tbuckley/cabot-search huggingface dataset:
Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.
Authors: Woojung Lee, Scott Spencer, Josh John Carlson, Tam Dinh, Victoria Dayer, Rachel Cummingham, Kathleen Kaa, Gary Martucci, Maggie Hynes, David Leroy Veenstra
Journal: Journal of Clinical Oncology (2021)

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]
KIR3DS1 directs NK cell–mediated protection against human adenovirus infections
Authors: Johannes M. Jung, Wilhelm Ching, Martin E. Baumdick, Helga Hofmann-Sieber, Jens B. Bosse, Tobias Koyro, Kimberly J. Möller, Lucy Wegner, Annika Niehrs, Kristina Russu, Mareike Ohms, Wenli Zhang, Anja Ehrhardt, Kevin Duisters, Eric Spierings, Angelique Hölzemer, Christian Körner, Suze A. Jansen, Sven Peine, Ingo Königs, Marc Lütgehetmann, Daniel Perez, Konrad Reinshagen, Caroline A. Lindemans, Marcus Altfeld, Mirjam Belderbos, Thomas Dobner, Madeleine J. Bunders
Journal: Science Immunology (2021)

KIR3DS1 + NK cells execute enhanced killing of adenovirus-infected cells, providing protection against severe infection in immunocompromised hosts.
Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity
Authors: Alexander Y. Payumo, Xi Chen, Kentaro Hirose, Xiaoxin Chen, Alison Hoang, Sheamin Khyeam, Hongyao Yu, Jiajia Wang, Qing Chen, Nevan Powers, Li Chen, Rachel B. Bigley, Jonathan Lovas, Guang Hu, Guo N. Huang
Journal: Circulation (2021)
Measurement of respiratory rate using wearable devices and applications to COVID-19 detection
Authors: Aravind Natarajan, Hao-Wei Su, Conor Heneghan, Leanna Blunt, Corey O’Connor, Logan Niehaus
Journal: npj Digital Medicine (2021)

We show that heart rate enabled wearable devices can be used to measure respiratory rate. Respiration modulates the heart rate creating excess power in the heart rate variability at a frequency equal to the respiratory rate, a phenomenon known as respiratory sinus arrhythmia. We isolate this component from the power spectral density of the heart beat interval time series, and show that the respiratory rate thus estimated is in good agreement with a validation dataset acquired from sleep studies (root mean squared error = 0.648 min-1, mean absolute error = 0.46 min-1, mean absolute percentage error = 3%). We use this respiratory rate algorithm to illuminate two potential applications (a) understanding the distribution of nocturnal respiratory rate as a function of age and sex, and (b) examining changes in longitudinal nocturnal respiratory rate due to a respiratory infection such as COVID-19. 90% of respiratory rate values for healthy adults fall within the range 11.8-19.2 min-1 with a mean value of 15.4 min-1. Respiratory rate is shown to increase with nocturnal heart rate. It also varies with BMI, reaching a minimum at 25 kg/m2, and increasing for lower and higher BMI. The respiratory rate decreases slightly with age and is higher in females compared to males for age <50 years, with no difference between females and males thereafter. The 90% range for the coefficient of variation in a 14 day period for females (males) varies from 2.3-9.2% (2.3-9.5%) for ages 20-24 yr, to 2.5-16.8% (2.7-21.7%) for ages 65-69 yr. We show that respiratory rate is often elevated in subjects diagnosed with COVID-19. In a 7 day window from D-1 to D+5 (where D0 is the date when symptoms first present, for symptomatic individuals, and the test date for asymptomatic cases), we find that 36.4% (23.7%) of symptomatic (asymptomatic) individuals had at least one measurement of respiratory rate 3 min-1 higher than the regular rate.
Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner
Authors: Cancan Zheng, Xiaomei Yu, Yiyao Liang, Yidong Zhu, Yan He, Long Liao, Dingkang Wang, Yanming Yang, Xingfeng Yin, Ang Li, Qingyu He, Bin Li
Journal: Acta Pharmaceutica Sinica B (2021)

As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.
Trends in pegfilgrastim average sales price and cost-effectiveness of primary prophylaxis for patients at intermediate risk for febrile neutropenia.
Authors: Edward C. Li, Kimberley J. Campbell, Bridgette Kanz Schroader, David Campbell, Stephen Chaplin, Gary H. Lyman
Journal: Journal of Clinical Oncology (2021)

