tbuckley/cabot-search huggingface dataset:
The genomic architechtures of tumor-adjacent tissues, plasma and saliva reveal evolutionary underpinnings of relapse in head and neck squamous cell carcinoma.
Authors: Ping Wu, Zicheng Yu, Chubo Xie, Ling Yang, Xuefeng Xia, Xin Yi, Yaoyun Tang
Journal: Journal of Clinical Oncology (2021)

e18046 Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by dismal prognosis, nonetheless limited studies have unveiled the mechanisms underlying HNSCC relapse. Methods: Next-generation sequencing 1 5 was performed to identify somatic mutations in 188 matched samples including primary tumors, tumor adjacent tissues (TATs), pre- and post-operative plasma, saliva and peripheral blood lymphocytes (PBLs) from 27 patients. Evolutionary relationship between TATs and tumors were analyzed. The dynamic changes of tumor- and TAT-specific mutations in liquid biopsies were monitored together with survival analysis. Results: Alterations were detected in 27/27 and 19/26 tumors and TATs respectively. TP53 was the most prevalent genes mutated in TATs. Some TATs shared mutations with primary tumors, while some other TATs were evolutionarily unrelated to tumors. Notably, TP53 mutations in TATs are stringently associated with premalignant transformation and indicative of worse survival (HR=14.01). TAT-specific mutations were also detected in pre- and/or post-operative liquid biopsies, and indicative of disease relapse. Conclusions: TATs might undergo the processes of premalignant transformation, tumorigenesis, and eventually relapse by either inheriting tumorigenic mutations from ancestral clones where tumor originated or gaining private mutations independent to primary tumor. Detection of tumor- and/or TAT-specific genetic alterations in post-operative biopsies shows profound potential in prognostic use.
Investigating the various predictive values of <i>POLE/POLD1</i> mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.
Authors: Yanling Niu, Tonghui Ma, Yanling Niu, Tao Li
Journal: Journal of Clinical Oncology (2021)

2606 Background: Both POLE and POLD1 encode the catalytic subunit of polymerase enzyme complexes involved in DNA replication and repair. The mutations of POLE and POLD1 have been shown to be oncogenic and lead to DNA repair defects and elevated tumor mutation burden (TMB). And patients with POLE/POLD1 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between POLE/POLD1 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of POLE/POLD1 mutations in some cancer types. Methods: The ICIs treatment cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of POLE/POLD1 mutations with ICIs efficacy. TCGA cohort was enrolled for characterizing tumor infiltrating lymphocytes (TILs) with CIBERSORT. The patients were classified into two groups: POLE/POLD1 mutations (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with POLE/ POLD1 mutations had significantly longer median OS after ICIs therapy (34.00 vs 19.00 months, P = 0.0143), indicating that POLE/POLD1 mutations were associated with better immunotherapy outcomes. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of POLE/POLD1 mutations with longer median OS in NSCLC (Undefined vs 12.00 months, P = 0.05) and esophagogastric cancer (27.00 vs 15.00 months, P = 0.05). However, the associations between POLE/POLD1 mutations and ICIs efficacy were not observed in bladder cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, and colorectal cancer. Furthermore, our data showed that the median TMB was significantly higher in the Mut group for NSCLC (20.2 vs 6.9 muts/Mb, P &lt; 0.0001) and esophagogastric cancer (21.4 vs 5.6 muts/Mb, P &lt; 0.0001). In TCGA esophagogastric cancer cohort, POLE/POLD1 mutations were correlated with decreased naive B cells (P = 0.0306) and increased activated memory CD4+ T cells (P = 0.0224). In TCGA NSCLC cohort, POLE/POLD1 mutations were correlated with elevated gamma delta T cells (P = 0.0219). These data suggested that POLE/POLD1 mutations were also involved in the infiltration of some immune cells. Conclusions: Although POLE/POLD1 mutations were associated with better ICIs efficacy for all the enrolled patients, the prolonged OS was only found in the Mut group for NSCLC and esophagogastric. These data suggested that POLE/POLD1 mutations may be a useful predictor for ICIs efficacy in these two types of cancer. Moreover, POLE/POLD1 mutations were correlated with the level of TILs in NSCLC and esophagogastric. The finding was consistent with the efficacy of immunotherapy.
Cost-effectiveness of apixaban versus other direct oral anticoagulants and low-molecular-weight-heparins for cancer associated venous thromboembolism in Spain.
Authors: Andres J. Muñoz Martín, Enrique Gallardo Díaz, Carlos Crespo, Roma Masana Domenech, Javier Soto, Daniel Arumi, Susana Fernandez
Journal: Journal of Clinical Oncology (2021)

