tbuckley/cabot-search huggingface dataset:
Virtual health in cancer care: Results from a semi-structured interview-survey of oncology health care providers.
Authors: Dan Le, Amanda Brain, Tamara Nina Shenkier, Paris-Ann Ingledew
Journal: Journal of Clinical Oncology (2021)

e13618 Background: The COVID-19 pandemic has compelled an increased use of virtual care delivery models in oncology. This study sought to examine the views of oncology health care providers (HCP) in British Columbia on the value and impact of virtual care models in clinical practice. Methods: A semi-structured interview-survey was developed to compare provider practice patterns between May 2019 and May 2020. Questions were designed to determine provider-perceived value and impact of virtual visits on clinical interactions with patients. HCP (including physicians, dentists, and nurse practitioners) at BC Cancer were invited to participate. Responses to the interview questions were de-identified and HCP names were replaced with a study code. Quantitative questions were interpreted with descriptive statistics. Qualitative results were analyzed and iteratively coded by multiple reviewers for emerging themes. Results: Among 531 invited participants, 61 completed the interview-survey and 60 were included in the final analysis. Of those interviewed, 47% were radiation oncologists and 33% were medical oncologists. The remainder of HCP interviewed (n = 12) included functional imaging physicians, general practitioners in oncology, hereditary cancer physicians, nurse practitioners, palliative care physicians, psychiatrists, and surgical oncologists. Most oncology providers (87%) desired the continuation of virtual visits as part of their clinical practice so long as barriers to integration were addressed. Barriers identified included limited access to physical resources, such as hardware (70% responses) and quiet spaces (54% responses), insufficient logistic support such as information technology services (84% responses) and operational workflows (46% responses), the absence of guidelines to select patients for this delivery model (38% responses), and concerns regarding HCP liability, security and privacy (30% responses). Conclusions: Oncology HCP value delivering patient care through virtual means, however, barriers to implementation must be better understood. These data may inform continued use and implementation of virtual care at other oncology centers.
Impact of clinicopathological features on survival in patients treated with immune-based combinations for metastatic urothelial carcinoma: A meta-analysis of randomized clinical trials.
Authors: Veronica Mollica, Alessandro Rizzo, Matteo Santoni, Andrea Marchetti, Matteo Rosellini, Francesco Massari
Journal: Journal of Clinical Oncology (2021)

e16534 Background: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma (mUC). Nonetheless, little is known regarding the impact of clinicopathological features in this setting. We performed a meta-analysis aiming to evaluate the predictive value of ECOG-PS, age, gender, liver metastases, and histology in randomized controlled trials (RCTs) comparing ICI-based combinations versus chemotherapy in mUC patients. Methods: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs comparing ICI-based combinations versus chemotherapy alone in mUC patients. The primary endpoint was overall survival (OS), measured as hazard ratio (HR) with corresponding 95% confidence interval (CI). All statistical analyses were performed using R studio software. Results: Overall, 1032 mUC patients were included in the analysis. Compared with chemotherapy, ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including no liver metastases (HR, 0.84; 95% CI, 0.74-0.95) and ECOG-PS 0 patients (HR, 0.84; 95% CI, 0.72-0.97). Similarly, ICI-based combinations were associated with prolonged OS in mUC patients who were &lt; 65 years old (HR, 0.82; 95% CI, 0.72-0.95), as well as in male (HR, 0.90; 95% CI, 0.82-0.99) and female patients (HR, 0.81; 95% CI, 0.68-0.97). Conversely, a non-statistically significant benefit was observed for chemotherapy alone in mUC patients with liver metastases (HR, 1.06; 95% CI, 0.86-1.31). Conclusions: According to our results, the magnitude of benefit of ICI-based combinations over chemotherapy in mUC was consistent across a number of clinicopathological subgroups, while a proportion of patients could respond to chemotherapy alone.Despite several limitations affect our analysis, we believe these results could guide in everyday treatment decision-making, also assisting in the design and interpretation of future clinical trials on ICIs in mUC.
Comparison of COVID-19 versus influenza on the incidence, features, and recovery from acute kidney injury in hospitalized United States Veterans
Authors: Bethany C. Birkelo, Sharidan K. Parr, Amy M. Perkins, Robert A. Greevy, Adriana M. Hung, Shailja C. Shah, Juan Pablo Arroyo, Jason Denton, Andrew J. Vincz, Michael E. Matheny, Edward D. Siew
Journal: Kidney International (2021)

