tbuckley/cabot-search huggingface dataset:
Associations between interaction effects of mutational events and efficient immunotherapy in squamous NSCLC: Results from 373 patients.
Authors: Fan Zhang, Lei Zhao, Tao Li, Yu Xu, Guoqiang Wang, Chengcheng Li, Shangli Cai, Hao Liu, Yi Hu, Jinliang Wang
Journal: Journal of Clinical Oncology (2021)

e21136 Background: Predictive biomarkers might not be similarly predictive in every single subpopulation, and they might be merely valid under certain circumstances, which is termed by “interaction effect”. Here, we proposed to investigate the interaction effect of mutational events on predicting efficacy of immune checkpoint inhibitors (ICIs), and to explore whether adding these interaction terms could optimize the prediction model based on genomic alterations. Methods: In total, 373 patients with squamous NSCLC were included. 191 patients with both PFS and OS data receiving monotherapy from the MSKCC, DFCI, SNCC, and POPLAR/OAK cohorts were included in the training set. 130 patients from the POPLAR/OAK cohort treated with docetaxel were included in the control set. Validation set-1 consists of 34 patients receiving monotherapy from the NCC and MSKCC cohorts, and validation set-2 comprises 18 patients treated with combination therapy from the MSKCC cohort. Risk models using single mutations (uni-model) and both single mutations and interactions (inter-model) were developed via multivariable Cox proportional hazards regression model. Results: Four single mutational events, including mutations of NOTCH1/2/3, LRP1B, RB1, and members in PI3K pathway, and two interactions ( TP53* NFE2L2 and TP53*HRR pathway) were identified as predictive biomarkers. The score of inter-model exhibited higher correlation with immunotherapeutic PFS in the training sets, compared to the uni-model ( Dxy: 0.196 vs. 0.175). Uni-score low was barely associated with the PFS (HR=0.32, 95% CI 0.07-1.50, P=0.15) and OS (HR=1.20, 95% CI 0.45-3.17, P=0.71) in the validation set-1, and the PFS in the validation set-2 (HR=0.96, 95% CI 0.31-2.95, P=0.94). Inter-score low showed better association with longer PFS (HR=0.17, 95% CI 0.03-0.84, P=0.029) and OS (HR=0.33, 95% CI 0.12-0.92, P=0.033) in the validation set-1, and longer PFS in the validation set-2 (HR=0.50, 95% CI 0.13-1.85, P=0.30). In addition, no association was observed between inter-score low and the PFS and OS in the control set, indicating that inter-score low might not be a prognostic biomarker, but a positive predictive biomarker to efficacious immunotherapy. Conclusions: Two interaction effects of mutational events on predicting efficacious immunotherapy in squamous NSCLC ( TP53* NFE2L2 and TP53*HRR pathway) were identified. Adding these interaction terms to the prediction model could optimize the predictive utility. Deeper understanding of these inter-relations might provide insights for basic research on anti-tumor immunity.
Non-invasive measurement of PD-L1 status and prediction of immunotherapy response using deep learning of PET/CT images
Authors: Wei Mu, Lei Jiang, Yu Shi, Ilke Tunali, Jhanelle E Gray, Evangelia Katsoulakis, Jie Tian, Robert J Gillies, Matthew B Schabath
Journal: Journal for ImmunoTherapy of Cancer (2021)

Currently, only a fraction of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) experience a durable clinical benefit (DCB). According to NCCN guidelines, Programmed death-ligand 1 (PD-L1) expression status determined by immunohistochemistry (IHC) of biopsies is the only clinically approved companion biomarker to trigger the use of ICI therapy. Based on prior work showing a relationship between quantitative imaging and gene expression, we hypothesize that quantitative imaging (radiomics) can provide an alternative surrogate for PD-L1 expression status in clinical decision support.
Nationwide trends in in-patient chemotherapy hospitalizations, cost, and mortality for patients with testicular carcinoma.
Authors: Saqib Abbasi, Elizabeth Marie Wulff-Burchfield, Rahul Atul Parikh
Journal: Journal of Clinical Oncology (2021)

