tbuckley/cabot-search huggingface dataset:
Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: A phase Ib/II study.
Authors: Mitesh J. Borad, Li-Yuan Bai, Ming-Huang Chen, Joleen M. Hubbard, Kabir Mody, Sun Young Rha, Donald A. Richards, S. Lindsey Davis, John Soong, Chi-En C-E Huang, Emmett Tse, Daniel H. Ahn, Heung-Moon Chang, Chia-Jui Yen, Do-Youn Oh, Joon Oh Park, Chiun Hsu, Carlos Roberto Becerra, Jen-Shi Chen, Yen-Yang Chen
Journal: Journal of Clinical Oncology (2021)

312 Background: Silmitasertib (CX-4945), an oral small molecule inhibitor of casein kinase 2 (CK2), has exhibited preclinical antitumor activity and strong synergism with gemcitabine + cisplatin. We investigated the safety and efficacy of silmitasertib in combination with gemcitabine + cisplatin in patients with unresectable cholangiocarcinoma (CCA). Methods: S4-13-001 is a multicenter, open-label, phase Ib/II study of silmitasertib in combination with gemcitabine + cisplatin in patients with locally advanced or metastatic CCA. The phase Ib portion included dose-escalation, expansion, and exploratory cohorts of silmitasertib with doses ranging from 200 to 1000 mg bid (6 days for the escalation/expansion cohorts and 10 and 21 days’ continuous dosing for the exploratory cohorts). In the phase II portion patients received silmitasertib 1000 mg bid for 10 days in combination with gemcitabine + cisplatin on days 1 &amp; 8 over a 21-day cycle. In this interim analysis, we present findings from the combined population of patients from the phase Ib and II portions of the study. Response to treatment was assessed by RECIST v1.1 every 6 weeks. Primary efficacy outcome measure was progression-free survival (PFS). ClinicalTrials.gov (NCT02128282). Results: A total of 87 patients were enrolled and received silmitasertib in the phase Ib (n=50) and phase II (n=37) portions of the study. Of these, 55 patients were evaluable for efficacy with details as follows: median PFS 11.1 (95% CI 7.6–14.7) months; median overall survival (OS) 17.4 (95% CI 13.4–25.7) months; overall response rate (ORR) 32.1%; and disease control rate (DCR) 79.3%. Almost all patients (79/87; 90.8%) evaluable for safety reported ≥1 treatment-related adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib were diarrhea (65.5%), nausea (50.6%), vomiting (33.3%), fatigue (31.0%), and anemia (21.8%). The most common grade ≥3 TEAEs were diarrhea (13.8%), neutropenia (11.5%), nausea (9.2%), anemia (8.0%), and thrombocytopenia (8.0%). Eleven patients (12.6%) discontinued treatment due to TEAEs. Conclusions: Silmitasertib in combination with gemcitabine + cisplatin yields promising preliminary evidence of efficacy in patients with locally advanced or metastatic CCA. Based on these data a randomized phase III trial is planned. Clinical trial information: NCT02128282.
Cost efficiency and budget-neutral expanded access to antineoplastic therapy from cost-savings derived from conversion to biosimilar pegfilgrastim-cbqv for the prophylaxis of chemotherapy-induced (febrile) neutropenia (CIN/FN):Simulation modeling in metastatic pancreatic cancer.
Authors: Ali McBride, Karen MacDonald, Ivo Abraham
Journal: Journal of Clinical Oncology (2021)