Acute kidney injury is a common complication in patients hospitalized with SARSCoV-2 (COVID-19), with prior studies implicating multiple potential mechanisms of injury. Although COVID-19 is often compared to other respiratory viral illnesses, few formal comparisons of these viruses on kidney health exist. In this retrospective cohort study, we compared the incidence, features, and outcomes of acute kidney injury among Veterans hospitalized with COVID-19 or influenza and adjusted for baseline conditions using weighted comparisons. A total of 3402 hospitalizations for COVID-19 and 3680 hospitalizations for influenza admitted between October 1, 2019 and May 31, 2020 across 127 Veterans Administration hospitals nationally were studied using the electronic medical record. Acute kidney injury occurred more frequently among those with COVID-19 compared to those with influenza (40.9% versus 29.4%, weighted analysis) and was more severe. Patients with COVID-19 were more likely to require mechanical ventilation and vasopressors and experienced higher mortality. Proteinuria and hematuria were frequent in both groups but more common in COVID-19. Recovery of kidney function was less common in patients with COVID-19 and acute kidney injury but was similar among survivors. Thus, findings from this study confirm that acute kidney injury is more common and severe among patients hospitalized with COVID-19 compared to influenza, a finding that may be driven largely by illness severity. Hence, the combined impact of these two illnesses on kidney health may be significant and have important implications for resource allocation.
Process redesign and daily management to improve cancer care access at the public healthcare system in Sao Jose dos Campos, Brazil.
Authors: Carlos Frederico Pinto, Danilo Stanzani, Elitania Pontes, Stela Maris Coelho, Margarete Correa, Joana Benjamin, Messias Borges Silva
Journal: Journal of Clinical Oncology (2021)

6530 Background: Cancer is the second leading cause of death in Sao Jose dos Campos (SJC, a mid-sized city with 720,000 hab. in Sao Paulo state, Brazil) and the most relevant budget in tertiary care. The City Healthcare Authority created in October 2018 a team to manage and provide more effective and efficient cancer care and access to the public healthcare system by using process redesign and daily management tools (Previna Project). The aim was to guarantee access to cancer specialist and care up to 60 days form diagnosis, understanding that this can impact in cancer morbidity, mortality, and cost. Methods: The Previna was grounded in 4 major actions: (1) process redesign (2) escalated daily management system, (3) improve communication channels to all providers connecting primary care to specialized care, (4) and emergency access. (1) Process Redesign involved connecting and linking access to several providers and eliminating unnecessary steps or repeated orders in the system, it also involved alerts into the system for specific conditions like elevated PSA or CEA; positive fecal occult blood test; BIRADS 4-5 mammogram; abnormal PAP smears; and new screening protocols for prostate and colorectal cancer. (2) Daily Management involved internal daily discussions about capacity and review of system alerts or demands. Weekly discussions on specialized procedures including imaging, biopsies, chemo, radiation or surgery flows; and biweekly meetings with all providers (3 hospitals and 4 specialized practices). (3) Communication channels improvements involved a hotline to access flow managers for primary and secondary care units, specialist’s consultancy by phone, and (4) emergency access provided for units with special needs or urgent care requirements. All actions were connected by flow managers using alert systems, visual boards, kanban and similar tools to manage daily progress. Results: The access to cancer care and treatment up to 60 days improved from 2017 to 2020 almost two-fold with the Previna (Table). Cancer diagnosis also increased substantially, and it is expected to be related to previous periods underdiagnosed patients. Flow redesign also reduced median time to process Her2, ER and PR for breast cancer from 38 days in 2018 to 9 days in 2019 and 4 days in 2020, positively impacting treatment decisions. The hotline access reviewed and answered 2,389 demands from care providers between 2018 and 2020. Access to Cancer Care for ICD C00 – C97 (excl. C44 and C73) in SJC. Conclusions: The combined use of daily management, lean tools and flow redesign in the Previna was able to improve access and anticipate cancer diagnosis in a public healthcare system using simple and low-cost initiatives.[Table: see text]
Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.
Authors: Ecaterina Elena Dumbrava, Amit Mahipal, Xin Gao, Geoffrey Shapiro, Jason S. Starr, Parminder Singh, Muhammad Furqan, Afzal Ahrorov, Denice Hickman, Amy Gubits, Eyal C. Attar, Mark M. Awad, Satya Das, Haeseong Park
Journal: Journal of Clinical Oncology (2021)

