tbuckley/cabot-search huggingface dataset:
Futibatinib, an Irreversible FGFR1–4 Inhibitor, in Patients with Advanced Solid Tumors Harboring<i>FGF</i>/<i>FGFR</i>Aberrations: A Phase I Dose-Expansion Study
Authors: Funda Meric-Bernstam, Rastislav Bahleda, Cinta Hierro, Marc Sanson, John Bridgewater, Hendrik-Tobias Arkenau, Ben Tran, Robin Kate Kelley, Joon Oh Park, Milind Javle, Yaohua He, Karim A Benhadji, Lipika Goyal
Journal: Cancer Discovery (2021)

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy. SIGNIFICANCE: This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1-4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population.This article is highlighted in the In This Issue feature, p. 275.
JTC PROLONGATION PROVIDES ADDITIONAL PROGNOSTIC INFORMATION FOR LIFE THREATENING ARRHYTHMIAS IN PATIENTS WITH QRS PROLONGATION
Authors: Mohsin Khan, Ana Cristina Perez Moreno, M. Eyman Mortada, Mohamed Djelmami-Hani, Atul Bhatia, Jodi Zilinski, Vikram Nangia, Ryan Cooley, Anwer Dhala, Imran Niazi, Jasbir Sra, Arshad Jahangir
Journal: Journal of the American College of Cardiology (2020)
Genomic evolution and the impact of SLIT2 mutation in relapsed intrahepatic cholangiocarcinoma
Authors: Shao‐Lai Zhou, Chu‐Bin Luo, Cheng‐Li Song, Zheng‐Jun Zhou, Hao‐Yang Xin, Zhi‐Qiang Hu, Rong‐Qi Sun, Jia Fan, Jian Zhou
Journal: Hepatology (2021)

Abstract Background and Aims Intrahepatic cholangiocarcinoma (ICC) is aggressive and has high rates of relapse, conferring poor long‐term survival after curative resection. Little is known about the genomic evolution that occurs during ICC relapse. Approach and Results We conducted whole‐exome sequencing of 30 paired primary and relapsed tumors from 10 patients with ICC who received curative resection. We sought to identify frequently altered genes, infer tumor subclonal architectures, and track genomic evolution from primary to relapsed tumors. We examined functional effects and the mechanism of action of SLIT2 , a gene specifically mutated in relapsed tumors, on tumor growth and metastasis and the tumor microenvironment. Our results indicated that relapsed ICCs were genetically derived from intrahepatic dissemination of primary tumors. However, they acquired additional mutations while maintaining most drivers, such as TP53 and IDH1 . Multiregion sequencing suggested polyclonal seeding of ICC dissemination. Four of 10 relapsed ICCs acquired SLIT2 mutations that were not present in the corresponding primary tumors. Validation in an expanded sample revealed SLIT2 mutations in 2.3% (1/44) of primary ICCs and 29.5% (13/44) of relapsed ICCs. Biofunctional investigations revealed that inactivating mutation of SLIT2 resulted in activation of PI3K–Akt signaling in ICC cells, directly enhanced neutrophil chemotaxis, mediated tumor‐associated neutrophil infiltration, and contributed to ICC growth and metastasis. Conclusions We characterized genomic evolution during ICC relapse and identified SLIT2 as a driver of tumor dissemination and tumor‐associated neutrophil infiltration.
Utilization of a prognostic question as a trigger for palliative care consultation.
Authors: Megan H. Begnoche, Dana Guyer
Journal: Journal of Clinical Oncology (2021)

