tbuckley/cabot-search huggingface dataset:
Longitudinal analysis of dynamic changes of T-lymphocytes during multimodal treatment of patients with inoperable stage III NSCLC.
Authors: Thomas Philipp Hofer, Lukas Käsmann, Carolyn Pelikan, Saloni Mathur, Chukwuka Eze, Julian Taugner, Amanda Tufman, Niels Reinmuth, Claus Belka, Elfriede Noessner, Farkhad Manapov
Journal: Journal of Clinical Oncology (2021)

e20503 Background: Acute lymphocytopenia is associated with poor survival in solid cancers treated with multimodal therapy. A prospective analysis of peripheral blood mononuclear cells (PBMCs) during multimodal treatment in inoperable stage III NSCLC patients was performed to assess a correlation of T-lymphocytes changes with 6-months progression-free survival rates (PFS6M). Methods: Twenty patients at median age of 65.5 years (range 33-77), 85% male, 55% with adenocarcinoma and 40% with squamous cell carcinoma, were prospectively enrolled in this study. Eighteen (90%) patients received platinum-based concurrent chemo-radiotherapy (cCRT); seven (35%) patients additional concurrent and/or sequential immune check-point inhibition (four patients nivolumab and three durvalumab); patients treated with nivolumab received induction chemotherapy. Thoracic irradiation (TRT) was applied in all patients with median cumulative dose in equivalent 2Gy fractions (EQD2) of 64Gy (range: 52-65Gy). Peripheral blood was collected 5-10 days before treatment begin (A1), on the last day of TRT (RTend), and during follow-up. Samples were analyzed using polychromatic flow cytometry. Results are reported for three time-points: A1, RTend, and 6 months after TRT (C3) or the last sample available before that time-point. Results: From A1 to RTend, 16 (80%) patients experienced severe T-cell (CD3+, CD3+CD4+, CD3+CD8+) depletion, including 3 (15%) patients who received two doses of concurrent nivolumab. T-lymphocyte nadir was independent of the absolute numbers of PBMCs before treatment begin. In two patients, T-cell count remained stable, and increased in two other patients. No correlation of dynamic changes from A1 to RTend with PFS6M was observed. From RTend to C3, T-lymphocytes recovered in 11 (55%) patients; in 6 (30%) T-cell count further decreased or remained at very low levels. For total CD3 T-cells, CD3+CD4+ and CD3+CD8+ subsets, progressive disease in the first six months after TRT was associated with a decrease of median values (P = 0.03 for total CD3+ and CD3+CD4+, P = 0.08 for CD3+CD8+ T-cells). In contrast, an increase of all medians was associated with PFS6M (P = 0.007 for total CD3+, P = 0.002 for CD3+CD4+, P = 0.06 for CD3+CD8+ T-cells). Conclusions: There is a significant difference between patients with regards to T-lymphocytes recovery after the end of TRT, which is predictive for PFS6M, with poor median recovery observed in patients with early progress.
Disparities in end-of-life inpatient care received by patients with metastatic cancer, 2010 to 2017.
Authors: Stephanie Deeb, Fumiko Chino, Lisa Diamond, Anna Tao, Abraham Aragones, Armin Shahrokni, Divya Yerramilli, Erin F. Gillespie, C. Jillian Tsai
Journal: Journal of Clinical Oncology (2021)

12008 Background: Many patients with metastatic cancer receive high-cost, low-value care near the end of life. We examined interventions during terminal hospitalizations for patients with metastatic cancer to identify those with high likelihood of receiving futile care. Methods: A retrospective population-based cohort analysis of encounter-level data from the National Inpatient Sample was conducted, including records from 2010-2017 for patients ages ≥18 with metastatic cancer who died during hospitalization. We fit multivariable binomial logistic regression models to examine associations between exposures, including patient demographics, and the main outcome of aggressive, low-value, and high-cost medical care (Table). Results: Out of 321,898 hospitalizations among patients with metastatic cancer, 21,335 (6.6%) were terminal. Of these, 65.9% were white, 14.1% Black, 7.5% Hispanic, 58.2% were insured by Medicare or Medicaid, and 33.2% were privately insured. Overall, 63.2% were admitted from the Emergency Department (ED), 4.6% received systemic therapy, and 19.2% received invasive ventilation. Median total charges were $43,681. Black patients and publicly insured patients had higher likelihoods of admission from the ED and receiving ventilation, as well as higher total charges; similar trends emerged among patients of Asian race and Hispanic ethnicity. Patients hospitalized at urban teaching hospitals had higher likelihoods of receiving systemic therapy, ventilation, and incurring higher total charges (Table). Conclusions: Metastatic cancer patients of racial and ethnic minority groups and those with Medicare or Medicaid were more likely to receive low-value, aggressive interventions at the end of life. Further studies are needed to determine the underlying causes of these disparities in order to implement prospective interventions and advance appropriate end-of-life care.[Table: see text]
<i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution
Authors: Giovanni Levi, Camille de Lombares, Cristina Giuliani, Vincenzo Iannuzzi, Rym Aouci, Paolo Garagnani, Claudio Franceschi, Dominique Grimaud-Hervé, Nicolas Narboux-Nême
Journal: Molecular Biology and Evolution (2021)

