is increased in the lungs of patients with COPD and in experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodeling, and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD.
Pre-screening as a tool for increasing oncology trial enrollment.
Authors: Jennifer J. Wu, Amin Yakubov, Mohammad Maher Abdul Hay, Erica Love, Gianna Kroening, Deirdre Jill Cohen, Christy Spalink, Ankeeta Joshi, Arjun Vasant Balar, Kathie-Ann P. Joseph, Joseph Ravenell, Janice M. Mehnert
Journal: Journal of Clinical Oncology (2021)

1577 Background: Recruiting underserved patients onto therapeutic oncology trials is imperative in light of cancer disparities. Many institutions have increased enrollment with data mining tools that match patients to clinical trials, but such expensive tools are unavailable in a public safety net healthcare system. Methods: The NYU Perlmutter Cancer Center Clinical Trials Office implemented a quality improvement program aimed to increase therapeutic trial enrollment at Bellevue Cancer Center (BCC), an affiliated public hospital. The initiative utilized one employee to manually pre-screen patients via the EMR, cancer registries, and conferences. The program aimed to identify eligible patients for therapeutic trials and those subsequently enrolled. Results: During the two years preceding the pre-screening program, 31 patients were enrolled onto therapeutic clinical trials at BCC. For a period of two years (7/2017-7/2019) following the initiation of this program, 255 patients were identified, of which 143 (56.1%) enrolled onto trials. Of those enrolled, 55 were referred to NYU for trials not open at BCC. Among the 143 enrolled patients, 64% were female, 56% were non-white, and 57% did not speak English (spanning 16 languages). The median age was 55, and the top three disease groups were breast, GI, and thoracic. 83% of our patients reside in low-income areas, with 62% in both low income and Health Professional Shortage Areas (HPSA). Conclusions: Dedicating one employee to screening led to a 4.6 fold increase in accruals, successfully augmenting therapeutic trial enrollment in a healthcare setting with scarce resources, providing broader access to clinical trials for underserved populations.[Table: see text]
Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score
Authors: Chi Gao, Eric C. Polley, Steven N. Hart, Hongyan Huang, Chunling Hu, Rohan Gnanaolivu, Jenna Lilyquist, Nicholas J. Boddicker, Jie Na, Christine B. Ambrosone, Paul L. Auer, Leslie Bernstein, Elizabeth S. Burnside, A. Heather Eliassen, Mia M. Gaudet, Christopher Haiman, David J. Hunter, Eric J. Jacobs, Esther M. John, Sara Lindström, Huiyan Ma, Susan L. Neuhausen, Polly A. Newcomb, Katie M. O'Brien, Janet E. Olson, Irene M. Ong, Alpa V. Patel, Julie R. Palmer, Dale P. Sandler, Rulla Tamimi, Jack A. Taylor, Lauren R. Teras, Amy Trentham-Dietz, Celine M. Vachon, Clarice R. Weinberg, Song Yao, Jeffrey N. Weitzel, David E. Goldgar, Susan M. Domchek, Katherine L. Nathanson, Fergus J. Couch, Peter Kraft
Journal: Journal of Clinical Oncology (2021)

This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population.
Effect of ethnicity and chemotherapy (mFOLFOX6) on zolbetuximab pharmacokinetics in patients with claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ).
Authors: Keun-Wook Lee, Samuel J Klempner, Jianning Yang, Amit Desai, Akihiro Yamada, Yoko Ueno, Tomasz Wojtkowski, Jung Wook Park, Janet Pavese, Fotios Loupakis, Yung-Jue Bang, Kohei Shitara
Journal: Journal of Clinical Oncology (2021)