e17012 Background: Salvage therapy for advanced Testicular Carcinoma involves patients receiving ifosfamide are treated in hospital for risk of neuro-toxicities. We evaluated annual trends to assess the health care burden of testicular patients admitted for chemotherapy, as well as co-morbidities and complications associated with mortality. Methods: The National Inpatient Sample is a nationwide sample of all US hospital discharges. We collected data from the years of 2002 to 2017 on patients with Testicular Carcinoma who were receiving chemotherapy, to capture patients recieving ifosfamide and cisplatin in an in-patient setting. Patients undergoing an autologous stem cell transplant were excluded. Annual trends for inpatient mortality, length of stay, and total costs of admission were assessed. A univariate logistic regression analysis was used to calculate odds ratios (OR) for the effect of comorbid conditions and acute inpatient complications on in-patient mortality. Results: Hospitalizations for ifosfamide and cisplatin based treatment among patients with Testicular Carcinoma remained stable from a weighted national estimate of 2,261 in 2002 to 2,160 in 2017. Length of stay increased from 4.6 days to 5.5 days (p=0.01). Cost of stay increased from $26,140 to $53,193 (p &lt;0.001) when adjusted for inflation. The average age of patients was 32.6 years. In-patient mortality was low at 0.2% in 2002 to &lt;0.1% in 2017. Among comorbid conditions, heart failure was associated with increased mortality (OR 21.9). Among acute complications – acute kidney injury (OR 32.6), infection (OR 15.3), neurotoxicity (OR 12.3) were associated with significantly higher mortality. Conclusions: The increase in cost of stay is out of proportion to increases in length of stay. Indicating a disproportionate increase in financial toxicity for these patients. Patients with underlying heart disease are at increased risk of complications. Care needs to be taken to specifically identify patients at risk for renal failure and infectious complications.[Table: see text]
Abstract 1777: Increases in Folic Acid Intake in the Preconceptual Period Reduce Birth Prevalence of Severe Congenital Heart Disease
Authors: Raluca Ionescu-Ittu, Ariane J Marelli, Louise Pilote
Journal: Circulation (2007)

Introduction. Preconceptual intake of folic acid reduces the risk of neural tube defects; animal studies suggest a similar protective effect for congenital heart disease (CHD). Guidelines to recomm...
Efficacy and safety of intermittent versus continuous dosing schedule of apatinib combined with docetaxel as second-line treatment for advanced gastric cancer.
Authors: Yifu He, Ying Yan, Gang Wang, Yubei Sun, Tengyun Xu, Shusheng Wu, Huiqin Luo, Lihong Ke, Xiaoxiu Hu, Jiayu Niu, Huimin Li, Wenju Chen, Huijun Xu, Lulu Cao, Yancai Sun, Chenxuan Liu, Chushu Ji, Bing Hu
Journal: Journal of Clinical Oncology (2021)