441 Background: Biosimilars have contributed to the reduction in the cost of prophylaxis of CIN/FN in recent years. Savings generated from conversion to biosimilars could be reallocated on a budget-neutral basis to provide expanded access to additional prophylaxis or to anti-neoplastic treatment. To demonstrate this, we simulated: 1) the savings that could be realized from CIN/FN prophylaxis with biosimilar pegfilgrastim-cbqv (BIOSIM-PEG) over reference pegfilgrastim with or without on-body injector (PEG/PEG-OBI), 2) a model of expanded access to BIOSIM-PEG from cost-savings achieved from conversion from PEG/PEG-OBI, 3) a model of expanded access to chemotherapy with oxaliplatin, leucovorin, irinotecan, and fluorouracil (FOLFIRINOX) for metastatic pancreatic cancer (mPC), 4) the number-needed-to-convert (NNC) to BIOSIM-PEG to purchase one additional treatment of BIOSIM-PEG, and 5) the NNC to purchase one cycle of FOLFIRINOX. Methods: This simulation modeling from the US payer perspective utilized: 1) a blended rate of average selling price (ASP; derived from CMS Q4 2020 reimbursement) and wholesale acquisition cost (WAC; Redbook) for PEG/PEG-OBI, BIOSIM-PEG, and all FOLFIRINOX agents proportionate to the estimated 2020 incident pancreatic cancer age distribution per Surveillance, Epidemiology, and End Results Program (67.6% Medicare-insured patients ≥65 years of age; 32.4% commercially insured patients &lt;65 years); 2) between one and twelve cycles of prophylaxis in a panel of 2,500 mPC patients treated with FOLFIRINOX; and 3) conversion rates from PEG/PEG-OBI to BIOSIM-PEG ranging from 10%—100%. Results: Using a current blended ASP/WAC rate, cost-savings of BIOSIM-PEG over PEG/PEG-OBI in a panel of 2,500 mPC patients range from $188,780 (for 1 cycle of prophylaxis at 10% conversion) to $22,653,609 (12 cycles at 100%). In a single cycle of chemotherapy, these savings translate into expanded access to additional BIOSIM-PEG prophylaxis ranging from 53 cycles at 10% conversion from PEG/PEG-OBI to 528 cycles at 100% or to between 321 to 3,214 cycles of FOLFIRINOX, respectively. The savings over twelve cycles could provide up to 6,330 additional cycles of BIOSIM-PEG or 38,571 cycles of FOLFIRINOX (at 100% conversion). The NNC from PEG/PEG-OBI to purchase one additional cycle of BIOSIM-PEG is 4.74; the NNC to purchase once cycle of FOLFIRINOX is 0.78. Conclusions: These simulated models demonstrate the magnitude of the cost savings for CIN/FN prophylaxis that can be generated by conversion to biosimilar pegfilgrastim-cbqv. Further, these savings could be reallocated to provide access to anti-neoplastic treatment on a budget-neutral basis, thus enhancing the value of cancer care to both payers and patients.
Predictors of uptake of aspirin (ASA) chemoprevention in Lynch syndrome (LS).
Authors: Michael J. Hall, Margie Clapper, Wen-Chi J Chang, Yana Chertock, Minhhuyen J Nguyen
Journal: Journal of Clinical Oncology (2021)

49 Background: Substantial data support efficacy of ASA in colorectal adenoma and cancer (CRC) chemoprevention. In 2011, the CaPP2 Phase 3 trial showed benefit of 600 mg ASA daily for prevention of LS-associated CRC (HR 0.41,p=0.02) in persons w/ASA adherence &gt;2 yrs. Anecdotally, uptake of ASA by LS pts has been low, but few data exist. We examined uptake and predictors of ASA chemoprevention among LS pts receiving follow-up at our center since 2011. Methods: Pts evaluated by Fox Chase’s Risk Assessment Program receive in-person medical recommendations and written information about cancer (CA) prevention measures including ASA. Medical records of 127 LS pts were retrospectively reviewed. Demographics, gene affected, personal Hx of CA, ASA use, and ASA dose were collected. Majority (94.5%) of cohort had documentation of ongoing LS endoscopic screening at our center—only 3.2% had no recent follow-up (past 3 yrs) and 2.4% had recently died (past 3 yrs). Chi-square tests and multivariable logistic regression were used in analyses. Results: Overall 24.4% (31/127) of pts reported ASA use for chemoprevention (see Table). Nearly half (48.4%) of ASA users took 81 mg ASA daily, and only 22.6% reported taking &gt;600 mg ASA daily. ASA use was associated with older age, MLH1/ MSH2+ vs MSH6/ PMS2+, and personal Hx of CRC. In the multivariable logistic model, older age (OR 2.80, p=0.04) and MLH1/ MSH2+ (OR 2.64,p=0.07) were significant and borderline significant, respectively. Adding race/ethnicity and gender strengthened the effect of age&gt;60 (OR 3.11, p=0.03), and improved fit (pseudoR 2 =16.8%). Conclusions: Uptake of ASA chemoprevention by LS pts is overall modest, but older age is associated with ASA uptake for chemoprevention. Among ASA users, fewer than 1 in 4 take the 600 mg daily dose shown effective in CaPP2. Confirmatory trials as well as efforts to elucidate barriers to ASA chemoprevention in LS are needed. [Table: see text]
Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer
Authors: Nina G. Steele, Giulia Biffi, Samantha B. Kemp, Yaqing Zhang, Donovan Drouillard, LiJyun Syu, Yuan Hao, Tobiloba E. Oni, Erin Brosnan, Ela Elyada, Abhishek Doshi, Christa Hansma, Carlos Espinoza, Ahmed Abbas, Stephanie The, Valerie Irizarry-Negron, Christopher J. Halbrook, Nicole E. Franks, Megan T. Hoffman, Kristee Brown, Eileen S. Carpenter, Zeribe C. Nwosu, Craig Johnson, Fatima Lima, Michelle A. Anderson, Youngkyu Park, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Arvind Rao, Filip Bednar, Andrzej A. Dlugosz, Jonathan B. Preall, David A. Tuveson, Benjamin L. Allen, Marina Pasca di Magliano
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment. Experimental Design: We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC. Results: We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression. Conclusions: Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.
Phase II study of anlotinib plus sintlimab as second-line treatment for patients with advanced biliary tract cancers.
Authors: Hong Zong, Qian Zhong, Ruihua Zhao, Shuiling Jin, Chuang Zhou, Xiaojian Zhang, Jianxiang Shi, Shishi Qiao, Jinming Han, Miao Jiang
Journal: Journal of Clinical Oncology (2021)