e18845 Background: Venous thromboembolism (VTE) causes substantial morbidity and mortality in patients with cancer. The guidelines for the treatment of VTE in cancer patients recommend low molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) for patients where major bleeding is a low risk factor. Several studies show that DOAC represent a convenient and effective treatment option in alternative to LMWH in patients with deep-vein thrombosis or pulmonary embolism. Even though some recent studies have compared the effectiveness of DOAC vs LMWH, there is no available a cost-effectiveness analysis (CEA) comparing the relative effectiveness and cost-effectiveness of apixaban, other DOAC and. LMWH. The study aim was to conduct a CEA of apixaban (API), edoxaban (EDO), rivaroxaban (RIVA) and LMWH for the treatment of cancer associated VTE in Spain. Methods: We developed a Markov model with 12 transition health states. The model has been face-validated by two oncologists from two different Spanish hospitals. The use of resources and costs were obtained from the 2021 Spanish Ministry of Health database, and the main references for obtaining the outcomes were derived from CARAVAGGIO, HOKUSAI-VTE, ADAM VTE and SELECT-D trials. Our model yielded the effectiveness score in terms of cost per life-year (LY) gained and cost per quality-adjusted for life-year (QALY) gained. The time horizon was 12 months. We performed a deterministic and probabilistic sensitivity analysis to validate the robustness. Results: API showed the lowest 12-month cost (1943 €), and the highest amount of life years (0.79) and highest amount of QALY (0.55) gained. RIVA and EDO were less effective in terms of LY (0.76 and 0.74, respectively) and QALY (0.53 and 0.52, respectively) gained than LMWH (LY of 0.76 and QALY of 0.53), and less costly. The Incremental Cost-Effectiveness Ratio (ICER) scores in terms both of €/LY and €/QALY gained show that API is dominant over LMWH, RIVA and EDO. Conclusions: Our results suggest that API is more effective and more cost-effective than LMWH, RIVA or EDO with the 2021 Spanish healthcare costs. For interpretation of the results, reader must consider that the costs of resources analyzed in this paper may vary from country to country, and dabigatran was not included in the analysis since there are not cancer associated VTE clinical trials with dabigatran data to calculate CEA from.[Table: see text]
Single-cell analysis of ploidy and the transcriptome reveals functional and spatial divergency in murine megakaryopoiesis
Authors: Shu Sun, Chen Jin, Jia Si, Ying Lei, Kunying Chen, Yueli Cui, Zhenbo Liu, Jiang Liu, Meng Zhao, Xiaohui Zhang, Fuchou Tang, Matthew T. Rondina, Yueying Li, Qian-fei Wang
Journal: Blood (2021)
Pilot trial treating recurrent GBM patients with precision medicine regimens.
Authors: Jennifer Leigh Clarke, David Solomon, Nancy Ann Oberheim Bush, Jennifer A. Grabowsky, Cassie Kline, Deanna L. Kroetz, Jennie Webster Taylor, Javier Villanueva-Meyer, Annette Molinaro, David Gibson, Meghan Tedesco, Jane E Rabbitt, Eduardo Rodriguez Almaraz, Jessica Schulte, Robin Arthur Buerki, Shawn L. Hervey-Jumper, Manish K. Aghi, Mitchel S. Berger, Edward Chang, Susan Marina Chang
Journal: Journal of Clinical Oncology (2021)

