tbuckley/cabot-search huggingface dataset:
ATRX<sup>Loss</sup> to impair glioma stem cell viability and self-renewal via proton radiotherapy induced necrosis.
Authors: Angel Adrian Garces, Lawrence Bronk, Krishna Bhat, David R Grosshans
Journal: Journal of Clinical Oncology (2021)

2046 Background: Glioblastoma Multiforme (GBM-Grade IV) is the most aggressive form of glioma in the USA carrying only a 15 month median survival time. Although IDH1 R132H is traditionally associated with improved glioma patient survival and clinical response to chemotherapy, astrocytoma (LGG) patients also harbor ATRX Loss , an inactivation of the ATRX chromatin remodeling protein shown to impair DNA damage repair via non-homologous end joining. The recent discovery of glioma stem cells (GSCs), a subpopulation of chemoradioresistant, self-renewable, tumor initiating cells known to promote tumor recurrence, presents a new target for therapeutic intervention. However, the mechanisms by which ATRX Loss contributes to GSC proton radiotherapy (PRT) sensitivity, a more tumor specific and cytotoxic form of radiation therapy than conventional X-rays (XRT), are not well understood. We hypothesize that ATRX Loss impairs GSC post-radiation viability and self-renewal capacity by promoting necrosis to a higher extent after PRT than XRT. Methods: Isogenic TS543-ATRX WT and TS543-ATRX Loss patient derived glioma cells were cultured as neurospheres and treated with 2-8 Gy XRT or PRT. GSC viability was quantified using the CellTiterGlo 3D assay 12 days after irradiation. The Annexin V apoptosis and necrosis assay was conducted every 8 hours up to 72 hours after irradiation. GSC self-renewal, based on neurosphere formation frequency, was quantified using extreme limiting dilution analysis (ELDA). Results: ATRX Loss significantly decreased TS543 GSC viability after 2-8 Gy radiation therapy compared to ATRX WT (Unpaired t-test with Welsh’s correction and Holm-Sidak’s Multiple Comparisons Test p&lt;0.0001). TS543-ATRX Loss also significantly inhibited GSC self-renewal over TS543-ATRX WT when subject to either 6 Gy PRT or XRT (Pairwise Pr(&gt;χ 2 )&lt;0.01). Interestingly, PRT significantly reduced GSC viability to a higher extent than XRT in both TS543-ATRX WT and TS543-ATRX Loss , which demonstrates the effectiveness of PRT to treat ATRX Loss gliomas. Follow up studies confirmed that ATRX Loss sensitizes TS543 GSCs more extensively to the cytotoxic effects of PRT compared to XRT via the upregulation of necrosis at 72 hours post-irradiation (Two-way ANOVA with Tukey’s post-hoc Multiple Comparisons Test p&lt;0.0001). Conclusions: We conclude that ATRX Loss substantially contributes to PRT sensitivity in GSCs, thereby supporting the benefits of PRT for astrocytoma patients. Our future experiments will further elucidate the biological mechanisms by which ATRX Loss confers PRT sensitivity, especially via dsDNA damage.
Automated computed tomography (CT)-derived skeletal muscle mass determination as a significant prognostic factor in colorectal cancer patients using deep neural network model.