e16078 Background: Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets Claudin 18.2 (CLDN18.2), a tight junction protein that is normally confined to gastric mucosa but is retained in G/GEJ. A phase 2 (NCT01630083, FAST) trial demonstrated significantly prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. Two global phase 3 studies are ongoing, comparing zolbetuximab + chemotherapy vs chemotherapy as first-line treatment in CLDN18.2-positive G/GEJ. This study assessed the influence of ethnic differences and chemotherapy on the pharmacokinetics (PK) of zolbetuximab in patients (pts) with G/GEJ and the potential effect of zolbetuximab on chemotherapy PK. Methods: In the Japanese phase 1 and global phase 2 studies, adult pts with CLDN18.2-postitive G/GEJ received zolbetuximab 800 mg/m 2 IV on Cycle 1 Day 1 (Cycle 1 Day 3 in Cohort 2 of phase 2) then 600 mg/m 2 Q3W. Phase 1 and Cohort 1A of the phase 2 study assessed zolbetuximab monotherapy in 21-day cycles. Cohort 2 of the phase 2 study assessed zolbetuximab + mFOLFOX (5-FU, folinic acid, oxaliplatin; 4 cycles) in 42-day cycles (Q2W from Cycle 1 Day 1). Blood samples for zolbetuximab PK following single and multiple doses, and for chemotherapy (5-FU and oxaliplatin) PK alone or with zolbetuximab were collected. Maximum serum drug concentration (C max ) and area under the concentration-time curve from 0-21 days (AUC 0-21 ) were assessed. Potential ethnic differences in zolbetuximab exposures across Japanese, other Asian (Korean and Taiwanese), and Western pts, and the potential drug-drug interaction between zolbetuximab and chemotherapy were evaluated. Results: Zolbetuximab concentration profiles and PK parameters were generally comparable across Japanese, other Asian, and Western populations (Table). Zolbetuximab PK properties were similar between monotherapy and combination therapy cohorts (Table). Chemotherapy PK was comparable with and without zolbetuximab. Conclusions: The analyses suggest no apparent ethnic differences in zolbetuximab PK across Japanese/Asian and Western pts and no PK interactions between zolbetuximab and mFOLFOX6. These results support the use of zolbetuximab and mFOLFOX without the need for dose adjustment in global phase 3 trials. Clinical trial information: NCT03505320, NCT03528629. [Table: see text]
Efficacy and safety of anlotinib plus TQB2450 in patients with advanced soft tissue sarcoma: A multicenter, single armed, phase 1b trial.
Authors: Jiayong Liu, Zhengfu Fan, Wei Guo, Tian Gao, Shu Li, Jie Xu, Chujie Bai, Ruifeng Xue, Lu Zhang, Lu Xie, Zhichao Tan
Journal: Journal of Clinical Oncology (2021)

11547 Background: Anlotinib, a multitargeted tyrosine kinase inhibitor, had been prove to be effective for the treatment of advanced or metastatic soft tissue sarcoma(STS) faild anthracycline chemotherapy. With the lack of prospective data of combination of PDL-1 inhibitor and antiangiogenic agent, we designed a phase 1b study to investigated the efficacy and safety of anlotinib plus TQB2450 in patients with STS. Methods: Eligible patients (age 18-70, ECOG 0-1, with histopathologically confirmed advanced STS, at least one measurable lesion according to RECIST 1.1, and previously received front-line anthracycline chemotherapy) were included and received anlotinib (12mg qd, D1-14, 21d/cycle) plus TQB2450 (1200 mg, IV, D1, 21d/cycle) until disease progression or intolerable toxicities.The primary endpoint was objective response rate (ORR), secondary endpoints included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR). Results: From January 2019 to January 2021, 30 pts were enrolled1, 12 alveolar soft part sarcoma and 18 others (7 synovial sarcoma, 4 leiomyosarcoma, 5 undifferentiated pleomorphic sarcoma, 1 fibrosarcoma and 1 epithelioid sarcoma). ORR by RECIST was 36.7%, DCR was 83.3%, 11/30 pts had PR, 14/30 (46.7%) had SD, 5/30 (16.7%) PD. Median PFS was 9.6 m in all pts and 4.9m. in non-ASPS, respectively. Median OS in non-ASPS was 10.27m, while mOS in all pts and both mPFS and mOS in ASPS had not been reached. Notably, to ASPS pts, ORR was 75%, and DCR was 100%. The most common 1-2 grade treatment-related adverse reaction (TRAE) was hypothyroidism (19/30,63.3%)，hypercholesterolemia (16/30, 53.3%) and hypertriglyceridemia (16/30, 53.3%), the most common ≥3 grade TRAEs were hypertriglyceridemia (3/30, 10%). 6 SAE (20%) occurred, including 2 pneumothorax, 1 Immune associated hapatic injury, 1 hypotension, 1 Immune myocarditis and 1 diabetic ketoacidosis. Conclusions: The combination of anlotinib and TQB2450 showed promising activity in second-line treatment of advanced STS, especially in ASPS, with well tolerance and acceptable toxicity.
Online consultations are the solution—but to which problems?
Authors: Richard Pratt
Journal: BMJ (2021)