e16018 Background: Apatinib, a VEGFR-2 tyrosine kinase inhibitor, is wildly used for the treatment of advanced or metastatic gastric cancer. However, dose modification and interruption are happened frequently due to poor patient conditions and treatment-related toxicity. This study was designed to explore the efficacy and safety of intermittent or continuous apatinib therapy in combination with docetaxel. Methods: This was an open-label, randomized clinical trial. Patients with advanced gastric cancer who progressed from first-line treatment were randomly assigned in a ratio of 1:1 to receive intermittent or continuous dosing schedule. In the intermittent dose group (IG), patients received oral apatinib 500 mg/d for 5 days followed by 2 days off. In the continuous dose group (CG), patients received 500 mg daily without interruption. Docetaxel 60 mg/m 2 was administered intravenously to patients on Day 1 in a 21-day cycle in both groups. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and the safety. Results: Between September 15, 2017 and November 30, 2020, 80 patients were screened for eligibility, of which 76 patients were randomly assigned into two groups (38 in the IG and 38 in the CG). In the IG and CG, 38 and 37 patients had ECOG PS 0-1, 16 and 19 patients had history of surgery, both 11 patients with more than 2 metastases, respectively. The baseline characteristics of the two groups were balanced. ORR in the IG was 21.05% vs 18.42% in the CG, and DCR was 60.53% vs 60.53%, respectively. Median PFS were 3.88 months (95% CI, 1.723-6.031) vs 3.98 months (95% CI, 1.055-6.896, p= 0.546), and median OS was 9 months (95% CI, 5.306-12.698) vs 9.40 months (95% CI, 5.204-13.588, p= 0.310) in two groups. The incidence of all grade adverse events (AEs) in the IG and CG were 94.7% and 92.1%, of which the most common AEs were hypertension (55.3% vs 65.8%), anemia (55.3% vs 63.2%), proteinuria (26.3% vs 31.6%), hand-foot syndrome (21.1% vs 26.3%). The incidence of grade ≥3 AEs were 36.8% and 39.5% in the IG and CG, respectively. In addition, the doses of 7 patients were reduced to the 250 mg in the IG, while that of 13 patients in the CG. Conclusions: Apatinib administered intermittently (5 days on/ 2 days off) exhibited similar efficacy to continuous schedule, while with less toxicity. Intermittent dosing schedule of apatinib may be an option for second-line treatment of patients with advanced gastric cancer. Clinical trial information: NCT03334591.
Evolution of CT findings after anticoagulant treatment for acute pulmonary embolism in patients with and without an ultimate diagnosis of chronic thromboembolic pulmonary hypertension
Authors: Natalia J. Braams, Gudula J.A.M. Boon, Frances S. de Man, Josien van Es, Paul L. den Exter, Lucia J.M. Kroft, Ludo F.M. Beenen, Menno V. Huisman, Esther J. Nossent, Anco Boonstra, Anton Vonk Noordegraaf, Dieuwertje Ruigrok, Frederikus A. Klok, Harm Jan Bogaard, Lilian J. Meijboom
Journal: European Respiratory Journal (2021)

Introduction The pulmonary arterial morphology of patients with pulmonary embolism (PE) is diverse and it is unclear how the different vascular lesions evolve after initiation of anticoagulant treatment. A better understanding of the evolution of computed tomography pulmonary angiography (CTPA) findings after the start of anticoagulant treatment may help to better identify those PE patients prone to develop chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the evolution of various thromboembolic lesions on CTPA over time after the initiation of adequate anticoagulant treatment in individual acute PE patients with and without an ultimate diagnosis of CTEPH. Methods We analysed CTPA at diagnosis of acute PE (baseline) and at follow-up in 41 patients with CTEPH and 124 patients without an ultimate diagnosis of CTEPH, all receiving anticoagulant treatment. Central and segmental pulmonary arteries were scored by expert chest radiologists as normal or affected. Lesions were further subclassified as 1) central thrombus, 2) total thrombotic occlusion, 3) mural thrombus, 4) web or 5) tapered pulmonary artery. Results Central thrombi resolved after anticoagulant treatment, while mural thrombi and total thrombotic occlusions either resolved or evolved into webs or tapered pulmonary arteries. Only patients with an ultimate diagnosis of CTEPH exhibited webs and tapered pulmonary arteries on the baseline scan. Moreover, such lesions always persisted after follow-up. Conclusions Webs and tapered pulmonary arteries at the time of PE diagnosis strongly indicate a state of chronic PE and should raise awareness for possible CTEPH, particularly in patients with persistent dyspnoea after anticoagulant treatment for acute PE.
Discovery and validation of methylation signatures in circulating cell-free DNA for early detection of esophageal cancer: A case-control study.
Authors: Weitao Zhuang, Xiao-song Ben, Chengcheng Li, Jiayue Xu, Dan Tian, Zihao Zhou, Gang Chen, Cheng Deng, Jiming Tang, Ruiqing Shi, Liang Xie, Dongkun Zhang, Haiyu Zhou, Bingsi Li, Zhihong Zhang, Hao Liu, Guoqiang Wang, Shangli Cai, Gui-Bin Qiao
Journal: Journal of Clinical Oncology (2021)