325 Background: The Lifespan Cancer Institute (LCI) initiated ClinicalPath in 2018 as an evidence-based decision tool to support oncologists in providing high quality care. The prognostic question used by the decision tool, “would you be surprised if this patient died in the next year,” is a validated question for predicting poor prognosis for patients with stage III, IV or extensive stage cancer. The palliative care (PC) team hypothesized that if an oncologist answered “no, I would not be surprised,” the patient would benefit from a PC consultation. The LCI prioritized efforts to provide PC upstream in the disease process by reviewing the “would not be surprised” patients and offering consultation to the ordering oncologist if deemed appropriate by the PC physician. Methods: Patients navigated through ClinicalPath from Jan to Dec 2019 were analyzed to allow for one full year after the last navigation for those marked as “would be surprised” and “would not be surprised,” and frequency of PC consultation was evaluated. Results: 729 patients triggered the prognostic question in 914 total navigations. Of those navigations, oncologists selected “I would not be surprised if patient died within the next year” 54% of the time. In 45% of decisions, the oncologist selected “I would be surprised if patient died within the next year,” suggesting that the oncologist expected the patient to live a year or more. 53% of the patients were categorized as Stage IV or extensive stage. The most common diseases were gastrointestinal malignancies, followed by thoracic and then neuro-oncology. Among the patients whose oncologist selected “I would be surprised,” 36% of patients had died within 365 days of the decision, 13% died more than a year after and 51% are still alive. Among the patients whose oncologist selected “I would not be surprised,” 60% died within 365 days of the decision and an additional 16% have since died, with 24% still alive at this time. PC consultation increased since initiation of the palliative physician conducting prognostic clinical review. In a review from Nov 19-April 20 (1157 visits) and Nov 20-April 21 (1656 visits), overall PC visits increased by 43%. Conclusions: LCI’s data aligns with prior published data that suggest the prognostic question is valid. We further examined if this question could be used as a screening tool to initiate a PC consultation since patients with a poor prognosis benefit from PC. 56% of patients navigated through the system had a PC consult at some time during their disease course, and 54% of those patients saw PC as an inpatient only. A simple screening process for those patients that were navigated to “I would not be surprised” is a way of providing earlier integration of PC. This prognostic question, which relies heavily on oncologist “gut feeling “or “intuition,” is a helpful indicator that PC consultation is appropriate and can be used effectively to ensure earlier integration of PC for oncology patients.
Association of Cardiovascular Outcomes and Mortality With Sustained Long-Acting Insulin Only vs Long-Acting Plus Short-Acting Insulin Treatment
Authors: Emily B. Schroeder, Romain Neugebauer, Kristi Reynolds, Julie A. Schmittdiel, Linda Loes, Wendy Dyer, Noel Pimentel, Jay R. Desai, Gabriela Vazquez-Benitez, P. Michael Ho, Jeffrey P. Anderson, Patrick J. O’Connor
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Cardiovascular events and mortality are the principal causes of excess mortality and health care costs for people with type 2 diabetes. No large studies have specifically compared long-acting insulin alone with long-acting plus short-acting insulin with regard to cardiovascular outcomes. <h3>Objective</h3> To compare cardiovascular events and mortality in adults with type 2 diabetes receiving long-acting insulin who do or do not add short-acting insulin. <h3>Design, Setting, and Participants</h3> This retrospective cohort study emulated a randomized experiment in which adults with type 2 diabetes who experienced a qualifying glycated hemoglobin A<sub>1c</sub>(HbA<sub>1c</sub>) level of 6.8% to 8.5% with long-acting insulin were randomized to continuing treatment with long-acting insulin (LA group) or adding short-acting insulin within 1 year of the qualifying HbA<sub>1c</sub>level (LA plus SA group). Retrospective data in 4 integrated health care delivery systems from the Health Care Systems Research Network from January 1, 2005, to December 31, 2013, were used. Analysis used inverse probability weighting estimation with Super Learner for propensity score estimation. Analyses took place from April 1, 2018, to June 30, 2019. <h3>Exposures</h3> Long-acting insulin alone or with added short-acting insulin within 1 year from the qualifying HbA<sub>1c</sub>level. <h3>Main Outcomes and Measures</h3> Mortality, cardiovascular mortality, acute myocardial infarction, stroke, and hospitalization for heart failure. <h3>Results</h3> Among 57 278 individuals (39 279 with data on cardiovascular mortality) with a mean (SD) age of 60.6 (11.5) years, 53.6% men, 43.5% non-Hispanic White individuals, and 4 years of follow-up (median follow-up of 11 [interquartile range, 5-20] calendar quarters), the LA plus SA group was associated with increased all-cause mortality compared with the LA group (hazard ratio, 1.27; 95% CI, 1.05-1.49) and a decreased risk of acute myocardial infarction (hazard ratio, 0.89; 95% CI, 0.81-0.97). Treatment with long-acting plus short-acting insulin was not associated with increased risks of congestive heart failure, stroke, or cardiovascular mortality. <h3>Conclusions and Relevance</h3> Findings of this retrospective cohort study suggested an increased risk of all-cause mortality and a decreased risk of acute myocardial infarction for the LA plus SA group compared with the LA group. Given the lack of an increase in major cardiovascular events or cardiovascular mortality, the increased all-cause mortality with long-acting plus short-acting insulin may be explained by noncardiovascular events or unmeasured confounding.
Virtual psychosocial services for the adult population in a large community oncology practice.
Authors: Stephanie Broadnax Broussard, Emily Pearcy, Vanessa Dunham, Kendra Burke, Jackeline Castillo, Rebecca Clinton, Penelope DeCou, Kelsey Espinosa, Maribel Flores, Tara Garza, Maygen Hansard, Heather Jordan, Debbi Newton, Brandi Jurecek, Jenn Paxton, Sandra Saenz, Vicki Wright, Isis Celestino, Sabrina Q. Mikan, Sarah Puckett
Journal: Journal of Clinical Oncology (2021)