Widespread adoption of online consultations during the pandemic has meant that they have been tested extensively in live settings. They were implemented to reduce the risk of transmission of covid-19, but what problems do they solve now and how can they help? Three broad themes occur: access, triage, and flexibility of working.

By priming a telephone encounter with information from an online template we can achieve shared understanding much earlier in the conversation and so build empathy, even …
Systematic literature review of the real-world burden and use of chemotherapies for treatment of advanced or recurrent endometrial carcinoma.
Authors: Qi Zhao, Rachel Hughes, Ishaaq Altaf-Haroon, Emma Schiller, Ananth Kadambi
Journal: Journal of Clinical Oncology (2021)

e17571 Background: Women diagnosed with advanced or recurrent endometrial cancer (EC) have a poor prognosis, with a 5-year survival of only 15% to 17%. While a multi-modality approach is often used for newly diagnosed EC including platinum-based chemotherapy, there are no definitively approved standard treatment options for advanced or recurrent EC following prior systemic therapy (FPST). The real-world evidence surrounding the effectiveness of chemotherapies in this setting is not well characterized. We conducted a systematic literature review to attempt to fill this evidence gap. Methods: Systematic searches were run in Embase, MEDLINE, and the Cochrane Library to identify English-language publications from January 2000 to July 2020. Additional hand searches of 5 key conferences held from 2018 to 2020 were also conducted. The review included observational studies reporting the clinical effectiveness, safety, or treatment patterns of pharmacological treatments in adult women with advanced or recurrent EC. Results: Seventy-seven observational studies met the inclusion criteria, of these 63 studies reported on the effectiveness of chemotherapies. While 57 studies described adjuvant chemotherapy use, 6 described use of chemotherapies FPST, including 1 study in the second line or later. Only one of these 6 studies reported a sample size greater than 100 patients. Chemotherapy FPST included paclitaxel/carboplatin (3 studies), doxorubicin (2 studies), etoposide (1 study), or any platinum-based chemotherapy (1 study). Shorter median overall survival (OS) was observed in patients with treatment-free intervals (TFI) &lt; 6 months from prior systemic therapy (5.5-11.3 months; 2 studies) compared to those with TFI &gt; 6 months (13.0-27.0 months; 3 studies). Similarly, shorter median progression-free survival (PFS) was seen in patients with TFI &lt; 6 months from prior systemic therapy (2.0-3.2 months; 2 studies) vs. those with TFI &gt; 6 months (6.0-10.0 months; 3 studies). Conclusions: Women with advanced or recurrent EC have poor OS and PFS with current chemotherapy regimens, especially for those with TFI &lt; 6 months. The time at recurrence from prior systemic therapy seems to correlate with the outcomes of subsequent treatment. Novel efficacious treatment strategies are required to improve patients’ outcomes in the FPST setting. While extensive real-world evidence exists for patients with EC receiving adjuvant chemotherapy, real world data is limited for use of chemotherapy in advanced or recurrent setting, warranting further research in larger samples of patients.
Valosin-Containing Protein Stabilizes Mutant p53 to Promote Pancreatic Cancer Growth
Authors: Jieqiong Wang, Yajie Chen, Canhua Huang, Qian Hao, Shelya X. Zeng, Sara Omari, Yu Zhang, Xiang Zhou, Hua Lu
Journal: Cancer Research (2021)