58 Background: The introduction of biosimilar colony-stimulating factors has led to the reduction in prices for these historically expensive therapies. To understand the impact of recent pricing trends on delivering efficient care, the cost-effectiveness of primary prophylaxis (PP) versus secondary prophylaxis (SP) using pegfilgrastim was assessed in patients with breast cancer, non–small-cell lung cancer (NSCLC), and non-Hodgkin lymphoma (NHL) receiving potentially curative chemotherapy at intermediate risk for febrile neutropenia per NCCN guidelines. Methods: A Markov decision analytic model was constructed from the US payer perspective over a lifetime horizon to evaluate pegfilgrastim PP versus SP in patients with breast cancer, NSCLC, and NHL receiving curative chemotherapy at intermediate risk of FN. Modeled chemotherapy regimens were adjuvant docetaxel (breast cancer), adjuvant carboplatin/paclitaxel (NSCLC), and R-CHOP (NHL) representing baseline FN risk of 16%, 18%, and 18%, respectively. Historical average sales prices (ASP) according to the Centers for Medicare and Medicaid Services of all pegfilgrastim products were obtained from January 2017 to April 2021. When more than one pegfilgrastim product was available, the average ASP was used as the cost input for the model. Cost-effectiveness for the base case scenario of each cancer type was evaluated over the range of years for cost per quality-adjusted life year (QALY) gained. Results: Pegfilgrastim as PP vs. SP provided an additional 0.069, 0.112, and 0.166 QALYs for breast cancer, NSCLC, and NHL, respectively. The peak ASP for pegfilgrastim was $4,554 per 6 mg during July 2018. Afterwards, a linear regression observed a declining ASP of approximately $134 dollars every 3 months to $3,024 per 6 mg during April 2021. At peak ASP, the incremental cost-effectiveness ratios (ICERs) for pegfilgrastim PP in patients with breast cancer, NSCLC, and NHL were $200,320, $113,942, and $103,495 per QALY, respectively. For April 2021, the ICERs were $124,845, $67,294, and $57,269 per QALY, respectively (Table). Conclusions: The trend of decreasing pegfilgrastim ASP improved the cost-effectiveness of PP vs. SP across intermediate risk breast cancer, NHL, and NSCLC indications between July 2018 to April 2021. For the most recent ASP, PP was cost-effective at a willingness-to-pay threshold of $100,000/QALY for NSCLC and NHL, and $150,000/QALY for breast cancer. This analysis provides support to expand the use of growth factor PP to intermediate risk patients. [Table: see text]
Bortezomib-Dexamethasone Re-Treatment at Biochemical Relapse Vs Observation in Relapsed/Refractory Multiple Myeloma Patients: Results of a Phase II Multi-Center, Randomized Study
Authors: Roberto Mina, Alessandra Larocca, Angelo Belotti, Francesco Di Raimondo, Anna Baraldi, Massimo Offidani, Monia Marchetti, Roberto Ria, Annarita Conconi, Norbert Pescosta, Mariella Grasso, Giusy Cetani, Anna Maria Cafro, Roberto Passera, Rossella Troia, Gianpietro Semenzato, Nicola Giuliani, Stelvio Ballanti, Claudia Cellini, Anna Marina Liberati, Tommaso Caravita di Toritto, Maria Teresa Petrucci, Pellegrino Musto, Antonio Palumbo, Pieter Sonneveld, Mario Boccadoro
Journal: Blood (2017)
Real-world trends in EU4 and the UK in frontline (1L) maintenance (MT) for nonsquamous (NSQ) advanced non-small cell lung cancer (aNSCLC) without actionable mutations after introduction of immune checkpoint inhibitors.
Authors: Cosmina Hogea, Linda Kalilani, Jasjit Multani, Vicky Casey, Sheila Mpima, Marie Yasuda, Chi-Chang Chen, Fil Manguid, Thomas J. Giove, Jessica Chao, Amine Aziez, Alexander Stojadinovic
Journal: Journal of Clinical Oncology (2021)