Abstract DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated with neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in behavioral and metabolic phenotypes notably increasing lifespan by 33%. Here, we show that Dlx5/6VgatCre mice present a hyper-vocalization and hyper-socialization phenotype. While only 7% of control mice emitted more than 700 vocalizations/10 min, 30% and 56% of heterozygous or homozygous Dlx5/6VgatCre mice emitted more than 700 and up to 1,400 calls/10 min with a higher proportion of complex and modulated calls. Hyper-vocalizing animals were more sociable: the time spent in dynamic interactions with an unknown visitor was more than doubled compared to low-vocalizing individuals. The characters affected by Dlx5/6 in the mouse (sociability, vocalization, skull, and brain shape…) overlap those affected in the “domestication syndrome”. We therefore explored the possibility that DLX5/6 played a role in human evolution and “self-domestication” comparing DLX5/6 genomic regions from Neanderthal and modern humans. We identified an introgressed Neanderthal haplotype (DLX5/6-N-Haplotype) present in 12.6% of European individuals that covers DLX5/6 coding and regulatory sequences. The DLX5/6-N-Haplotype includes the binding site for GTF2I, a gene associated with Williams–Beuren syndrome, a hyper-sociability and hyper-vocalization neurodevelopmental disorder. The DLX5/6-N-Haplotype is significantly underrepresented in semi-supercentenarians (&amp;gt;105 years of age), a well-established human model of healthy aging and longevity, suggesting their involvement in the coevolution of longevity, sociability, and speech.
<i>SYK</i> gene mutations with TMB-H and MSI-H in solid tumors.
Authors: Jian Shi, Rongfeng Liu, Guanglei Huang, Lixing Wang, Baoen Shan, Ningning Luo, Qin Zhang, Yaqing Wu, Yingxue Qi, Chuang Qi
Journal: Journal of Clinical Oncology (2021)