307 Background: Gemcitabine combined with cisplatin (GP) has been established as the standard first-line treatment in patients with unresectable biliary tract cancers (BTC), a heterogeneous group of rare and aggressive malignancies arising from the epithelium of the biliary duct system. Nevertheless, there has been no approved standard of care for second-line treatment. In this study, we explored the efficacy and safety of the combination of anlotinib and sintlimab as a novel second-line regimen in BTC. Methods: In this phase II trial, patients with advanced BCT, who experienced progression after first-line chemotherapy, received anlotinib (12 mg, PO, D1-14, Q3W) combined with sintlimab (200 mg, iv, D1, Q3W) until disease progression or unacceptable toxicity. The primary endpoint was OS, and the secondary endpoints included ORR, PFS, DCR, and safety. The exploratory endpoint was the correlation of clinical outcomes with biomarkers. Results: From Aug 2019 to Sep 2020, 17 patients were enrolled. 9(52.9%) were men, and the median age was 59(43-69) years. Nine patients were diagnosed with ICC, 2 with ECC, and 6 with GBC. 15 patients were assessable for response. At a median follow-up of 8.76 months (95%CI: 3.60-13.94 months), the primary endpoint OS has not been reached, the median PFS was 6.50 months (95%CI: 3.60-9.40 months). ORR was 40.00%, and DCR was 86.67%. The incidence of treatment-related adverse events (TRAEs) was 70.60%, and the most common grade 1-2 AEs were hypertension (70.60%), diarrhea (17.65%), and hypothyroidism (17.65%). Conclusions: Anlotinib plus sintlimab demonstrates significant clinical activity and acceptable toxicity in patients with advanced BTC who failed first-line chemotherapy. Clinical trial information: ChiCTR1900022003.
Effects of Chronic Exposure to Crack Cocaine on the Respiratory Epithelium of Mice
Authors: Ruy Camargo Pires-Neto, Percyleine Pelegrini Herculiani, Heloisa Maria de Siqueira Bueno, Júlio Cezar Zorzetto, Raphael Caio Tamborelli Garcia, Maurício Yonamine, Paulo Saldiva, Thais Mauad
Journal: European Respiratory Journal (2007)
Mapping Racial and Ethnic Inequities in Health and Opportunity
Journal: New England Journal of Medicine (2020)

Throughout the United States, health status and outcomes, access to care, and socioeconomic status vary by race and ethnic group. This Interactive Perspective, which uses data aggregated by the Health Opportunity and Equity (HOPE) Initiative, allows readers to view and compare data on a range of indicators for each state and for six racial and ethnic groups.
The Role of Controversial Research in the IRB's Risk/Benefit Analysis
Authors: John Lunstroth
Journal: The American Journal of Bioethics (2011)