283 Background: Psychological and social supports are essential to address the emotional impact of cancer. The Covid-19 pandemic exacerbated emotional distress for patients with cancer and impeded many of the traditional service delivery models for supportive services. An increase in patient reported distress from routine distress screenings highlighted the need to transition to virtual Social Work (SW) services. Methods: Patients were referred to virtual SW services three ways: self-referral, distress screenings, and clinic staff. A virtual support group registration site was created to increase awareness which was promoted by our marketing team. Three different SW facilitated virtual support groups were offered: Stronger Together, Empower Your Recovery: A Program for Healing and Growth for Living Beyond Cancer©*, and Paving the Way for Your Journey: A Cancer Support Program (PTW). Of note, the PTW six-week psychoeducation support group curriculum was developed by six employed SW facilitators. Groups included closed and open formats with scheduled frequencies. In addition to virtual support groups, standard social support including, psychosocial assessments, Advance Care Planning, virtual counseling visits were offered virtually with patients via the VSee telemedicine platform. Results: Social Work referrals increased by 154% from 949 in 2019 to 2413 in 2020 due to positive distress screening. From March 2020-21, 14,948 patients received SW services which was an increase from 10,208 seen from March 2019-20. Of these, 372 received virtual psychosocial telemedicine services from March 2020-21. There were 4092 unique webpage views to the support group information and registration website. Total number of all virtual registrants in the 3 groups from May 2020 to February 2021 was 326. Conclusions: The COVID19 pandemic required us to use, technology and virtual tools to ensure continued patient access to psychosocial services and expand access to support groups, in addition to the in-person SW services that remained. Limitations of virtual support groups and telemedicine included lack of internet access felt to be from socioeconomic barriers. Further research is needed to evaluate the benefits of providing structured psychoeducational virtual support groups to patients with cancer. Virtual counseling and support groups may continue to benefit patients with cancer.
A molecularly integrated grade for meningioma
Authors: Joseph Driver, Samantha E Hoffman, Sherwin Tavakol, Eleanor Woodward, Eduardo A Maury, Varun Bhave, Noah F Greenwald, Farshad Nassiri, Kenneth Aldape, Gelareh Zadeh, Abrar Choudhury, Harish N Vasudevan, Stephen T Magill, David R Raleigh, Malak Abedalthagafi, Ayal A Aizer, Brian M Alexander, Keith L Ligon, David A Reardon, Patrick Y Wen, Ossama Al-Mefty, Azra H Ligon, Adrian M Dubuc, Rameen Beroukhim, Elizabeth B Claus, Ian F Dunn, Sandro Santagata, Wenya Linda Bi
Journal: Neuro-Oncology (2021)

Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.
Controlled Human Infection Model — Fast Track to HCV Vaccine?
Authors: T. Jake Liang, Jordan J. Feld, Andrea L. Cox, Charles M. Rice
Journal: New England Journal of Medicine (2021)

The moratorium on experimentation with chimpanzees has impeded the progress of research on a vaccine against hepatitis C virus. Given the availability of highly effective, direct-acting antiviral therapy for HCV, the authors argue for the use of a controlled human infection model, or CHIM, to accelerate HCV vaccine research.
Takes one to B1a: Dismantling the origin of mantle cell lymphoma
Authors: Anna E. Beaudin
Journal: The Journal of Experimental Medicine (2021)