e14572 Background: Spleen tyrosine kinase ( SYK) gene encodes a cytoplasmic non-receptor tyrosine kinase (NRTK) and mediates signal transduction downstream of multiple transmembrane receptors, which plays an important role in a variety of signaling pathways. The change of SYK gene expression and gene mutations may lead to the formation and metastasis of multiple solid tumors. Previous studies on SYK mostly focus on the protein isomers and the methylation of SYK gene promoter. We previously used next generation sequencing (NGS) to explore SYK gene mutations on DNA level and found novel mutation types of SYK gene. Herein, NGS were performed to explore the relationship of SYK gene mutations with TMB and MSI in solid tumors for further clinical research. Methods: We retrospectively collected NGS detection data by 539-gene panel in 5648 patients with pan-cancer, of which 3931 patients by tumor tissue and 1717 patients by blood ctDNA, and screened out somatic SYK gene mutations. 539-gene panel contained all exon regions of SYK gene. Then we divided 5648 patients into four groups depending on whether SYK gene mutations: tumor tissue mutant group (T-mut) / non-mutant group (T-non-mut), and ctDNA mutant group (ctDNA-mut) / non-mutant group (ctDNA-non-mut). The difference in TMB between T-mut and T-non-mut groups; between ctDNA-mut and ctDNA-non-mut groups were analyzed via the Wilcoxon sign test respectively. The difference in MSI between T-mut and T-non-mut groups were analyzed via Fisher test. Results: In 5648 patients with solid tumors, 64 patients (48/3931 in tumor tissue and 16/1717 in blood ctDNA) were found harboring SYK gene mutations and the mutation frequency was 1.13%. TMB in T-mut group was higher than in T-non-mut group and significant difference of TMB was found via the Wilcoxon sign test (p = 5.3e-12) between the two groups. TMB in ctDNA-mut group was higher than in ctDNA-non-mut group and significant difference of TMB was found too (p = 4.6e-05). 12 patients were found MSI-H in T-mut group (12/48) and 53 patients were found MSI-H in T-non-mut group (35/3875). We found significant difference in the probability of MSI-H occurrence between the two groups by Fisher test (p = 6.531e-12, HR: 23.933, 95%CI: 10.734-50.415). Conclusions: This is the first report on the relationship between SYK gene mutations with TMB and MSI in solid tumors and we found that SYK gene mutations are associated with TMB-H and MSI-H in solid tumors. As a retrospective study in solid tumors, the conclusion and the mechanism need to be studied in the future.
Myocarditis After BNT162b2 and mRNA-1273 Vaccination
Authors: Kathryn F. Larson, Enrico Ammirati, Eric D. Adler, Leslie T. Cooper, Kimberly N. Hong, Gianluigi Saponara, Daniel Couri, Alberto Cereda, Antonio Procopio, Cristina Cavalotti, Fabrizio Oliva, Tommaso Sanna, Vincenzo Antonio Ciconte, George Onyango, David R. Holmes, Daniel D. Borgeson
Journal: Circulation (2021)
Risk of hepatocellular carcinoma after spontaneous and nucleos(t)ide analogue induced hepatitis B surface antigen seroclearance.
Authors: Sunghwan Yoo, Hyun Woong Lee
Journal: Journal of Clinical Oncology (2021)

e16162 Background: Despite a favorable clinical course, the risk of hepatocellular carcinoma (HCC) still exists in patients achieving HBsAg seroclearance. Therefore, we investigated the incidence of HCC after spontaneous and nucleos(t)ide analogue (NA) induced HBsAg seroclearance in real-life clinical practice. Methods: A cohort study was conducted using data from Gangnam Severance Hospital. We identified all subjects with positive HBsAg between January 1, 2001 and March 21, 2018. NA use, liver biochemistries, serial HBsAg and anti-HBs results were retrieved. The primary endpoint was the incidence of HCC after naturally and NA induced HBsAg seroclearance. Results: Among the 5,609 HBsAg-positive patients, 83 chronic hepatitis B (CHB) patients achieved HBsAg seroclearance during 19 years. The cumulative incidence of HBsAg seroclearance was 0.024% at 2 years to 32.4% at 19 years. Of the 83 patients with HBsAg seroclearance, 52 patients achieved spontaneous HBsAg seroclearance and 31 patients achieved NA-induced HBsAg seroclearance. Of 52 patients with spontaneous HBsAg seroclearance, only one patient (2%) developed HCC 6 months after HBsAg seroclearance. On the other hands, there was no development of HCC in patients with NA-induced HBsAg seroclearance. No significant difference was observed in the cumulative incidence of HCC between two groups ( P=0.443). All patients had sustained HBsAg seroclearance and there was no HBsAg seroreversion. Conclusions: The incidence of HCC was extremely rare after spontaneous and NA induced HBsAg seroclearance in real-life clinical practice. NA-induced HBsAg seroclearance is also as durable as spontaenous HBsAg seroclearance.
Machine learning models to quantify HER2 for real-time tissue image analysis in prospective clinical trials.
Authors: Benjamin Glass, Michel Erminio Vandenberghe, Surya Teja Chavali, Syed Ashar Javed, Marlon Rebelatto, Shamira Sridharan, Hunter Elliott, Sudha Rao, Michael Montalto, Murray Resnick, Ilan Wapinski, Andrew Beck, Craig Barker
Journal: Journal of Clinical Oncology (2021)

