tbuckley/cabot-search huggingface dataset:
Bifunctional TGF-β trap/IL-15 protein complex elicits potent NK cell and CD8+ T cell immunity against solid tumors
Authors: Bai Liu, Xiaoyun Zhu, Lin Kong, Meng Wang, Catherine Spanoudis, Pallavi Chaturvedi, Varghese George, Jin-an Jiao, Lijing You, Jack O. Egan, Christian Echeverri, Victor L. Gallo, Jilan Xing, Kristine Ravelo, Caitlin Prendes, Julian Antolinez, Julia Denissova, Gabriela J. Muniz, Emily K. Jeng, Peter R. Rhode, Hing C. Wong
Journal: Molecular Therapy (2021)

Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently reported. Here we describe the creation of a heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology. This complex comprises extracellular domains of the human transforming growth factor-β (TGF-β) receptor II and a human interleukin-15 (IL-15)/IL-15 receptor α complex. HCW9218 can be readily expressed in CHO cells and purified using antibody-based affinity chromatography in a large-scale manufacturing setting. HCW9218 potently activates mouse natural killer (NK) cells and CD8+ T cells in vitro and in vivo to enhance cell proliferation, metabolism, and antitumor cytotoxic activities. Similarly, human immune cells become activated with increased cytotoxicity following incubation with HCW9218. This fusion complex also exhibits TGF-β neutralizing activity in vitro and sequesters plasma TGF-β in vivo. In a syngeneic B16F10 melanoma model, HCW9218 displayed strong antitumor activity mediated by NK cells and CD8+ T cells and increased their infiltration into tumors. Repeat-dose subcutaneous administration of HCW9218 was well tolerated by mice, with a half-life sufficient to provide long-lasting biological activity. Thus, HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors.
Assessment of Changes of Membrane Properties and Platelets Function in Patients with Chronic Myeloid Leukaemia
Authors: Viola Popov, Vladareanu Ana Maria, Matei Mircea Bogdan, Matei Christien Oktaviani, Mihaela Georgeta Moisescu, Kovacs Eugenia, Meilin Omer, Mihaela Andreescu, Oana Patrinoiu, Savopol Tudor, Horia Bumbea
Journal: Blood (2017)
Oncologist phenotypes and associations with response to a behavioral intervention to increase serious illness conversations.
Authors: Eric Li, Christopher Manz, Manqing Liu, Jinbo Chen, Corey Chivers, Jennifer Braun, Lynn Mara Schuchter, Pallavi Kumar, Mitesh S. Patel, Lawrence N. Shulman, Ravi Bharat Parikh
Journal: Journal of Clinical Oncology (2021)

12126 Background: Interventions to increase serious illness conversations (SICs) between oncologists and patients may improve goal-concordant care, patient mood and quality of life. Randomized studies suggest that behavioral nudges to oncologists may prompt more and earlier SICs. Identifying characteristics of oncologists associated with response to such interventions may clarify barriers to SIC adoption. Methods: This was a secondary analysis of a randomized trial showing that machine learning (ML)-based behavioral nudges among 42 oncologist-advanced practice provider (APP) dyads (79 total oncology clinicians total) caring for 14,607 patients in a large academic health system led to a quadrupling of SIC rates (NCT03984773). Latent profile analysis identified oncologist phenotypes based on oncologist, patient, and practice data. We used difference-in-differences analyses among patients with predicted 180-day mortality risk ≥10% (n=2695 [12.6% of cohort]) to test the association between oncologist phenotype and response to the nudge, adjusted for patient and oncologist demographic and practice characteristics. Results: Three oncologist phenotypes were identified: 1) Higher-volume specialists 2) Lower-volume specialists; and 3) Higher-volume generalists. Compared with higher-volume specialists and higher-volume generalists, lower-volume specialists had fewer patients per week (9.2 vs 24.3 vs 53.2), fewer days in clinic per week (1.6 vs 2.5 vs 4.4), a higher proportion of new patients per week (34.9% vs 21.0% vs 17.6%), and higher baseline SIC rates (3.9% vs 1.6% vs 0.8%). Lower-volume specialists had a significantly greater response to the intervention than higher-volume specialists and generalists (see Table), demonstrating a nearly six-fold increase in SIC rate from baseline. Conclusions: Response to an ML-based behavioral nudge to prompt SICs was driven by specialist oncologists with lower patient volume and greater SIC adoption at baseline, although the nudge was associated with significantly higher SIC rates among all phenotypes. While effective among lower-volume oncologists, nudges to prompt supportive care interventions may have limited impact among higher-volume oncologists. Other strategies, including default involvement of specialty palliative care, may be more effective for higher-volume oncologists.[Table: see text]
Increased PD-1 and EGFR expression levels of T lymphocytes in patients with non-small cell lung cancer.
Authors: Ayca Ceylan, Mehmet Artac, Hasibe Artac
Journal: Journal of Clinical Oncology (2021)