2045 Background: Recurrence of GBM after initial treatment with surgery, radiation, and chemotherapy is nearly universal. Salvage therapies have limited efficacy with median overall survival (OS) of approximately 9 months and 6-month-progression-free survival (PFS-6) of 10-25% for both targeted and traditional therapies. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. Methods: The primary objective was to demonstrate the feasibility of implementing a personalized drug regimen for patients (pts) with surgically resectable recurrent GBM within 35 days of surgery. Secondary objectives included safety and efficacy. Eligible pts signed consent before surgery, and tumor tissue was analyzed using the CLIA-approved “UCSF500” next-generation sequencing panel with paired tumor/germline sequencing. A specialized genomic tumor board made individualized treatment recommendations incorporating sequencing results of the recurrent tumor and clinical history for each pt, using up to 4 FDA-approved drugs in combination (all drugs provided by study). Correlative studies will be reported separately. Results: 19 pts signed consent and 16 pts had surgery on trial, 1 with pathology showing treatment effect only. The remaining 15 pts were all genetically profiled and successfully started their individualized treatment within 35 days of surgery, meeting the primary feasibility endpoint. Conclusions: Implementation of an individualized treatment regimen was feasible in a timely fashion in surgically resectable recurrent GBM pts, with encouraging preliminary efficacy results. Further investigation is warranted, both to validate efficacy and to streamline this approach in larger pt populations. Clinical trial information: NCT03681028. [Table: see text]
Red blood cell folate, high-risk human papillomavirus risk and cervical intraepithelial neoplasia development: A large Chinese community-based cohort study of cervical screening.
Authors: Wei Wang, Aimin Yang, Yuanxing Li, Haixia Luo, Jing Yang, Weihong Zhao, Zhilian Wang, Zhe Wang, Chen Wang, Lili Zhang, Xiaoqiang Su, Wenhao Wang, Jintao Wang, Weiguo Lu, Li Li, Jinghui Song, Min Hao
Journal: Journal of Clinical Oncology (2021)

10547 Background: Although low folate status has been implicated in cervical carcinogenesis, large-scale population-based prospective cohort studies controlling for high-risk types of human papillomavirus (hrHPV) infection are lacking. The aim of this study is to evaluate the associations of red blood cell (RBC) folate, hrHPV infection risk and cervical intraepithelial neoplasia (CIN) development. Methods: In this prospective, population-based cohort study, we analyzed the cross-sectional data of 2304 women from a large cervical cancer screening program of 40,000 women aged 19-65 years in the Chinese rural area from 2014-2015. We conducted a nested case-control study including 35 CIN1 progression cases and 105 CIN1 regression controls. A logistic regression model was used to evaluate the associations of RBC folate and hrHPV infection risk and CIN1 development. Results: The median RBC folate concentration decreased gradually with cervical lesion severity. The risks of CIN 1 and CIN2 or worse (CIN 2+) in the 1st quartile of RBC folate concentration were significantly higher than those in the 4th quartile (Odds Ratio [OR], 2.27; 95% confidence interval [CI], 1.71-3.01 and OR, 2.33; 95% CI,1.52-3.56; respectively). We did not observe a significant relationship between hrHPV infection and CIN1 risk in the unadjusted and adjusted models, however, a statistically significant association was observed for CIN2+. Interestingly, RBC folate concentration was not associated with hrHPV infection among women with CIN1 or CIN2+. After full adjustment for potential confounders, a highly significant inverse linear relation between RBC folate concentration and CIN2+ was observed ( P-overall＜0.001, P-nonlinearity = 0.969). We further observed a positive additive interaction between RBC folate concentration and hrHPV infection on the risk of CIN2+ ( P-interaction＜0.01). Moreover, during the 21-month follow-up, CIN1 progression risk was significantly higher in the lowest RBC folate quartile (1st quartile compared with 4th quartile: OR, 3.86; 95% CI,1.01-14.76). Conclusions: Our findings indicates that RBC folate is inversely associated with the risk of higher-grade CIN and CIN1 progression in the Chinese rural population, either with or without hrHPV infection. Therefore, improving folate status has the potential to prevent higher-grade CIN and cervical cancer among women in the areas without mandatory folic acid food fortification. Clinical trial information: ChiCTR-ROC-15006479 .
ESMO Magnitude of Clinical Benefit Scale (MCBS): An evaluation of systemic treatment trials for soft tissue sarcomas (STS).
Authors: Abdulazeez Salawu, Christopher Lemieux, Albiruni Ryan Abdul Razak
Journal: Journal of Clinical Oncology (2021)