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.
Partitioning of cancer therapeutics in nuclear condensates.
Authors: Isaac Klein, Ann Boija, Lena Afeyan, Susana Hawken, Mengyang Fan, Dylan Taatjes, Arup Chakraborty, Phillip Sharp, Young Tae Chang, Anthony Hyman, Nathanael Gray, Richard Young
Journal: Journal of Clinical Oncology (2021)

3131 Background: The molecules of the cell are compartmentalized into membrane- and non-membrane-bound organelles. Many non-membrane-bound organelles are phase-separated biomolecular condensates with distinct physicochemical properties that can absorb and concentrate specific proteins and nucleic acids involved in discrete biochemical processes. We reasoned that selective condensate partitioning might also occur with small molecule drugs whose targets occur within condensates, and that the therapeutic index and efficacy of such compounds might therefore relate to their ability to partition into condensates. Methods: To study the behavior of drugs within condensates, these were modeled in cells and in vitro with purified proteins and visualized by fluorescent confocal microscopy. The functional outcomes of condensate partitioning were queried in cells. Results: We found that cisplatin, tamoxifen, JQ1, THZ1, and mitoxantrone are concentrated in specific protein condensates in vitro, and that this occurs through physicochemical properties independent of the drug target. A screen of a chemically diverse fluorescent probes and mutant-protein condensates demonstrated that pi-system interactions between aromatic moieties in the protein and small molecule govern concentration in condensates. These results show that clinically important drugs partition into specific protein condensates in vitro by virtue of defined chemical properties, thereby altering their local concentration. In vitro droplet assays revealed that cisplatin is selectively concentrated in transcriptional condensates, and that this ability is required for efficient platination of target DNA. In cell studies revealed that cisplatin preferentially targets DNA contained within MED1 condensates, and disrupts the genetic regulatory elements that compose phase-separated transcriptional condensates. Live cell imaging demonstrated that transcriptional condensates are dissolved by cisplatin, whereas other condensates remain intact. Conclusions: Our results show that antineoplastic drugs partition selectively into biomolecular condensates, that this can occur through physicochemical properties independent of their molecular targets, and that drug activity may occur through condensate-related mechanisms. These results have implications for development of efficacious cancer therapeutics; effective target engagement will depend on factors such as drug partitioning in condensates. Assays of the type described here may thus help optimize condensate partitioning, target engagement, and the therapeutic index of drugs for cancer treatment.
Statewide rates of adjuvant checkpoint inhibitor use after definitive chemoradiation for stage III non-small cell lung cancer.
Authors: Alex K. Bryant, Huiying Yin, Matthew J. Schipper, Peter Alexander Paximadis, Thomas Pence Boike, Derek P. Bergsma, Benjamin Movsas, Munther Isa Ajlouni, Robert Timothy Dess, Melissa A. Mietzel, Randi Kendrick, Merita Seferi, Michael M. Dominello, Martha Matuszak, Reshma Jagsi, James Hayman, Lori J. Pierce, Shruti Jolly
Journal: Journal of Clinical Oncology (2021)