296 Background: Immune checkpoint (PD-1, PD-L1) inhibitors are important in the treatment (Tx) of aNSCLC, as reflected in European Society for Medical Oncology (ESMO) guidelines. Pembrolizumab (pembro) combined with pemetrexed and platinum-based chemotherapy is a standard induction option in 1L Tx of NSQ aNSCLC. Decisions about 1L maintenance consider response and toxicity after induction, performance status, and patient preference. This study documents recent real-world 1L MT patient characteristics and Tx in EU4 (France, Germany, Italy, Spain) and UK. Methods: This retrospective analysis used patient chart review completed by treating physicians in EU4 and UK between 1 Jan 2018 and 31 Dec 2020 in the IQVIA Oncology Dynamics (OD) database. Adults (≥21 years) with confirmed NSQ aNSCLC (stage IIIB/C or IV) without actionable oncogenic driver mutations and with Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 were included. 1L MT and Tx characteristics and trends over time were evaluated overall and by country. Results: In total, 1,814 NSQ aNSCLC patients receiving 1L MT Tx met the inclusion criteria; 29% of patients entered the analysis in 2018, 40% in 2019, and 31% in 2020. Most patients were male (61%), in the 46–65 age group (51%), current/ex-smokers (87%), and treated in the UK (29%) or Germany (24%); 94% were metastatic (stage IV), 10% presented with CNS/brain metastases, and 77% had ECOG score of 1. Overall, 91% were tested for PD-L1; of these, 47% had tumor proportion score (TPS) of ≥1% to 49%, 22% had TPS of ≥50%, and 21% tested negative. Baseline demographic and clinical characteristics were generally similar among countries. The top two Tx in 1L MT were pemetrexed (40%; range: 12% in Germany to 66% in Italy) and pembro (28%; range: 14% in Spain to 49% in Germany) monotherapies. Overall use of pemetrexed-based Tx in 1L MT decreased from 68% in 2018 Q1 to 56% in 2020 Q4, while pembro-based Tx increased from 18% in 2018 Q1 to 73% in 2020 Q4 in 1L MT. Conclusions: Despite ESMO guidelines, this real-world data suggests notable differences between European countries in 1L MT Tx for NSQ aNSCLC, with trends over time likely reflecting introduction and adoption of pembro regardless of PD-L1 status. Awareness of country and time-variability in clinical practice are critical for implementing clinical trials and updating clinical practice guidelines to maximize Tx benefits with improved tolerability.[Table: see text]
P13.07 Cysteine induces glioblastoma cytotoxicity through mitochondrial reductive stress
Authors: E Noch, L Palma, I Yim, D Barnett, B BHinder, E Benedetti, J Krumsiek, O Elemento, L Cantley
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, therapies targeting GBM metabolism, whether through the use of small-molecule compounds or dietary interventions to limit nutrient sources, have failed in clinical trials. Metabolic bypass is an important mechanism that is often overlooked in GBM trials, since many trials have focused instead on combining anti-metabolic therapy with cytotoxic treatments. The goal of this research is to use a multi-pronged treatment approach with targeted drug and dietary therapy to leverage metabolic susceptibilities in GBM. MATERIALS AND METHODS We first interrogated the TCGA database and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. We identified the amino acid cysteine as contributing to a novel metabolic susceptibility pathway in GBM. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cysteine-promoting compounds in vitro, including N-acetylcysteine (NAC). We measured cell proliferation, energy production, mitochondrial metabolism, and reactive oxygen species to study mechanisms of oxidoreductive stress. Results: From our TCGA and cancer metabolite database analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. Cysteine compounds, including NAC, reduce growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP generation, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Through measurement of mitochondrial hydrogen peroxide, we found that NAC-treated cells exhibit a paradoxical increase in mitochondrial hydrogen peroxide levels, likely due to inhibition of thioreductase and glutathione reductase systems. Through genetic and pharmacological studies, we found that induction of thioredoxin-2 rescues NAC-mediated cytotoxicity and that inhibition of thioreductase and glutathione reductase exacerbates mitochondrial toxicity and reductive stress. CONCLUSIONS We show that cysteine compounds reduce cell growth and induce mitochondrial toxicity in GBM through reductive stress. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.
Comparing U.S. Preventive Services Task Force 2013 versus 2021 lung cancer screening eligibility.
Authors: Matthew Smeltzer, Wei Liao, Meghan Brooke Taylor, Carrie Fehnel, Nicholas Faris, Jordan Goss Lane, Sara Cat Williams, Olawale Akinbobola, Alicia Pacheco, Amanda Epperson, Joy Luttrell, Denise McCoy, Elizabeth Smith, Kim Adams, Meredith Ray, Todd Robbins, Jeffrey Wright, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2021)