3061 Background: Patient eligibility for HER2-targeting treatments is commonly informed by testing tumor HER2 expression using immunohistochemistry. As HER2 expression is visually assessed by pathologists, inter- and intra-rater variability might affect treatment decisions. Here, we report the development of an automated machine learning (ML)-based algorithm to quantify HER2 cell membrane expression across a diversity of breast cancer phenotypes as a clinical tool for monitoring HER2 testing quality. Methods: A total of 689 breast cancer tissue samples were either procured (Avaden Biosciences) or were anonymized samples from the AstraZeneca biobank comprising tissues from primary and metastatic tumors, core needle biopsies and surgical resections, lobular and ductal carcinomas, across tumor grades and HER2 expression levels. Samples were stained for HER2 detection (Ventana HER2 (4B5) Assay) and digitized (Leica Biosystems) across 5 laboratories in the US. Whole-slide images (WSIs) were stratified into training (n = 407), validation (n = 110), and test sets (n = 172). Multiple convolutional neural network based ML models (PathAI, Boston, MA) were trained using 190,000 manual annotations provided by 30 board-certified pathologists to identify artifacts, invasive tumor, identify individual cancer cells and measure tumor cell membrane HER2 expression as partial or complete, and negative, weak-or-moderate, or intense. Cell-level scores were validated against a consensus of manual cell counts from 5 independent pathologists in 320 representative regions of test set WSIs. HER2 scores were generated by automatically applying rules derived from 2018 ASCO/CAP guidelines and then compared in the test set with consensus scores from 3 independent pathologists. Results: Cell counts provided by the ML model were strongly consistent with cell counts obtained by pathologist consensus in all cell-types except for faintly positive HER2 cells where ML-based quantification identified more cells on average. Automatically generated ML-ASCO/CAP HER2 scores using WSI showed substantial consistency across IHC categories with the consensus of pathologists (ICC 0.88, 95%CI 0.82-0.92) in the test set and improved further when ML models were trained to agree with pathologists by adjusting cut offs (ICC 0.91, 95%CI 0.89-0.94). The ML-based model was deployed through the PathAI cloud platform to calculate HER2 testing quality control metrics in real-time in multicentric clinical trials. Conclusions: Automated image analysis of HER2-stained breast cancer tissues using ML-based models is consistent with pathologist consensus across breast cancer tissue types. The results support evidence that ML-based algorithms can help pathologists assess HER2 testing reproducibility in clinical trials.
Impact of COVID-19 pandemic on well-being and work-related burnout among healthcare workers at an academic center.
Authors: Richa Dawar, Estelamari Rodriguez, Kunal Gawri, Deukwoo Kwon, Frank J. Penedo
Journal: Journal of Clinical Oncology (2021)

11019 Background: COVID-19 pandemic has not only caused an unprecedented distress in the community, but also significant physical and psychological exhaustion amongst healthcare workers (HCWs), that could lead to serious effects on our healthcare system. This study was conducted to assess burnout among oncologists and other healthcare professionals at a large academic center. Methods: An electronic 10-minute questionnaire was sent to actively employed physicians, APRNs and PAs at the University of Miami. Survey items evaluated various personal and professional characteristics including COVID related stress. Burnout was examined with Maslach Burnout Inventory (MBI), which evaluated severity across two domains: emotional exhaustion and depersonalization. The logistic regression model was used to estimate association between study variables and high burnout levels. Odds ratio (ORs) and corresponding 95% confidence interval (CI) were obtained. Continuous variables were tested using two-sample t-test by high burnout status. Results: The survey was sent to 739 HCWs, out of which 182 (24.6%) completed the entire survey; 63.7% were physicians, 8.6% fellows, and 27.4% APRN or PA. The pandemic led to rescheduling of professional activities (22.2%), increased workload (59.5%), job insecurity (28.6%), and decreased leadership opportunities (32.2%). 62.3% of respondents reported decreased exercise; 44.8% reported new sleep disorder; 56.1% reported increased home responsibilities; childcare arrangements were affected in 60.6%; 61.4% struggled to maintain work-life balance. 70 of 182 respondents were broadly from the fields of Oncology and Palliative Care. 9 out of these 70 respondents reported high depersonalization, 27 reported high emotional exhaustion, and 33 reported overall high burnout symptoms on either emotional exhaustion or depersonalization scales. Amongst physicians holding positions from PGY4 through licensed attendings with less than 5 years’ experience, 62.5% (95%CI=35.4-84.8) showed high burnout rate (10 of 16), which was not statistically different from older physicians (11 of 27=40.7% (95%CI=22.4-61.2)). No difference in burnout was seen for other study variables including gender, marital status, and race/ethnicity. Conclusions: COVID-19 pandemic has incited not only an unmatched level of practice changes, but also extraordinary psycho-social uncertainty, leading to a considerable impact on HCWs’ wellbeing. Long working hours, lack of sleep, fear of losing job, transition to tele-medicine, risk of getting infection and putting their family at risk, lack of childcare, pressure of home schooling- all seem to have caused an increased physical and psychological pressure among HCWs and warrants an examination of potential coping mechanisms. This study sets the stage for more elaborate research to illustrate and guide the development of wellness programs imperative to the well-being of HCWs.
Optical real-time biopsy by endocytoscopy: a case of sessile serrated lesion with dysplasia
Authors: Kengo Kasuga, Yutaka Saito, Hiroyuki Takamaru, Masayoshi Yamada, Taku Sakamoto, Shigeki Sekine, Toshio Uraoka
Journal: Endoscopy (2021)