When an institutional review board (IRB) is asked to approve potentially controversial research, such as research into genetic enhancement or harm reduction in illegal activities, is it prohibited from considering the long-range sociopolitical effects of the research in its risk/benefit analysis? I evaluate the history of the Common Rule (45 CFR 46) to answer this question, and on the way discuss the problem of non-lawyer bioethicists and medical scientists interpreting legal documents such as 45 CFR 46.
Attitudes of healthcare workers towards COVID-19 vaccination: a survey in France and French-speaking parts of Belgium and Canada, 2020
Authors: Pierre Verger, Dimitri Scronias, Nicolas Dauby, Kodzo Awoenam Adedzi, Cathy Gobert, Maxime Bergeat, Arnaud Gagneur, Eve Dubé
Journal: Eurosurveillance (2021)

In October and November 2020, we conducted a survey of 2,678 healthcare workers (HCWs) involved in general population immunisation in France, French-speaking Belgium and Quebec, Canada to assess acceptance of future COVID-19 vaccines (i.e. willingness to receive or recommend these) and its determinants. Of the HCWs, 48.6% (n = 1,302) showed high acceptance, 23.0% (n = 616) moderate acceptance and 28.4% (n = 760) hesitancy/reluctance. Hesitancy was mostly driven by vaccine safety concerns. These must be addressed before/during upcoming vaccination campaigns.
Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032
Authors: Alice L. Yu, Andrew L. Gilman, M. Fevzi Ozkaynak, Arlene Naranjo, Mitchell B. Diccianni, Jacek Gan, Jacquelyn A. Hank, Ayse Batova, Wendy B. London, Sheena C. Tenney, Malcolm Smith, Barry L. Shulkin, Marguerite Parisi, Katherine K. Matthay, Susan L. Cohn, John M. Maris, Rochelle Bagatell, Julie R. Park, Paul M. Sondel
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Previously our randomized phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 mAb, GM-CSF, and IL2 improved survival for children with high-risk neuroblastoma that had responded to induction and consolidation therapy. These results served as the basis for FDA approval of dinutuximab. We now present long-term follow-up results and evaluation of predictive biomarkers. Patients and Methods: Patients recieved six cycles of isotretinoin with or without five cycles of immunotherapy which consists of dinutuximab with GM-CSF alternating with IL2. Accrual was discontinued early due to meeting the protocol-defined stopping rule for efficacy, as assessed by 2-year event-free survival (EFS). Plasma levels of dinutuximab, soluble IL2 receptor (sIL2R), and human anti-chimeric antibody (HACA) were assessed by ELISA. Fcγ receptor 2A and 3A genotypes were determined by PCR and direct sequencing. Results: For 226 eligible randomized patients, 5-year EFS was 56.6 ± 4.7% for patients randomized to immunotherapy (n = 114) versus 46.1 ± 5.1% for those randomized to isotretinoin only (n = 112; P = 0.042). Five-year overall survival (OS) was 73.2 ± 4.2% versus 56.6 ± 5.1% for immunotherapy and isotretinoin only patients, respectively (P = 0.045). Thirteen of 122 patients receiving dinutuximab developed HACA. Plasma levels of dinutuximab, HACA, and sIL2R did not correlate with EFS/OS, or clinically significant toxicity. Fcγ receptor 2A and 3A genotypes did not correlate with EFS/OS. Conclusions: Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample size than originally planned, yet clinically significant long-term differences in survival were observed.
FRI0068 102-wk clinical and radiologic results from the attract trial: a 2 year, randomised, controlled, phase 3 trial of infliximab (remicade®) in pts with active ra despite mtx
Authors: R Maini, D Van der Heijde, J Smolen, J Kalden, F Breedveld, P Emery, E Keystone, G Harriman, P Lipksy
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The ATTRACT trial studied the long term efficacy and tolerability of infliximab in 428 pts with active RA despite MTX (median dose of 15 mg/wk). <h3>Objectives</h3> <h3>Methods</h3> While continuing MTX, pts were randomly assigned to one of five therapeutic arms in which infliximab at 3 or 10 mg/kg or placebo infusions were given at 0, 2, and 6 wks and every 4 or 8 wks thereafter. Clinical benefit was assessed by maintenance of at least an ACR20 level of response. Using the van der Heijde modified Sharp system assessing bone erosions and joint space narrowing, the total radiologic score (TRS) was calculated for each patient at 0, 30, 54, and 102 wks. Adverse events were tabulated. <h3>Results</h3> Infliximab in combination with MTX is well tolerated and results in a sustained clinical benefit at all doses and frequencies over 2 years. Additionally, radiologic progression was essentially arrested in all infliximab plus MTX treatment arms as compared to the MTX control group. All infliximab dose regimens were comparable in clinical and radiologic benefit. No unexpected adverse events, nor an increase in any previously observed side effect were reported. <h3>Conclusion</h3> Infliximab in combination with MTX is well tolerated and results in a sustained clinical benefit at all doses and frequencies over 2 years. Additionally, radiologic progression was essentially arrested in all infliximab plus MTX treatment arms as compared to the MTX control group. All infliximab dose regimens were comparable in clinical and radiologic benefit.
Unusual Wide QRS Complex Rhythm in a Teenager
Authors: Nicolas Combes, Alice Maltret, Victor Waldmann
Journal: JAMA Cardiology (2021)