11553 Background: Patients with STS have poor prognosis in the metastatic setting. Although some treatment options are associated with improved outcomes, such as progression-free (PFS) or overall survival (OS), the overall magnitude of clinical benefit can be unclear. The ESMO MCBS is a validated and reproducible tool developed to quantify the clinical benefit of treatments evaluated in trials ( www.esmo.org/guidelines/esmo-mcbs ). Herein, we report the application of ESMO MCBS to systemic treatment trials involving metastatic STS patients. Methods: A systematic search of Medline, Embase and Cochrane databases for adult phase II and III trials in advanced STS (01/1998 to 12/2020) was carried out. Gastrointestinal stromal tumor trials were excluded. Outcomes, including but not limited to OS, PFS, objective response rate (ORR), toxicity and quality of life (QoL) data were extracted and analyzed. Studies with outcomes that met the criteria for ESMO MCBS v1.1 were evaluated to generate a score of 1 to 5 (score of ≥ 4: substantial benefit). MCBS scoring of each study was performed by at least 2 co-authors for consensus. Results: Among 3454 abstracts screened, a total of 140 Phase II and 28 phase IIII trials were identified. A total of 41 studies fulfilled the criteria for ESMO MCBS scoring. These include 5 phase III studies, as well as 9 randomized and 27 single-arm phase II trials. Fifteen studies involved specific histology, while remaining 26 studies were of all STS subtypes. Chemotherapy, alone or in combination was evaluated in 29 trials, while molecular-targeted agents (MTA) and immune checkpoint inhibitors (IO) were evaluated in 11 and 3 studies, respectively (Table). The median MCBS score was 2 (range 1-4), regardless of drug class or combination. Only 3 studies, all randomized in design, had a MCBS score of 4. All three trials were in the 2nd line setting or beyond, where there is no standard control treatment. None of the trials, irrespective of drug class had a score of 5 and no study showed evidence of significant improvement in QoL. The observed MCBS scores were low, partly because the trials evaluated mainly comprise single-arm studies without QoL assessments, restricting to a maximum MCBS score of 3. Conclusions: Most systemic therapy trials in advanced STS did not confer substantial clinical benefit when evaluated using MCBS. Although randomized phase 3 trials remain the gold standard of treatment evaluation, clinical benefit evaluation of STS trials using tools such as MCBS may be useful. Incorporation of QoL evaluation, even in single-arm studies should be prioritized in metastatic STS trials.[Table: see text]
Governments should be made to work harder to keep public trust
Authors: Fiona Godlee
Journal: BMJ (2021)

In their AAI President9s Addresses reproduced in this issue, Jeremy M. Boss, Ph.D. (AAI 994; AAI president 2019–2020), and Jenny P.-Y. Ting, Ph.D. (AAI 997; AAI president 2020–2021), welcomed attendees to the AAI annual meeting, Virtual IMMUNOLOGY2021™. Due to the SARS-CoV-2 pandemic and the cancellation of IMMUNOLOGY2020™, Dr. Boss and Dr. Ting each presented their respective president9s address to open the meeting.
Noninvasive Human-Prosthesis Interfaces for Locomotion Intent Recognition: A Review
Authors: Dongfang Xu, Qining Wang
Journal: Cyborg and Bionic Systems (2021)

The lower-limb robotic prostheses can provide assistance for amputees’ daily activities by restoring the biomechanical functions of missing limb(s). To set proper control strategies and develop the corresponding controller for robotic prosthesis, a prosthesis user’s intent must be acquired in time, which is still a major challenge and has attracted intensive attentions. This work focuses on the robotic prosthesis user’s locomotion intent recognition based on the noninvasive sensing methods from the recognition task perspective (locomotion mode recognition, gait event detection, and continuous gait phase estimation) and reviews the state-of-the-art intent recognition techniques in a lower-limb prosthesis scope. The current research status, including recognition approach, progress, challenges, and future prospects in the human’s intent recognition, has been reviewed. In particular for the recognition approach, the paper analyzes the recent studies and discusses the role of each element in locomotion intent recognition. This work summarizes the existing research results and problems and contributes a general framework for the intent recognition based on lower-limb prosthesis.
Fractional Exhaled Nitric Oxide Nonsuppression Identifies Corticosteroid-Resistant Type 2 Signaling in Severe Asthma
Authors: Simon Couillard, Rahul Shrimanker, Rekha Chaudhuri, Adel H. Mansur, Lorcan P. McGarvey, Liam G. Heaney, Stephen J. Fowler, Peter Bradding, Ian D. Pavord, Timothy S. C. Hinks
Journal: American Journal of Respiratory and Critical Care Medicine (2021)
Correlation between work productivity loss (WPL) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) domains from the MONALEESA-7 (ML-7) trial of premenopausal women with HR+/HER2- advanced breast cancer (ABC).
Authors: Debu Tripathy, Tristan Curteis, Sara A. Hurvitz, Denise A. Yardley, Fabio Franke, Govind Babu Kanakasetty, Paul Wheatley-Price, Young-Hyuck Im, Radost Pencheva, David Chandiwana, Purnima Pathak, Brad Lanoue, Nadia Harbeck
Journal: Journal of Clinical Oncology (2021)