Abstract Approximately 80% of human pancreatic ductal adenocarcinomas (PDAC) harbor TP53 mutations, among which, R273H is the most frequent. Although p53-R273H is known to possess gain-of-function properties, how it is regulated in PDAC has not been extensively explored. Here we identify valosin-containing protein (VCP) as a regulator of p53-R273H by conducting immunoprecipitation-tandem mass spectrometry analysis. VCP bound p53-R273H at its DNA binding domain. Ectopic or endogenous VCP stabilized p53-R273H by binding to MDM2 and disrupting its association with mutant p53. Inhibition of VCP either by genetic depletion or the pharmacologic inhibitor CB-5083 increased ubiquitination and degradation of p53-R273H, leading to cell death. Consistently, ablation of VCP markedly retarded growth of cultured PDAC cells and xenograft PDAC tumors. Together, these results unveil VCP as a novel partner of p53-R273H in promoting PDAC growth and as a potential target for developing anti-PDAC therapy. Significance: These findings identify valosin-containing protein (VCP) as a novel regulator of p53-R273H stability and suggest VCP as a potential target for development of pancreatic cancer therapy.
A real-world clinical study of camrelizumab in the treatment of esophageal cancer.
Authors: Guoping Sun, Dong Qian, Dong Zhao, Hui Liang, Huaidong Cheng, Genhe Wang, Fan Wang, Hao Jiang, Tengyun Xu, Qibing Wu, ShaoJin Zhu, Dong Xu
Journal: Journal of Clinical Oncology (2021)

e16008 Background: Camrelizumab, a fully humanized monoclonal antibody against PD-1, has been approved in the treatment of advanced esophageal squamous carcinoma in China. The purpose of this study was to observe the efficacy and safety of Camrelizumab in the treatment of esophageal cancer in the real world. Methods: This is an open-label, prospective, multicenter, observational study. Eligible patients (pts) who received Camrelizumab had esophageal cancer; age≥18, ECOG PS of 0-2; and measurable disease. Results: As of November 30, 2020, a total of 229 patients were enrolled, of which 192 were male (83.8%). The ECOG PS score was 0 in 48 cases (21.0%), 1 in 149 cases (65.0%), and 2 in 32 cases (14.0%). Among the 134 patients of stage IV patients (58.5%), 174 patients had metastases (76.0%), and 99% of patients did not undergo PD-L1 testing. A history of radiotherapy accounted for 57.6%, and a history of surgery on the primary lesion accounted for 42%. Camrelizumab accounted for 26.2% of the first-line treatment, 33.6% of the second-line treatment, and 35.4% of the third-line and above. Camrelizumab combined with chemotherapy accounted for 40%, combined with anti-angiogenesis therapy accounted for 38.0%, combined with anti-angiogenesis + chemotherapy accounted for 9.0%, and combined radiotherapy accounted for 6.2%. Among 145 patients with evaluable efficacy, 5 cases of CR, 14 cases of PR, 97 cases of SD, and 29 cases of PD. The ORR reached 13.1% and the DCR reached 80.0%. The overall adverse event rate was 42.8%, the major adverse event RCCEP rate was 11.7%, pneumonia was 8.3%, and fatigue was 4.1%. Adverse events greater than or equal to grade 3 included 1 case of RCCEP, 3 cases of bleeding, 1 case of diarrhea, and 1 case of fever. Conclusions: In this real-world study of esophageal cancer, most of the patients enrolled were patients with poor PS score and late stage, but the efficacy and safety of Camrelizumab in patients with advanced esophageal cancer were still confirmed. The dominant population and combination therapy are still under study. Clinical trial information: ChiCTR1900027275.
Antibiotic use during end of life in patients with advanced malignancy: A retrospective analysis.
Authors: Shamali Poojary, Jayita Deodhar, Akanksha Chodankar, Anuja Damani, Arunangshu Ghoshal, Mary Ann Muckaden
Journal: Journal of Clinical Oncology (2021)