Authors: Dongjin Seo, Han Sang Kim, Yu Rang Park
Journal: Journal of Clinical Oncology (2021)

3534 Background: Although recent evidence suggests skeletal muscle depletion predicts the survival of patients with cancer, the retrieval and manual measurement of the computed tomography (CT) images hinder clinical application in routine clinical practice. The advent of recent deep learning applications enables highly accurate noninvasive longitudinal evaluation of skeletal muscle mass (SMM) changes. Here, we evaluated the prognostic impact of DNN-measured skeletal muscle changes in colorectal cancer (CRC) patients. Methods: A total of 6,196 newly diagnosed CRC patients were analyzed in the Yonsei Cancer Registry Database between Jan 1, 2010, and Sep 30, 2020. SMM is measured by the Skeletal muscle index (SMI). The formula used was: L3 skeletal muscle cross-sectional area (cm 2 )/height 2 (m 2 ). Patients’ SMI patterns were grouped by difference ratio of initial and last SMI. Patients were also classified by BMI pattern with the result of K-means clustering. Association of baseline SMI, baseline body mass index (BMI), SMI changes, BMI changes, and demographic factors with overall survival (OS) were evaluated. Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test the predictive accuracy of survival models. Results: Fully automated UNet architecture-based deep learning algorithms were applied for the third lumbar transverse CT detection, skeletal muscle segmentation, and skeletal muscle area quantification in CRC patients undergoing abdominal CT between at the time of diagnosis and one year after the diagnosis. Baseline BMI distribution was 28% obese, 26% overweight, 42% normal weight, and 4% underweight. Patients in all SMI categories varied widely in BMI. Changes in SMI were categorized into three groups: SMI increase (33%), steady (45%), and decrease (22%) group. Similarly, BMI changes were categorized into three groups: BMI increase (24%), BMI stable (57%), and BMI decrease (19%) group. Low baseline SMI, low baseline BMI, SMI decrease, and BMI decrease were independently prognostic of survival. Intriguingly, BMI and SMI changes had a different prognostic impact in men and women. For women, the SMI increase group (hazard ratio [HR], 0.4; 95% CI, 0.3-0.7; P= 0.001) was associated with longer OS, while the SMI decrease group (HR, 1.2; 95% CI, 0.6-2.2; P= 0.619) was not associated with shorter OS, both compared with SMI steady group. Conclusions: Automated CT-derived SMM depletion had a negative prognostic impact independent of BMI and age in CRC patients. A noninvasive automatic deep learning algorithm provides a unique opportunity to apply to routine clinical practice and understand how and when cachexia impacts cancer prognosis.
Analysis of opioid and adjunctive pain medication prescriptions in lung cancer patients.
Authors: Benjamin Aaron Bleiberg, Kyle Andrew Westbrook, Chul Ahn, Saad A. Khan
Journal: Journal of Clinical Oncology (2021)

e24073 Background: Between 1999-2018, the CDC reported 232,000 deaths from prescription opioids. Lung cancer patients receive many opioid and adjunctive pain medication prescriptions. The frequency, duration, and impact of these prescriptions is unknown. Methods: We used the electronic medical record to catalogue opioid and adjunctive pain medication prescriptions given to adult cancer patients at our academic and county-affiliated health systems from 2009-2016. We identified the association of opioid and adjunctive pain medication use with patient characteristics including cancer stage and radiation therapy. Results: 1510 lung cancer patients were identified, of which 1061 had opioid prescriptions (70%). Of patients with prescriptions: hydrocodone was prescribed to 90%, morphine 35%, hydromorphone 17%, fentanyl 16%, and oxycodone 13%. 330/1061 patients had adjunctive medication prescriptions, of which, gabapentin was prescribed to 90%, pregabalin 14% and carbamazepine 2%. 296/330 patients prescribed adjunctive medications also had an opioid prescription with the following frequency: hydrocodone 90%, hydromorphone 33%, fentanyl 27%, morphine 41%, and oxycodone 23% 7/1061 patients with opioids had naloxone prescribed. Opioid usage by cancer stage is shown in the table. 211/1510 patients (13%) had prescriptions for ≥3 different opioids; 97/330 (33%) patients with adjunctive prescriptions, had prescriptions for ≥3 different opioids. Of patients treated with radiation for &gt;4 weeks, 66% received opioids, with the proportion receiving opioids increasing with each fraction of radiation up to a rate of 90% with 5 or more fractions. 87% of patients prescribed opioids alone had an active opioid prescription 3 months after their last date of radiation as did 91% of those prescribed adjunctive medications in addition to opioids. In the total dataset: 55% of patients were from the university system and 45% were from the county system and other settings. Of the lung cancer patients with opioid prescriptions: 69% were from the university system and 31% were from other settings. Conclusions: Opioids are commonly prescribed in patients with any stage of lung cancer, particularly those with stage &gt;1 with hydrocodone being the most prescribed. In the period under study, adjunctive medications such as gabapentin were prescribed much less than and rarely without opioids. Some lung cancer patients received ≥3 distinct opioids, with higher rates seen in those with adjunctive medicine prescriptions. Further studies to evaluate system wide opioid prescribing trends and discrepancies related to demographic factors are needed.[Table: see text]
Mediators of racial disparity in the use of prostate MRI.