1051 Background: The international, randomized, double-blind, placebo-controlled, Phase III ML-7 trial (NCT02278120) assessed ribociclib + endocrine therapy (ET) vs ET alone in premenopausal women with HR+/HER2– ABC. To our knowledge, the relationship between WPL and domains of the EORTC QLQ-C30 and the tumor-specific module for breast cancer (QLQ-BR23) has not been explored in ABC. In this post hoc analysis (data cutoff, November 30, 2018) of all patients (pts) enrolled in ML-7, we assessed the correlation between the WPL component of the Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire and domains of the EORTC QLQ-C30/BR23. Methods: We analyzed EORTC and WPAI:GH data from all pts enrolled in ML-7 who were employed at any point during the trial (N = 329 of 672 total pts). Domains of the EORTC QLQ-C30 and QLQ-BR23 that had the greatest correlation (pairwise Pearson correlation) with WPL were prioritized for analysis. Separate univariable mixed-model repeated-measures regression models were fitted for each domain, with WPL as the dependent variable and each EORTC domain as a single fixed-effect covariate. Linear and quadratic relationships were considered. Model selection was based on the Akaike information criterion (AIC). Results: Linear models were favored over quadratic models. WPL was negatively correlated with global health status (GHS) and the physical, role, social, and emotional functioning domains and was positively correlated with the fatigue and pain domains of the QLQ-C30 ( P &lt;.001; Table). The coefficients indicated the estimated mean change in WPL was associated with a 1-unit increase in each QLQ-C30 domain. For example, a 10-point increase in GHS was associated with an estimated mean decrease of 7.8% (95% CI, 7.1%-8.5%) in WPL. Conclusions: Greater WPL was associated with higher levels of fatigue and pain and with lower levels of overall quality of life and physical, role, social, and emotional functioning among pts with HR+/HER2− ABC in ML-7. Further investigation of the correlation with QLQ-BR23 and multivariable analysis could determine which EORTC domains and items independently drive these findings. Clinical trial information: NCT02278120 .[Table: see text]
The intra-tumor heterogeneity of ER and HER2 expression in patients with ER-positive and HER2-positive breast cancer.
Authors: Jie Ju, Feng Du, Songlin Gao, Yiran Si, Nanlin Hu, Dongxu Liu, Xue Wang, Jian Yue, Fangchao Zheng, Yikun Kang, Zixuan Yang, Fei Ma, Binghe Xu, Peng Yuan
Journal: Journal of Clinical Oncology (2021)

e12550 Background: ER- positive and HER2-positive (double-positive) breast cancers are known to display significant heterogeneity; however, traditional immunohistochemistry (IHC) only reflects inter-tumor heterogeneity. Studies are needed to demonstrate the intra-tumor heterogeneity of ER and HER2 expression and to further explore its impact. Methods: The retrospective study included three double-positive breast cancer cohorts. Data from a total of 141 patients from The Cancer Genome Atlas (TCGA) and 104 patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to investigate the molecular characteristics of double-positive breast cancers at the tissue level via somatic mutation and RNA-seq analyses, while 43 patients treated at our hospital were selected to analyze ER and HER2 expression and localization at a single-cell level using multiple IF. The rH/R was proposed to reflect ER and HER2 expression profiles based on multiple IF or RNA-seq results, as follows: rH/E = HER2+ cell percentage / (ER+ cell percentage + 1) or rH/E = ERBB2 expression quantity / (ESR1 expression quantity + 1). Results: In the first two cohorts, we found that the HER2-enriched subtype displayed unique molecular characteristics, including increased TP53, ERBB3, and PI3KCA mutation rates and the abnormal expression of important signaling pathways (e.g., G2/M cell cycle checkpoint and epithelial mesenchymal transition); The rH/E was a significant index for diagnosing HER2-enriched patients (area under the receiver operating characteristic curve [AUC] = 0.92 and 0.75, both P &lt; 0.0001). In the third cohort, we found that 86 % of the patients contained all four tumor cell types (ER+HER2+, ER+HER2-, ER-HER2+, and ER-HER2- cells); The rH/E was an independent risk factor for recurrence (hazard ratio [HR] = 2.63, P = 0.02) and patients with a rH/E ≥ 1.5 had a significantly shorter 5-year disease-free survival (DFS = 67 % vs. 92 %, P = 0.046). Conclusions: The significant intra- and inter-tumor heterogeneity of double-positive breast cancers is closely related to the prognosis of patients, which is of great significance for precision treatment.