e24002 Background: Patients with advanced malignancy have complex symptoms towards end of life. Some of these symptoms include febrile illness and infections. Benefits of treating infection and fever with antibiotics should be weighed out with goals of care for these patients. This study aims to understand the frequency of use of antibiotics and its association with symptom control in the last two weeks of life in advanced cancer patients on best supportive care. Methods: This is an observational retrospective analysis of medical records maintained for advanced cancer patients who have been enrolled in home-based palliative care services. 8 months data was analyzed. Sociodemographic variables, cancer diagnoses, symptoms, use and type of antibiotics prescribed were noted. Relevant statistical analysis was done using IBM SPSS v 25. Results: Of 256 patients included in the analysis, 133 (52%) were male. 57 (22.3% ) patients had gastrointestinal (GI) cancer and 45 ( 17.6%) had lung cancer. 175 (68.4)% died at home and 50 (19.5%) in hospital. 9 (3.1 %) patients had fever. 10 (3.9%) patient had respiratory, and 18 (7%) had gastrointestinal symptoms, respectively. Other symptoms noted were wound infection (10,3.9%), skin and soft tissue (5,2%). Other symptoms noted were wound infection (10,3.9%), skin and soft tissue (5,2%). Only 2 patients had urinary tract symptom. 49 (19.1%) patients had received antibiotics in their last two weeks of life. Intravenous (IV) route of administration was slightly higher than oral (28 vs 21 patients).More than half the patients received 2 antibiotics. Amoxicillin/clavulanate was the most common oral antibiotic and Cefoperazone/ sulbactam was the most common IV antibiotic. Symptom relief was noted in 9 patients (18.4%) however it was statistically significant (p&lt;0.001). Conclusions: Of 256 patients included in the study, 19% had received antibiotics in last two week of their life. Use of intravenous route for antibiotic administration was more than oral route. Gastrointestinal and respiratory symptoms were common cause for antibiotic prescription. Symptomatic benefit was noted with antibiotics use in these patients. Judicious use of antibiotics during end of life care should be considered.
Efficacy of avelumab + axitinib (A + Ax) versus sunitinib (S) by IMDC risk group in advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.
Authors: John B. A. G. Haanen, James Larkin, Toni K. Choueiri, Laurence Albiges, Brian I. Rini, Michael B. Atkins, Manuela Schmidinger, Konstantin Penkov, Despina Thomaidou, Jing Wang, Mariangela Mariani, Alessandra Di Pietro, Robert J. Motzer
Journal: Journal of Clinical Oncology (2021)

4574 Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), treatment-naive patients with aRCC receiving A + Ax showed improved progression-free survival (PFS) and objective response rate (ORR) across International Metastatic RCC Database Consortium (IMDC) risk groups (favorable [F], intermediate [I], and poor [P]) compared with patients receiving S. Here we report updated efficacy results for A + Ax vs S by IMDC risk groups from the third interim analysis. Methods: Patients were randomized 1:1 to receive either A (10 mg/kg intravenously every 2 weeks) plus Ax (5 mg orally twice daily) or S (50 mg orally once daily) for 4 weeks (6-week cycle). Patients were categorized per IMDC risk group into F, I, and P subgroups, and outcomes were assessed for F, I, P, and I + P. Overall survival (OS) and PFS, ORR, complete response (CR), and duration of response (DoR) per investigator assessment (RECIST v1.1) were assessed. Results: The study enrolled 886 patients with aRCC. At data cutoff (Apr 2020), median (95% CI) follow-up for OS in the A + Ax was NR (42.2-NE) vs 37.8 (31.4-NE) months with S. The Table shows OS, PFS, ORR, CR, and DOR by IMDC risk group. A + Ax generally showed improved efficacy compared with S across IMDC groups. Conclusions: Consistent with previously reported results from prior interim analyses, extended follow-up confirms the efficacy benefits of A + Ax vs S across IMDC risk groups in patients with aRCC. Patients continue to be followed up for the final OS analysis. Clinical trial information: NCT02684006. [Table: see text]