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Absent Blood Oxygen Level–Dependent Functional Magnetic Resonance Imaging Activation of the Orbitofrontal Cortex in a Patient With Persistent Cacosmia and Cacogeusia After COVID-19 Infection
Authors: Ismail Ibrahim Ismail, Khaled A. Gad
Journal: JAMA Neurology (2021)

This case report describes absent blood oxygen level–dependent (BOLD) functional magnetic resonance imaging (fMRI) activation of the orbitofrontal cortex in a 25-year-old woman with persistent cacosmia and cacogeusia after coronavirus disease 2019 (COVID-19) infection.
マウスIFNアルファA単独療法およびFK788(複製欠乏性組換えアデノウイルス感染マウスの肝炎上の新奇なIPアゴニスト)との組合せの比較研究
Authors: Maeda N, Nishio M, Takakura K, Mutoh S
Journal: Hepatology (2004)
Differential gain of chromosomal regions 20q or 13q with loss of 8p and 18q differentiates disease-free survival in colorectal cancer.
Authors: Eva Chao, Qi Xu, Anna Capasso, S. Gail Eckhardt, Jeanne Kowalski
Journal: Journal of Clinical Oncology (2021)

126 Background: In microsatellite stable (MSS) colorectal cancer (CRC) cases, frequent amplifications in 13q and 20q regions have been reported with limited understanding of their potential role for prognosis and treatment. Based on an internal research molecular tumor board case analysis of a KRAS WT, MSS left-sided (LS), metastatic CRC patient, we noted 50% of the 11 listed variants of unknown significance were on 20q. This study aims to investigate the potential prognostic role for gain of 20q chromosomal regions relative to other chromosomal imbalances using a retrospective cohort. Methods: We performed a genome-wide CN cluster analysis using the TCGA data with resulting patient clusters compared based on Kaplan-Meier estimated disease-free interval (DFI) in months (mos) using a log-rank. We examined associations between CN-derived clusters and CRC phenotypes. Results: Using TCGA data, we identified four CN-derived patient clusters of which two had significantly different DFI’s. One longer DFI cluster (n = 83; median DFI = 28mos) was defined by a signature of copy neutral genes along Chr8p and 18q regions. The shorter DFI cluster (n = 46; median DFI = 20mos) was defined by a signature of Chr8p and 18q regions of loss. The two clusters significantly differed in terms of site (85% right-sided in the shorter vs. 85% LS in the longer DFI cluster) and MS status (81% MSS in the shorter vs. 72% MSI in the longer DFI cluster) with no significant differences in age (mean of 70 years at diagnosis) and KRAS status (around 50% WT) between clusters. The shorter DFI was able to be further differentiated based on gain of chromosomal regions 20q (n = 26; median DFI = 24mos) and 13q (n = 20; median DFI = 18mos). No significant differences in mean age, tumor stage, site, and MS status between the shorter DFI subgroups were noted. Enriched pathways in the Chr20q gain sub-cluster include cell differentiation (Hippo, Rap1, VEGF), whereas metabolic signaling pathways via AGE-RAGE and AMPK, as well as cell growth and malignant transformation via RAS are enriched in the Chr13q gain sub-cluster. Conclusions: Clinical sequencing is able to identify regions of gain in Chr20q and Chr13q as part of VUS’s. Gain of Chr20q has been reported with better survival in mCRC patients. Gain of chromosomal region 20q and loss of 18q has been reported to discriminate between Lynch Syndrome and familial colorectal cancer. Herein, we show that gain of the 20q region with 18q and 8p regions of loss is associated with shorter DFI and gain of 13q region with loss of 8p even worse prognosis.