8523 Background: In the landmark PACIFIC trial, adjuvant durvalumab after definitive chemoradiation for unresectable stage III non-small-cell lung cancer (NSCLC) produced a 11% absolute overall survival benefit at two years compared to placebo, and the US Food and Drug Administration approved durvalumab for this indication in February 2018. We investigated the real-world use of adjuvant durvalumab and other immune checkpoint inhibitors (ICI) in a contemporary cohort of patients. Methods: We identified patients with unresectable stage III (AJCC 8th edition) NSCLC treated with definitive chemoradiation from February 2018 to March 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers, 336 patients) and academic practice settings (n=5 centers, 64 patients) across the state of Michigan. Use of adjuvant durvalumab or other ICI (atezolizumab, nivolumab, or pembrolizumab) was ascertained at the time of routine three- or six-month follow-up after completion of chemoradiation. Baseline characteristics of patients treated with or without adjuvant ICI were compared with the Chi-squared test for categorical variables and a two-sided t-test for continuous variables. Results: Of 400 patients with unresectable stage III NSCLC treated with definitive chemoradiation, 268 (67%) received adjuvant ICI. Of these, the majority received durvalumab (86%) followed by pembrolizumab (7.5%) and nivolumab (6.0%). The proportion of patients receiving ICI remained stable throughout the study period with no discernable time trends. Eight-five percent of white patients received ICI compared with 77% of black patients (p=0.04), but there were no differences in gender (54.5% male in ICI vs 52.3% no ICI), current smoking (42.2% ICI vs 37.9% no ICI, p=0.68), number of comorbidities (29.5% with 3 or more comorbidities in ICI vs. 26.5% in no ICI, p=0.86), baseline oxygen use (8.9% ICI vs 10.6% no ICI, p=0.59), age (median 66.4 years [IQR 60.3-73.4] for ICI vs. 66.9 years [IQR 61.1-72.2] no ICI, p=0.89), treatment at an academic center (16.0% ICI vs 15.9% no ICI, p=0.97), or ECOG performance status (59.3% ECOG 0 in ICI vs 62.8% no ICI). Conclusions: In a broad range of academic and community-based practices across a state including 27 sites, only two-thirds of potentially eligible stage III NSCLC patients received adjuvant durvalumab or other ICI agents despite a proven overall survival benefit. Receipt of ICI was not strongly associated with baseline demographic or comorbidity variables. Further work will seek to clarify the patient-level reasons behind non-initiation of adjuvant ICI.
Baseline modified Glasgow prognostic score (mGPS) in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI).
Authors: Jacqueline T Brown, Yuan Liu, Dylan J. Martini, Julie M. Shabto, Greta Russler, Sarah Caulfield, Lauren Beth Yantorni, Shreyas S. Joshi, Haydn Kissick, Kenneth Ogan, Bassel Nazha, Bradley Curtis Carthon, Omer Kucuk, Wayne Harris, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2021)

e16546 Background: The IMDC and MSKCC risk models for mRCC were validated before the era of ICI. The mGPS incorporates albumin and C-reactive protein and reflects systemic inflammation. mGPS may be a useful prognostic biomarker of particular relevance in mRCC given the current, largely ICI-based treatment paradigm and hypothesis that systemic inflammation may contribute to ICI resistance. Methods: We retrospectively assessed mRCC patients treated with ICI (including anti-PD-1 and anti-PD-L1 agents) in any line of therapy at Winship Cancer Institute of Emory University from 2015-2018. Primary outcomes assessed included overall survival (OS) and progression-free survival (PFS). mGPS was calculated by giving 1 point for CRP &gt; 10 mg/L and/or albumin &lt; 3.5 g/dL with 0 points awarded for solitary low albumin. The relationship between mGPS and survival outcomes was assessed in UVA and MVA using Cox proportional hazard model and in Kaplan-Meier analysis. Results: We assessed 156 eligible patients. Median follow up was 24.2 months. Median age was 64 years, 69% were male, 20% were Black, and 78% had clear cell histology. 57.1% received anti-PD-1 monotherapy whereas all others received dual ICI or ICI combined with an antiangiogenic agent or experimental therapy in trial. Higher baseline mGPS was significantly associated with worse OS and PFS (Table). The median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (CI 27.3, NA), 15.3 (CI 11, 24.2) and 10 (CI 4.6, 17.5) months, respectively (p&lt;0.0001), while the median PFS of these three cohorts was 6.7 (CI 3.6, 13.1), 4.2 (CI 2.9, 6.2) and 2.6 (CI 2, 5.6) months, respectively (p=0.0216). Conclusions: A higher mGPS at the start of therapy was negatively prognostic in patients with mRCC receiving ICI. These results should be validated in a larger, prospective study. [Table: see text]