e21018 Background: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are proteins that negatively regulate immune responses. Increased expression of PD-L1 in cancer cells leads to inhibition of the immune response against cancer, and causes cancer development and metastasis. Epidermal growth factor receptor (EGFR) activation upregulates PD-L1 expression in lung cancer cells and contribute to escape from immune response. In this study, we aimed to investigate the circulating T lymphocyte subsets and, PD-1 and EGFR expression levels of these cells in non-small cell lung cancer (NSCLC) progression. Methods: 40 NSCLC patients with 63.8 ± 8.0 mean age and 40 healthy controls with 60.9 ± 14.6 mean age were included in the study. In the peripheral blood samples of the patients taken at the time of diagnosis and controls, CD4 + T helper (Th) subsets (Th1, Th2, Th9, Th17, Th1Th17, CD4 + follicular T [Tfc] and peripheral T cells [Tpcs]), CD8 + cytotoxic T cell (CTL) subsets (CD8 + Tfcs and Tpcs), EGFR and PD-1 expression levels of T cells were determined by flow cytometric analysis. Results: Total lymphocyte ratio was decreased in patients with NSCLC compared to control (11.5 ± 5.2 in patients and 17.6 ± 6.1 in controls, p = 0.001), but there was no significant difference in CD3 + total T, Th and CTLs as well as their subsets (p &lt; 0.05). Increased PD-1 expression level (mean fluorescence intensity-MFI) on total lymphocyte (p = 0.001), CD3 + T (p = 0.001), CD4 + Th (p = 0.001), CTL (p = 0.016), CD4 + Tpc (p = 0.002) and CD8 + Tpc subsets (p = 0.017) were determined in the patients compared with controls. EGFR expressions were also increased on total lymphocyte, CD3 + T, Th and Th2 cells (p = 0.034, p = 0.020, p = 0.030, respectively). 19 NSCLC patients were metastatic, while 21 patients were non-metastatic. There was no significant difference in mean age between metastatic and non-metastatic NSCLC patients. Reduced total lymphocytes and Th cells, increased Th1Th17 cells were found in metastatic NSCLC patients (p = 0.003, p = 0.046 and p = 0.022, respectively). The percentage of EGFR in CD3 + T cell and Th17 cells decreased in metastatic patients. Conclusions: This study showed the increased PD-1 and EGFR expression levels of T lymphocytes in patients with NSCLC. Cancer cells may upregulate PD-1 expression by inducing EGFR activation on lymphocytes to suppress immune responses, leading to programmed cell death of lymphocytes and a decrease in the percentage of these cells in NSCLC. Therapeutic approaches focused on changing EGFR need to be considered for the distribution of T cell subsets and EGFR expressions.
Adrenal-permissive <i>HSD3B1</i> genetic inheritance and risk of estrogen-driven postmenopausal breast cancer.
Authors: Nima Sharifi, Megan Lynn Kruse, Jeffrey McManus, Yoon-Mi Chung, Wei Wei, Peter Bazeley, Fumihiko Nakamura, Aimalie Hardaway, Erinn Downs Kelley, Sarat Chandarlapaty, Mathew Thomas, Halle C. F. Moore, George Thomas Budd, Wai Hong Wilson Tang, Stanley L. Hazen, Aaron Bernstein, Serena Nik-Zainal, Jame Abraham
Journal: Journal of Clinical Oncology (2021)