Authors: Michael S. Leapman, Michaela Ann Dinan, Saamir Pasha, Samuel L. Washington, Xiaomei Ma, Cary Philip Gross
Journal: Journal of Clinical Oncology (2021)

6554 Background: Evidence of racial disparity in the use of prostate MRI presents new obstacles to closing recognized gaps in treatment and outcome for black men with prostate cancer. To anticipate strategies for improving equity in cancer care, we examined mediators of racial disparity in the use of prostate MRI surrounding the diagnosis of prostate cancer. Methods: We conducted a multiple mediation analysis among patients with localized prostate cancer in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database between January 2008 and December 2015. We assessed claims for prostate MRI within the six-month period preceding or following diagnosis. We first identified candidate clinical and sociodemographic meditators based on their association with both race and prostate MRI, including the Index of Concentrations at the Extremes (ICE), a measure of racialized residential segregation calculated at the zip code or census tract level. We used non-linear Multiple Additive Regression Trees (MART) models to estimate the direct and indirect relative effects of mediators. Results: We identified 71,597 eligible patients. Black patients with prostate cancer were less likely (5.3%) to receive a prostate MRI when compared with white patients (7.0%; unadjusted odds ratio 0.75, 95% CI 0.67-0.84, p &lt; 0.001). 33.1% (95% CI 20.6-44.9) of the racial disparity in prostate MRI use was attributable to variation in SEER region, 22.5% (95% CI 13.0-30.2) to residence in a high poverty area, 17.2% to residential segregation (ICE group 17.2%, 95% CI 8.1-27.9%), and 13.2% to dual eligibility for Medicaid (95% CI 8.6-20.2%). Clinical and pathologic factors were not significant mediators. After accounting for the mediators, the direct effects of race accounted for 6.2% of the observed disparity in prostate MRI use. Conclusions: Sociodemographic factors including geographic region, and area-level measures of income and residential segregation explain the majority of the observed racial disparity in the use of prostate MRI among older Americans with prostate cancer. The findings underscore that measurable structural factors can be readily identified that underlie racial disparity in access to emerging diagnostic tools for patients with cancer.
Evaluation of in silico tools for variant classification in clinically actionable NSCLC variants.
Authors: Eugene Kim, Samantha Duarte, Stas Fridland, Myungwoo Nam, Jin Young Hwang, Alice Daeun Lee, Grace Lee, Emma Yu, Young Kwang Chae
Journal: Journal of Clinical Oncology (2021)

e13545 Background: Genetic variants beyond FDA-approved drug targets are often identified in NSCLC patients. To address this challenge, in silico variant classification tools are available to determine whether specific variants contribute to disease pathogenicity or remain benign. Although the performance of in silico tools has been analyzed in previous studies, it has not been analyzed for actionable targets of FDA-approved therapies for NSCLC. The aim of this study is to compare the performance of commonly used in silico tools in classifying the pathogenicity of actionable variants in NSCLC. Methods: We evaluated the performance of several in silico tools: PolyPhen-2, Align-GVGD, and MutationTaster2. A curated set of targetable NSCLC missense variants (n = 179) was used. The dataset consisted of variants in the BRAF, EGFR, ERBB2, KRAS, MET, ALK, and ROS1 genes based on their indications as molecular targets in the NCCN Guidelines for NSCLC. Pathogenic variants (n = 80) were curated based on available literature and annotations according to the NCCN Guidelines, OncoKB, My Cancer Genome, and AACR Project GENIE. Benign variants (n = 99) were curated from the dbSNP database with the inclusion criteria of a benign or likely benign ClinVar assertion. The overall accuracy, sensitivity, specificity, and Matthews correlation coefficient (MCC) of each in silico tool were determined. The performance of each in silico tool in predicting pathogenicity for subsets of sensitizing (n = 18) and resistant (n = 57) variants was also evaluated. Results: PolyPhen-2 HumVar demonstrated the highest overall accuracy (0.80), specificity (0.69), and MCC (0.63) of the in silico tools analyzed. PolyPhen-2 HumDiv (0.75) and MutationTaster2 (0.69) had similar overall accuracies while Align-GVGD (0.50) had the lowest overall accuracy. Align-GVGD also had the lowest MCC (0.08), with the other in silico tools ranging from 0.50 to 0.63. All the in silico tools achieved high sensitivities, with MutationTaster2 performing the highest (1.00) and Align-GVGD performing the lowest (0.86). The specificities were remarkably low (0.20-0.69) for all the in silico tools, with the lowest specificity demonstrated by Align-GVGD. The overall accuracies when classifying the subsets of sensitizing and resistant variants were generally high, ranging from 0.84 to 1.00. Conclusions: These results suggest that the performance of the evaluated in silico tools to predict the pathogenicity of clinically actionable NSCLC missense variants is not fully reliable. The tools analyzed in this study could be acceptable to rule out pathogenicity in variants given their higher sensitivities, but are limited when it comes to identifying pathogenicity in variants due to low specificities.