Sessile serrated lesions (SSLs) are early precursor lesions in the serrated neoplasia pathway, which progresses through SSL with dysplasia (SSLD) to invasive carcinoma. In SSLD, certain endoscopic characteristics, including double elevation, central depression, and reddishness, have been found frequently, and type IIIL, IV, and VI pit patterns were observed more frequently using magnifying chromoendoscopy with indigo carmine or crystal violet staining [1]. Endocytoscopy is useful for distinguishing SSLD [2], but the endocytoscopy findings of SSLD are poorly understood. Herein, we report a case of SSLD observed using endocytoscopy ([Video 1]).
Assessment of differences in demographic characteristics and clinical diagnoses among black and white oncology patients with COVID.
Authors: Sudip Bhandari, Judith Mueller, Warren Whyte, Samuel P. Heilbroner
Journal: Journal of Clinical Oncology (2021)

e18711 Background: Health disparities between black and white COVID-positive patients are well documented. To help address these disparities, clinicians need to understand the specific health challenges faced by black COVID patients compared to their white counterparts. These challenges are understudied in the oncologic setting. Hence, we present the demographic and clinical features of black COVID-positive cancer patients compared to whites. Methods: We used ConcertAI’s database of oncology EMR data, which includes clinical data from CancerLinQ Discovery. We conducted two-sample t-tests and chi-squared tests to measure the differences in black and white COVID-positive cancer patients across age, gender, ethnicity, state, region, ECOG, BMI, all cancer indications, stage, and Charlson comorbidities. COVID positivity was defined using claims data. Only relevant significant results are reported to save space. Results: Table summarizes the differences in 429 black and 980 white cancer patients with COVID. Black patients were younger, more likely to have an elevated BMI, and have a higher prevalence of breast cancer, congestive heart failure, diabetes, multiple myeloma, peptic ulcer disease, and renal disease. They also had less melanoma. Results were statistically significant at 0.05 level. Analyzing only black patients by COVID status shows very similar results. Conclusions: Black cancer patients suffer from multiple comorbid conditions that increase their risk of adverse outcomes when infected with COVID-19. The CDC lists eight comorbidities that put patients at a higher risk of severe COVID infection. Black patients in our cohort have a higher prevalence of four out of eight of these conditions—elevated BMI, renal disease, congestive heart failure, and diabetes. Clinicians should inspect for these comorbidities while treating this at-risk population. [Table: see text]
Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes
Authors: Catherine C. Robertson, Jamie R. J. Inshaw, Suna Onengut-Gumuscu, Wei-Min Chen, David Flores Santa Cruz, Hanzhi Yang, Antony J. Cutler, Daniel J. M. Crouch, Emily Farber, S. Louis Bridges, Jeffrey C. Edberg, Robert P. Kimberly, Jane H. Buckner, Panos Deloukas, Jasmin Divers, Dana Dabelea, Jean M. Lawrence, Santica Marcovina, Amy S. Shah, Carla J. Greenbaum, Mark A. Atkinson, Peter K. Gregersen, Jorge R. Oksenberg, Flemming Pociot, Marian J. Rewers, Andrea K. Steck, David B. Dunger, Linda S. Wicker, Patrick Concannon, John A. Todd, Stephen S. Rich
Journal: Nature Genetics (2021)
心外膜脂肪組織(EAT)と心膜外脂肪組織(PAT)に対するエゼチミブの有効性
Authors: Koyama Yasushi, Iwakura Katsuomi, Okamura Atsunori, Date Motoo, Inoue Koichi, Fujii Kenshi
Journal: Circulation (2013)