e16027 Background: The pivotal goal of esophageal cancer (ESCA) screening is to identify early-stage cancer or precancerous lesions when curable treatments are available. Methylation of circulating-free DNA (cfDNA) has shown promising results in the early detection of multiple tumors recently. Here we conducted a prospective study to investigate the performance of cfDNA methylation in the early detection of ESCA. Methods: Specific methylation markers for ESCA were identified and optimized based on 24 esophageal tumor and its corresponding adjacent tissues. Age-matched participants with ESCA (n = 136), benign esophageal disease (n = 21) and healthy controls (n = 126) were randomized into the training and testing sets to develop an early-detection classifier. Results: In total, 921 differentiated methylation blocks (DMBs) between tumor and adjacent tissues were identified, of which 679 (73.7%) showed higher methylation level and 242 (26.3%) had lower methylation level in tumor tissues. In the training set, the specificity of the model built with these DMBs was 94.1% (95% CI, 85.5%−98.4%) and the sensitivity was 86.0% (95% CI, 72.2%−94.8%). The sensitives increased with stages, which were 77.8% (95% CI, 39.8%−97.2%), 90.9% (95% CI, 58.7%−99.8%), 83.3% (95% CI, 51.7%−97.9%) and 100.0% (95%CI, 63.1%−100.0%) for stage I-IV, respectively. Similar results were observed in the testing set with area under curve (AUC) of 0.932 (95% CI, 0.887−0.977). Conclusions: The cfDNA methylation profiles distinguished ESCAs from healthy individuals and benign esophageal diseases with promising sensitivity and specificity. Consideration of the potential value of early detection in ESCAs, further evaluation in larger prospective studies is warranted.
Case 18-2021: An 81-Year-Old Man with Cough, Fever, and Shortness of Breath
Authors: Kathryn A. Hibbert, Reece J. Goiffon, Annemarie E. Fogerty
Journal: New England Journal of Medicine (2021)

A Man with Cough, Fever, and Shortness of Breath An 81-year-old man presented with fever, cough, and shortness of breath. Within a few hours after presentation, chest pain and respiratory distress ...
Clinical trial in progress: Phase II trial of defactinib (VS-6063) combined with VS-6766 (CH5126766) in patients with metastatic uveal melanoma.
Authors: Rino S. Seedor, Marlana Orloff, J. Silvio Gutkind, Andrew E. Aplin, Mizue Terai, Erin Sharpe-Mills, Haley Klose, Michael J. Mastrangelo, Takami Sato
Journal: Journal of Clinical Oncology (2021)

TPS9588 Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. Currently there is no US FDA-approved treatment for metastatic uveal melanoma (MUM). Activating mutations in genes encoding alpha subunits of the heterotrimeric G proteins, GNAQ and GNA11, are found in 80-90% of UM. Recent information suggests that GNAQ/GNA11-oncogenic signaling involves a non-canonical pathway conferring the activation of YAP1, distinct from the activation of PLCβ and PKC-MEK-ERK, which may explain the failure of MEK inhibitors in MUM patients. Focal Adhesion Kinase (FAK) is a tyrosine kinase that provides a direct link between Gαq and tyrosine phosphorylation networks controlling YAP and UM growth. Interestingly, UM represents the human cancer harboring the highest level of FAK overexpression. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single arm, single-institution, phase II trial evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (VS-6766, CH5126766) for the treatment of patients with metastatic uveal melanoma [NCT04720417]. The primary endpoint of the study is disease control rate (DCR) of 50% including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST criteria version 1.1. Secondary endpoints include progression free survival, overall survival, and causality of adverse events. Exploratory endpoints include analysis of the pharmacodynamic profile, mechanism of resistance to the combination, and investigation of circulating free DNA as a biomarker. The efficacy of this combination treatment will be assessed using the Simon’s two stage design. In stage I, a total number of 8 patients are accrued and if there are 2 or fewer overall responses among these 8 patients, further enrollment of patients may be stopped with the conclusion that DCR cannot be 50% or greater. Otherwise, an additional 10 patients will be accrued in stage II, resulting in a total sample size of 18 patients. Patients at 18 years or older with metastases from uveal melanoma will be eligible (any line of therapy). Defactinib (200 mg) will be administered orally twice a day in combination with VS-6766 (3.2 mg) administered orally twice a week for 3 weeks, in 28-day cycles. Dose modification will be considered based on toxicity. Treatment will be continued until maximum clinical benefit is obtained; disease progression or the development of intolerable side effects. Enrollment to stage 1 began in February 2021. Clinical trial information: NCT04720417.
Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-β signaling pathway.
Authors: Ehsan Malek, Sunjin Hwang, Paolo Fabrizio Caimi, Leland L. Metheny, Benjamin Kent Tomlinson, Brenda W. Cooper, Kirsten M. Boughan, Folashade Otegbeye, Molly Gallogly, James Joseph Driscoll, Marcos J.G. De Lima
Journal: Journal of Clinical Oncology (2021)