JAK3 Variants in Adults with Myeloid Malignancies and Potential for Response to JAK3 Inhibition
Authors: Rita Assi, Christopher B Benton, Ahmed Al Rawi, Kamal Chamoun, Feng Wang, Sherry Pierce, Keyur P. Patel, Betty K. Hamilton, Courtney D. DiNardo, Guillermo Garcia-Manero, Hagop M. Kantarjian, Tapan Kadia, Srdan Verstovsek, Michael Andreeff
Journal: Blood (2017)
The effectiveness of a provincial symptom assessment program in reaching adolescents and young adults with cancer: A population-based cohort study.
Authors: Sumit Gupta, Rinku Sutradhar, Qing Li, Natalie G. Coburn
Journal: Journal of Clinical Oncology (2021)

12101 Background: Symptom control is prioritized by cancer patients and may improve overall survival. Several jurisdictions have thus launched population-wide initiatives to assess symptoms at regular intervals. In Ontario, Canada, for example, all cancer patients are screened using the Edmonton Symptom Assessment System (ESAS) at every outpatient visit. Few studies have examined symptom burdens in adolescents and young adults (AYA). Previous work suggests that AYA symptoms differ from those in older patients, and that general screening tools may not be appropriate. Despite this, whether current symptom screening initiatives reach AYA with cancer are unknown. We therefore determined 1) Whether AYA with cancer were participating in ESAS screening, and 2) Which AYA were at highest risk of not being screened. Methods: We identified all Ontario AYA diagnosed with cancer at age 15-29 years between 2010-2018 and treated in adult centers. Patients were linked to population-based databases to identify all cancer-related outpatient visits in the year following diagnosis and whether visits involved completion of an ESAS form. Each patient’s first year was divided into two-week periods. For each period, AYA were considered either “unscreened” if they had a cancer-related visit but no ESAS score, or “screened” if they had a cancer-related visit with at least one ESAS score. Periods without cancer-related visits were not considered, given no potential for ESAS screening during such periods. Covariates included age at diagnosis, sex, cancer type, neighbourhood income quintile, and institution type [regional cancer centre (RCC) vs. community]. Multivariable logistic regression models were implemented under a generalized estimating equations approach to account for individual-level correlation. Results: The final cohort included 5,435 AYA. Within any given two-week period, only 36-45% of AYA attending cancer-related outpatient visits were screened. In adjusted analyses, age and sex were not associated with being screened. However, AYA living in the lowest income quintile neighbourhood were less likely to be screened [odds ratio (OR) 0.86, 95 th confidence interval (95CI) 0.77-0.97; p = 0.01] compared to those in the highest. Patients with hematologic malignancies were least likely to be screened (OR 0.77, 95CI 0.67-0.88; p &lt; 0.001), as were AYA attending community centers (OR 0.48, 95CI 0.42-0.55; p &lt; 0.001). Conclusions: Despite a population-wide symptom assessment program, only a minority of AYA are screened. Though patients with hematologic cancers suffer from particularly high symptom burdens, they were less likely to be screened. Interventions targeting AYA are required to increase uptake, particularly among those in disadvantaged neighborhoods or attending community hospitals. Studies of AYA-specific symptom assessment tools are also warranted.