10503 Background: Genetic factors that contribute to endogenous estrogen synthesis and postmenopausal breast cancer risk are unknown. We set out to test the hypothesis that homozygous inheritance of the common 1245A→C missense-encoding polymorphism in HSD3B1, which is common (8-10%) in White populations, functionally adrenal permissive and increases synthesis of the aromatase substrate, androstenedione, is associated with postmenopausal estrogen receptor-positive breast cancer. Methods: A prospective single institution study of postmenopausal estrogen receptor-driven breast cancer for determination of HSD3B1 genotype, circulating steroid concentrations, and adrenal-permissive genotype frequency compared with the genotype frequency in the general population and in estrogen receptor-negative breast cancer. Validation was performed in 2 breast cancer genomic studies with estrogen receptor documentation. The primary outcome is the adrenal-permissive genotype frequency in postmenopausal estrogen receptor-positive breast cancer and the general population. Genotype comparisons were also done with postmenopausal estrogen receptor-negative breast cancer and the association with circulating adrenal androgen concentrations determined. Results: The prospective and validation studies had 199 and 1628 women, respectively. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 9.6% (429/4451) in the general population [p = 0.0077]. The adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using the Cambridge and TCGA genomic datasets together: 14.4% (56/389) compared with 6.0% (9/149) for estrogen receptor-negative breast cancer (p = 0.007) and the general population (p = 0.005). Circulating androstenedione concentration was significantly higher for women with the adrenal-permissive genotype compared with the other genotypes (p = 0.03). Conclusions: The adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer and have broad implications for risk stratification, prevention, potential biomarkers for hormonal therapy response and possibly other clinical outcomes related to estrogen physiology in postmenopausal women.
Thromboembolism (TE) and adjuvant endocrine therapy (AET) in hormone receptor positive (HR+) early breast cancer (EBC): Did the evolution of treatment change the incidence of the adverse event? A metanalysis.
Authors: Luca Moscetti, Claudia Omarini, Isabella Sperduti, Fabio Canino, Monica Barbolini, Cecilia Nasso, Angela Toss, Massimo Dominici, Federico Piacentini
Journal: Journal of Clinical Oncology (2021)

e12516 Background: The AET of HR+ EBC has been changing in the recent years. Aromatase inhibitors (AI) as upfront, or in a planned switch strategy after Tamoxifen (T), have been added to the choice of T alone. An increased risk of TE is well known in the T treated patients while AIs have showed a reduced rate of TE. Recently, adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) abemaciclib to AIs, has showed a positive impact in the high risk HR+ EBC subgroups, but we are seeing an increase of the TE rate. We conducted this meta-analysis to evaluate the impact of the new AETs on the incidence of TE if compared to the standard monotherapy. Methods: We performed a meta-analysis of the randomized phase III trials comparing the experimental AETs and the endocrine standard therapy. A random-effect model to find differences in the rate of TE events between the experimental treatments and the standard therapy has been used. Results: Twelve phase III trials were included. Five trials evaluated the upfront strategy, 6 studies the switch and one the combination with a CDK4/6inhibitor (i.e. abemaciclib). Overall, the new AETs did not significantly modify or affect the rate of TE events (OR 0.708, 0.444-1.130, p = 0.148) with high heterogeneity among studies (I 2 87, p &lt; 0.0001). Excluding the abemaciclib trial, the incidence of TE is reduced (OR 0.609, 0.462-0.802, p &lt; 0.0001) with a moderate heterogeneity among the studies (I 2 59, p &lt; 0.006). Considering the upfront strategies with AIs, the TE events are reduced (OR 0.507, 0.394-0.651, p &lt; 0.0001) but they are not if we consider the trials in which T is used upfront before AIs (OR 0.762, 0.546-1.065, p = 0.112). Conclusions: Overall, the new treatments (AIs alone or plus CDK4/6 inhibitors) did not affect the rate in TE events. AIs as upfront strategy is the safest AETs of HR+ EBC, being associated to the lowest incidence of TE. The switch strategy increases the TE rate whereas the addition of abemaciclib to the standard AET showed to significantly increase the TE events. The results of the currently ongoing trials with the CDK4/6 inhibitors will help to obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and to clarify the weight of the TE adverse events in the balance of benefit/risk of this new adjuvant strategy.
Germline mutations among patients with non-small cell lung cancer.
Authors: Tongtong Yang, Huanhuan Liu, Mingwei Li, Yanrui Zhang, Yun Zhang, Xiayuan Liang, Feng Lou, Shanbo Cao, Huina Wang
Journal: Journal of Clinical Oncology (2021)