8039 Background: Immunosuppression and osteoclast activation are two hallmarks of the bone marrow environment in Multiple Myeloma (MM). Corticosteroids have been used historically as part of anti-myeloma regimens due to their anti-plasma cell activity, however they potentially could suppress immune system and activate osteoclast further; therefore there is an unmet need for corticosteroid-free approaches in the era of emerging anti-cancer immunotherapy modalities. There is an abundance of Transforming Growth Factor-beta (TGF-β), a crucial cytokine in suppression of immune system as well as catabolic bone remodeling, in the MM microenvironment. Vactosertib (Vacto) is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model. Here, we report the phase Ib trial of Vacto in combination with pomalidomide (Pom) without any corticosteroids (NCT03143985). Methods: pts with relapsed MM with at least two lines of therapies enrolled on a 3 + 3 dose escalation design and received Vacto, 60 mg/d, 120 mg/d, 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The primary objectives of the study was to assess safety and recommended phase 2 dose. Vacto tablets, taken once or twice daily for 5 days followed by 2 days without treatment, is administered in 28-day cycles, until progression of disease or intolerable toxicity. Results: 15 pts were enrolled on the study (Table). The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt, one episode of grade III renal failure that took less than 7 days to get back to baseline on another patient, sinus bradycardia that reversed to sinus rythem and an Afib that was rate controlled with beta blocerks. No grade IV non-hematologic AE was observed. Three pts had grade III hematologic AE, no grade IV hematologic AE. Three out of 15 pts experienced progression of disease (PFS-6: 80%). Conclusions: The phase Ib data shows safety of this agent in combination with Pom. The efficacy assessment (PFS-6: 80%) is higher than the historical control (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Clinical trial information: NCT03143985. [Table: see text]
Identifying pre-existing dementia in older adults diagnosed with cancer using a national claims database.
Authors: Melody K. Schiaffino, Alison Moore, Jessica R. Schumacher, Paul Gilbert, Vinit Nalawade, Timothy Schempp, James Murphy
Journal: Journal of Clinical Oncology (2021)

e18678 Background: Older adults over the age of 65 represent the majority of patients diagnosed with (60%), among them, 15-30% have a pre-existing Alzheimer’s disease or related dementia (ADRD) that puts them at higher risk for over and under treatment. Studying the role of pre-existing ADRD in cancer patients is vital to understanding treatment planning behavior, patterns of health care utilization, and adverse treatment outcomes. Massive administrative datasets, or “big data” represent the information rich environment that is useful for this endeavor. Methods: Our study utilized a clinically validated algorithm to assess the prevalence of pre-existing ADRD and cancer across six cancer types. We utilized the SEER-Medicare dataset for analyzing the study years 2004-2015 (N = 337 932). We extracted ICD-9 codes to identify ADRD using the Centers for Medicaid Services Chronic Conditions Warehouse (CCW) algorithm. In sensitivity analysis we compared the prevalence of ADRD+Cancer using the NCI (2014) and CCW algorithms. Results: We found a significant difference between the two algorithms (p &lt; .0001) and a higher overall prevalence of comorbid ADRD+Cancer using the CCW (6.6%). Additionally, we found ADRD+Cancer prevalence was significantly higher among racial and ethnic subgroups compared to White and unstaged tumors compared with any numbered American Joint Committee on Cancer (AJCC) stages (p &lt; .0001). Conclusions: Using a clinically validated algorithm we were able to identify more cases of ADRD+Cancer in big data. This figure remains underestimated for ADRD+cancer compared to clinically-validated studies. Further research into the validation approach and codes that are used for ADRD classification can improve how we identify ADRD in massive administrative data. This is critical given the growing population of diverse older adults in the U.S.