A NGS-based Blood Test For the Diagnosis of Invasive HPV-associated Carcinomas with Extensive Viral Genomic Characterization
Authors: Xavier Sastre-Garau, Mamadou Diop, Fernando Martin, Gilles Dolivet, Frédéric Marchal, Claire Charra-Brunaud, Didier Peiffert, Léa Leufflen, Birama Dembélé, Jessica Demange, Priscillia Tosti, Jacques Thomas, Agnès Leroux, Jean-Louis Merlin, Halimatou Diop-Ndiaye, Jean-Marc Costa, Julia Salleron, Alexandre Harlé
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Use of circulating tumor DNA (ctDNA) for diagnosis is limited regarding the low number of target molecules in early-stage tumors. Human papillomavirus (HPV)–associated carcinomas represent a privileged model using circulating viral DNA (ctHPV DNA) as a tumor marker. However, the plurality of HPV genotypes represents a challenge. The next-generation sequencing (NGS)-based CaptHPV approach is able to characterize any HPV DNA sequence. To assess the ability of this method to establish the diagnosis of HPV-associated cancer via a blood sample, we analyzed ctHPV DNA in HPV-positive or HPV-negative carcinomas. Experimental Design: Patients (135) from France and Senegal with carcinoma developed in the uterine cervix (74), oropharynx (25), oral cavity (19), anus (12), and vulva (5) were prospectively registered. Matched tumor tissue and blood samples (10 mL) were taken before treatment and independently analyzed using the CaptHPV method. Results: HPV prevalence in tumors was 60.0% (81/135; 15 different genotypes). Viral analysis of plasmas compared with tumors was available for 134 patients. In the group of 80 patients with HPV-positive tumors, 77 were also positive in plasma (sensitivity 95.0%); in the group of 54 patients with HPV-negative tumors, one was positive in plasma (specificity 98.1%). In most cases, the complete HPV pattern observed in tumors could be established from the analysis of ctHPV DNA. Conclusions: In patients with carcinoma associated with any HPV genotype, a complete viral genome characterization can be obtained via the analysis of a standard blood sample. This should favor the development of noninvasive diagnostic tests providing the identification of personalized tumor markers. See related commentary by Rostami et al., p. 5158
Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer.
Authors: Jessica Jiyeong Lin, Shivaani Kummar, Daniel Shao-Weng Tan, Ulrik Niels Lassen, Serge Leyvraz, Yongmei Liu, Victor Moreno, Jyoti D. Patel, Lee S. Rosen, Benjamin Maurice Solomon, Ricarda Norenberg, Laura Dima, Nicoletta Brega, Lin Shen, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2021)

9109 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a diverse array of tumor types including lung cancer. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients (pts) with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). Here, we report the updated data on pts with lung cancer treated with larotrectinib. Methods: Pts with lung cancer harboring a NTRK gene fusion enrolled in two clinical trials (NCT02576431 and NCT02122913) were identified for this analysis. Larotrectinib 100 mg PO BID was administered on a continuous 28-day schedule until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by the investigator per RECIST v1.1. Results: As of July 20, 2020, a total of 20 pts with TRK fusion-positive lung cancer (19 with non-small cell lung cancer and 1 with small cell lung cancer) were enrolled. Median age was 48.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n = 16; 80%) or NTRK3 (n = 4; 20%). Pts were heavily pre-treated with a median of 3 systemic therapies (range 0–6). Among 15 evaluable pts, the confirmed ORR was 73% (95% CI 45–92): 1 complete response, 10 partial responses (PR), 3 stable disease (SD) and 1 progressive disease (PD). The median time to response was 1.8 months. Among 8 evaluable pts with baseline measurable and non-measurable CNS metastases, the ORR was 63% (95% CI 25–91): 5 PR, 2 SD, and 1 PD. In all evaluable pts, the 12-month rates for duration of response and progression-free survival were 81% and 65%, respectively. Median overall survival was 40.7 months (95% CI 17.2 to not estimable) at a median follow-up of 16.2 months. Duration of treatment ranged from 0.03+ to 51.55+ months. Adverse events (AEs) were predominantly Grade 1–2. Treatment-related AEs were reported in 16 pts, of which 2 experienced Grade 3 events (myalgia, hypersensitivity, weight increase). There were no treatment discontinuations due to AEs. Conclusions: These data confirm that larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results underscore the importance of screening for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 and NCT02122913.