e20527 Background: Lung cancer is currently a leading cause of cancer-associated mortality worldwide. Germline mutations potentially predisposing patients to lung cancer have not been systematically defined. In this study, we sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline mutations in patients with NSCLC. Methods: A total 1562 patients with NSCLC were included in this study. Leukocyte DNA was extracted and detected were using next generation sequencing technology. Allele frequencies were compared with publicly available database. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Results: Overall, median age at testing of individuals was 63 years (range 12 to 91). The majority of individuals tested were male (56.15%, 877/1562). of 1562 NSCLC, P/LP mutations were identified in 94 (6.02%) in 42 Cancer Susceptibility genes. No individuals carried more than 1 germline variant. The most common P/LP mutations in genes were MUTYH (n = 11, 0.70%), TP53 (n = 10, 0.64%), BRCA2 (n = 8, 0.51%), PALB2(n = 5, 0.32%), PTEN(n = 4, 0.26%), BLM(n = 3, 0.19%), WRN(n = 3, 0.19%), and ATR, BRCA1 and BRIP1 (n = 2, 0.13% each). Twenty eight patients were carried germline mutations in homologous recombination repair(HRR), including BRCA2 (8), PALB2 (5), PTEN (4), BRCA1 (2), BRIP1 (2), CHEK2 (2), FANCA (2), ATM (1), RAD51B (1), RAD54L(1). Of note, the clinical features of patients with HRR mutations were not young adult (median age [range], 57 [41-80] years). Conclusions: Of 1562 patients with NSCLC, 94 (6.02%) had germline mutations and 27 (1.73%) had mutations in HRR genes. The presence of HRR germline mutations could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. More extensive germline testing in NSCLC should be considered.
Cancer patients diagnosed with COVID-19 infection: A multicenter retrospective cohort of nine Brazilian cancer centers.
Authors: Tiago Costa de Padua, Mariana Ribeiro Monteiro, Kaique Almeida, Camila Brambilla Souza, Daniela Pezzutti, Maria Clara Borges De Andrade, Angelo Maiolino, Rafael Luis Moura Lima do Carmo, Tuane Borges do Livramento Freitas, Cecilia Longo, Maria Carolina Lopes Perdigao, Cynthia Lemos Ferreira, Tercia Tarciane Soares de Sousa, Sueli Monterroso da Cruz, Ana Beatriz Kinupe Abrahao, Gustavo Henrique Munhoz Piotto, Fernando Meton de Alencar Camara Vieira, Luiz H. Araujo
Journal: Journal of Clinical Oncology (2021)

e13600 Background: The COVID-19 infection was declared pandemic in March 2020. Since then, multiple studies have attempted to correlate clinical factors with risk of complications from COVID-19, including cancer. However, cancer patients are underrepresented in clinical trials and the results vary between different cohorts. Methods: We conducted a multicentre retrospective study, based on systematic review of medical records, including nine cancer centers, located in five different Brazilian cities. Patients were diagnosed with COVID-19 through RT-PCR between March 15, 2020 and August 13 , 2020. Poisson regression models were then used to test for an association between clinical characteristics and severity of COVID-19 infections. Results: 102 patients had data collected for analysis, 85 (83.3%) of whom were hospitalized due to complications from COVID-19 infection. The median age was 65.8 years, most were female patients (61.8%) and white (73,5%). 78.4% had a performance status of 0-1, and the most common cancer subtypes were gastrointestinal (30.4%), breast (22.6%) and hematological (13.7%). Almost 40% of population had stage IV disease. Mortality rate for all hospitalized patients was 36.5%, while for those admitted to the ICU it was 68.4%. Key univariable risk factors for mortality included age (RR 1.03), ECOG ≥ 2 (RR 1.83), hypertension (RR 1.72), lung metastasis (RR 1.67), and lymphocytes ≤ 1000 admission (RR 2.40). At the multivariable analysis, the risk factors were also age (RR 1.02), primary lung cancer (RR 2.61), lung metastasis (RR 2.86), and coronary disease (RR 3.76). Conclusions: Despite the high mortality of patients hospitalized with COVID-19, our data are compatible with other cohorts. Cancer patients must be carefully monitored in pandemic periods of infectious diseases.
Evolving oncology provider perspectives on care delivery during the COVID-19 pandemic.
Authors: Divya Ahuja Parikh, Meera Vimala Ragavan, Sandy Srinivas, Sarah Garrigues, Eben Lloyd Rosenthal, Manali I. Patel
Journal: Journal of Clinical Oncology (2021)