Therapeutic discovery for mantle cell lymphoma (MCL) has been hindered by a lack of preclinical mouse models that recapitulate human disease. In this issue, Pieters and colleagues (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202280) establish a novel mouse model of MCL driven by overexpression of cyclin D2 and identify fetal-derived B1a cells as putative cell of origin for MCL.
Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in <i>ARID1A</i>-Mutant Ovarian Cancers
Authors: Joseph A. Zundell, Takeshi Fukumoto, Jianhuang Lin, Nail Fatkhudinov, Timothy Nacarelli, Andrew V. Kossenkov, Qin Liu, Joel Cassel, Chih-Chi Andrew Hu, Shuai Wu, Rugang Zhang
Journal: Cancer Research (2021)

The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component
Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer
Authors: Kurt W. Evans, Erkan Yuca, Stephen S. Scott, Ming Zhao, Natalia Paez Arango, Christian X. Cruz Pico, Turcin Saridogan, Maryam Shariati, Caleb A. Class, Christopher A. Bristow, Christopher P. Vellano, Xiaofeng Zheng, Ana Maria Gonzalez-Angulo, Xiaoping Su, Coya Tapia, Ken Chen, Argun Akcakanat, Bora Lim, Debu Tripathy, Timothy A. Yap, Maria Emilia Di Francesco, Giulio F. Draetta, Philip Jones, Timothy P. Heffernan, Joseph R. Marszalek, Funda Meric-Bernstam
Journal: Cancer Research (2021)

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.
Establishing the need for provider education on cancer and nutrition (PECAN): Survey results on nutrition practices at a large community oncology practice.
Authors: Karen Smith, Lance Ortega, Lalan S. Wilfong, Sabrina Q. Mikan, John F. Sandbach, Kathryn Elizabeth Hudson
Journal: Journal of Clinical Oncology (2021)

49 Background: Oncology providers and patients benefit from evidence-based nutritional resources to support cancer care. For patients, proper nutrition care can prevent inappropriate weight loss, improve treatment tolerance, and improve quality of life. Recent literature has noted the lack of both adequate dietitian resources at outpatient centers and comprehensive nutrition guidelines in cancer care. At a large community practice with 210 locations across Texas and Oklahoma, a survey was developed and administered to assess nutrition practices. Methods: Clinic directors in the practice completed a survey to assess for the presence or absence of a malnutrition screen; how nutrition concerns are addressed; and the availability of a dietitian. Results: A total of 26 responses detailed the nutrition processes at 50 unique locations. At 37 (74%) locations, a malnutrition screening tool was utilized and of these, 30 (81%) locations reported utilizing the Malnutrition Screening Tool (MST), a brief, validated tool for outpatient settings including oncology. Seven (19%) sites did not specify what tool was used. Of the clinics that reported completing a malnutrition screen for patients, the screen was completed by the advanced practice provider (APP)/physician in 18 (49%) clinics, a nurse in 4 (11%) clinics, a dietitian in 4 (11%) clinics and a medical assistant in 1 (3%) clinic. At 10 sites more than one provider type was responsible for completing the screen. Nutrition issues were addressed by physicians, APPs, and nurses in 15 (50%), 35 (70%), and 9 (14%) sites respectively (see table). Twenty-two locations (44%) reported referring patients to a dietitian and 10 sites (20%) had a dietitian available in clinic. Forty-one (82%) clinics employed more than one method for addressing nutrition issues. Sixteen of 26 respondents (62%) reported that increased dietitian access would be helpful; this included respondents whose locations already had a dietitian available. Conclusions: Overall, 74% of reporting locations used a malnutrition screening tool and 20% had access to a dietitian on site. Forty-four percent of sites referred to a dietitian if there was a need. This indicates that multiple providers are involved in the nutritional care of oncology patients. In response to these findings, the multidisciplinary PECAN Taskforce was created to develop comprehensive malnutrition screening, implement a referral process for all at-risk patients, enhance nutrition education, and expand dietitian services. Further study will measure the impact of expanded nutrition access on patient outcomes.[Table: see text]