13 Background: Early detection of lung cancer provides the best opportunity for long-term survival. In 2021 US Preventive Services Task Force (USPSTF) expanded the 2013 risk-based Low-dose CT (LDCT) screening criteria, in part to reduce unintended race and gender disparities in lung cancer detection. We evaluated the impact of the updated USPSTF criteria in a cohort of patients from an incidental lung nodule program (ILNP). Methods: We implemented an ILNP in a community healthcare system in the mid-south US. Patients with lung lesions on routinely-performed radiologic studies were triaged using evidence-based guidelines. We prospectively tracked patient demographics, clinical characteristics, procedures, complications, and health outcomes. We classified all patients in the ILNP cohort based on USPSTF 2013 and 2021 screening criteria. Statistical analysis used the chi-square test. Results: The ILNP cohort included 14,642 patients from 2015-2021. This cohort was 56% female, 65% White, 29% Black, with a median age of 64 years. Overall 1,581 (10.8%) met 2013 and 2,051 (14.0%) met 2021 USPSTF criteria. 1.9% of subjects eligible by 2013 criteria were diagnosed with lung cancer compared to 2.2% by 2021 criteria. 470 additional patients met screening criteria when we expanded from USPSTF 2013 to 2021. As expected, these patients were younger and less likely to have Medicare insurance. These additional eligible patients were significantly more likely to be female (58% v 49%, p = 0.0011) or Black (28% vs. 18%, p &lt; 0.0001) compared to those eligible by 2013 criteria. 44 of the 470 (9%) were diagnosed with cancer: 36% adenocarcinoma, 18% squamous, and 11% small cell, 11% non-lung primary, 9% non-small cell lung cancer NOS, and 15% other or unknown histology. The median tumor size was 3 cm with an interquartile range from 1.7 to 4.2 cm. The clinical stage distribution was 34% I, 4.5% II, 15.9% III, and 31.8% IV. Conclusions: In this selective community-based cohort, USPSTF 2021 criteria identified a higher percentage of subjects with lung cancer and were more inclusive of women and minorities compared to USPSTF 2013 criteria.
Abstract 687: The Size of Soft Regions in Carotid Atherosclerotic Lesions is Associated With the Presence of Intraplaque Hemorrhage or Ulceration: An Ultrasound Elasticity Imaging and Multi-contrast Weighted MRI Pilot Study
Authors: Vijay Shamdasani, Li Dong, Baocheng Chu, Robert Entrekin, Chun Yuan, Thomas Hatsukami
Journal: Circulation (2009)

Purpose: Prospective studies using multi-contrast weighted MRI have shown that intraplaque hemorrhage and ulceration in carotid atherosclerotic lesions are associated with higher risk of subsequent...
Development and Validation of a Model Including Distinct Vascular Patterns to Estimate Survival in Hepatocellular Carcinoma
Authors: Wen-Ping Lin, Kai-Li Xing, Jian-Chang Fu, Yi-Hong Ling, Shao-Hua Li, Wu-Shen Yu, Yong-Fa Zhang, Chong Zhong, Jia-Hong Wang, Zhi-Yuan Chen, Liang-He Lu, Wei Wei, Rong-Ping Guo
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Because of tumor heterogeneity, traditional clinical variables remain insufficient to predict recurrence, which impairs long-term survival among patients undergoing radical hepatectomy for hepatocellular carcinoma (HCC). Vessels encapsulating tumor clusters (VETC) constitute a novel vascular pattern distinct from microvascular invasion (MVI), representing biological aggressiveness of HCC. <h3>Objective</h3> To establish a model to estimate individualized recurrence-free survival (RFS) in HCC by integrating VETC and MVI. <h3>Design, Setting, and Participants</h3> This prognostic study included 498 patients undergoing radical hepatectomy for HCC from 5 academic centers in China from January 1, 2013, to December 31, 2016, and consisted of 3 cohorts: training (243 [48.8%]), internal validation (122 [24.5%]), and external validation (133 [26.7%]). Follow-up was completed on March 30, 2020, and the data were analyzed from December 1 to 31, 2020. <h3>Exposures</h3> VETC, MVI, tumor number, and maximum tumor size. <h3>Main Outcomes and Measures</h3> The primary end point was RFS. The risk score for relative recurrence and nomogram for absolute RFS probability were derived from the final model, which contained variables recommended by multivariate least absolute shrinkage and selection operator Cox proportional hazards regression analysis. Their performance was quantified using the Harrell concordance index (C index), the time-dependent area under the receiver operating characteristic curve, and calibration curves and was compared with 6 prognostic systems. Recurrence-free survival was estimated by the Kaplan-Meier method, and RFS curves were compared using a log-rank test. <h3>Results</h3> Among the 498 patients, 432 (86.7%) were men; the mean (SD) age at diagnosis was 51.4 (11.3) years. Independent predictors for RFS identified included VETC, MVI, tumor number, and maximum tumor size, which were incorporated into the multivariate model (VMNS model). The C index (0.702; 95% CI, 0.653-0.752) for the VMNS score of the training cohort was significantly higher than those of 6 conventional systems (0.587 [95% CI, 0.535-0.638] to 0.657 [95% CI, 0.606-0.708]). Different recurrence risk groups defined by the VMNS score showed significantly different 2-year RFS (low-risk group, 81.4% [SE, 0.036]; medium-risk group, 62.1% [SE, 0.054]; high-risk group, 30.1% [SE, 0.079];<i>P</i> &lt; .001). Calibration curves of the VMNS nomogram showed good agreement between the nomogram-predicted RFS probability and actual RFS proportion. The internal and external validation cohorts confirmed the results. <h3>Conclusions and Relevance</h3> The VMNS model enabled individualized prognostication of RFS in patients with HCC undergoing curative resection.