e18609 Background: The COVID-19 pandemic prompted rapid changes in cancer care delivery. We sought to examine oncology provider perspectives on clinical decisions and care delivery during the pandemic and to compare provider views early versus late in the pandemic. Methods: We invited oncology providers, including attendings, trainees and advanced practice providers, to complete a cross-sectional online survey using a variety of outreach methods including social media (Twitter), email contacts, word of mouth and provider list-serves. We surveyed providers at two time points during the pandemic when the number of COVID-19 cases was rising in the United States, early (March 2020) and late (January 2021). The survey responses were analyzed using descriptive statistics and Chi-squared tests to evaluate differences in early versus late provider responses. Results: A total of 132 providers completed the survey and most were white (n = 73/132, 55%) and younger than 49 years (n = 88/132, 67%). Respondents were attendings in medical, surgical or radiation oncology (n = 61/132, 46%), advanced practice providers (n = 48/132, 36%) and oncology fellows (n = 16/132, 12%) who predominantly practiced in an academic medical center (n = 120/132, 91%). The majority of providers agreed patients with cancer are at higher risk than other patients to be affected by COVID-19 (n = 121/132, 92%). However, there was a significant difference in the proportion of early versus late providers who thought delays in cancer care were needed. Early in the pandemic, providers were more likely to recommend delays in curative surgery or radiation for early-stage cancer (p &lt; 0.001), delays in adjuvant chemotherapy after curative surgery (p = 0.002), or delays in surveillance imaging for metastatic cancer (p &lt; 0.001). The majority of providers early in the pandemic responded that “reducing risk of a complication from a COVID-19 infection to patients with cancer” was the primary reason for recommending delays in care (n = 52/76, 68%). Late in the pandemic, however, providers were more likely to agree that “any practice change would have a negative impact on patient outcomes” (p = 0.003). At both time points, the majority of providers agreed with the need for other care delivery changes, including screening patients for infectious symptoms (n = 128/132, 98%) and the use of telemedicine (n = 114/132, 86%) during the pandemic. Conclusions: We found significant differences in provider perspectives of delays in cancer care early versus late in the pandemic which reflects the swiftly evolving oncology practice during the COVID-19 pandemic. Future studies are needed to determine the impact of changes in treatment and care delivery on outcomes for patients with cancer.
Metabolome subtyping of severe bronchiolitis in infancy and risk of childhood asthma
Authors: Zhaozhong Zhu, Carlos A. Camargo, Yoshihiko Raita, Michimasa Fujiogi, Liming Liang, Eugene P. Rhee, Prescott G. Woodruff, Kohei Hasegawa
Journal: Journal of Allergy and Clinical Immunology (2021)
First-in-human dose escalation and food effect study of oral ONC206 in adults with recurrent primary CNS neoplasms.
Authors: Brett James Theeler, Jinkyu Jung, Eric Burton, Heather Leeper, Jing Wu, Kareem Zaghloul, Abhik Ray-Chaudhury, Martha Quezado, Mark Raffeld, Ying Yuan, Kenneth D. Aldape, Marta Penas-Prado, Varun Vijay Prabhu, Martin Stogniew, Joshua E. Allen, Terri S. Armstrong, Mark R. Gilbert
Journal: Journal of Clinical Oncology (2021)

TPS2072 Background: The majority of recurrent CNS tumors lack effective systemic therapy options following surgical resection and adjuvant radiotherapy. ONC201, the founding member of the imipridone class of small molecules, has induced durable tumor regressions in patients with diffuse midline glioma, H3 K27M-mutant (DMG H3K27M). ONC206, the second imipridone to enter clinical development, is a DRD2 antagonist and ClpP agonist that exhibits differentiated receptor pharmacology and gene expression profiles in tumors relative to ONC201. The compound is orally bioavailable, penetrates the blood-brain barrier, and exhibits anti-cancer efficacy without toxicity in several preclinical cancer models with pronounced efficacy in myc-overexpressing CNS tumors. Methods: A first-in-human, open label, dose escalation, and food effect Phase I study of oral ONC206 (NCT04541082) is currently enrolling. Patients must be 18 years or older and diagnosed with a recurrent, primary CNS neoplasm. Eligible diseases include recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, DMG H3K27M, ependymoma, medulloblastoma, malignant meningiomas, and other rare primary CNS neoplasms. Dose escalation, initially with weekly dosing, will follow a standard 3+3 design. After the MTD is established, a food effect cohort will enroll with a balanced, single-dose, two-arm, two-period, crossover design. The primary endpoint is to determine DLT during the first 28-day cycle. Secondary endpoints will include objective response rate by RANO criteria, overall and progression-free survival, and disease control rate. Exploratory biomarker analyses based on preclinical correlations with efficacy will include DRD2, DRD2 dimer, ClpP, DRD5, c-myc, and n-myc expression. Clinical trial information: NCT04541082.
Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury
Authors: Anissa A. Widjaja, Jinrui Dong, Eleonora Adami, Sivakumar Viswanathan, Benjamin Ng, Leroy S. Pakkiri, Sonia P. Chothani, Brijesh K. Singh, Wei Wen Lim, Jin Zhou, Shamini G. Shekeran, Jessie Tan, Sze Yun Lim, Joyce Goh, Mao Wang, Robert Holgate, Arron Hearn, Leanne E. Felkin, Paul M. Yen, James W. Dear, Chester L. Drum, Sebastian Schafer, Stuart A. Cook
Journal: Science Translational Medicine (2021)

Inhibition of IL11 signaling limits drug-induced liver damage and promotes hepatic regeneration in a mouse model.