tbuckley/cabot-search huggingface dataset:
First-line pembrolizumab (pembro) in cisplatin-ineligible patients with advanced urothelial cancer (UC): Response and survival results up to five years from the KEYNOTE-052 phase 2 study.
Authors: Peter H. O'Donnell, Arjun Vasant Balar, Jacqueline Vuky, Daniel Castellano, Joaquim Bellmunt, Thomas Powles, Dean F. Bajorin, Petros Grivas, Noah M. Hahn, Elizabeth R. Plimack, Jin Zhi Xu, James Luke Godwin, Blanca Homet Moreno, Ronald De Wit
Journal: Journal of Clinical Oncology (2021)

4508 Background: Pembro was approvedfor cisplatin-ineligible patients with untreated advanced UC based on initial results of the phase 2 KEYNOTE-052 study (NCT02335424), which showed an ORR of 29%. Updated results after up to 5 years of follow-up are presented. Methods: KEYNOTE-052 is a single-arm, multi-site, open-label trial. Patients had advanced or metastatic UC, were cisplatin ineligible (criteria: ECOG PS 2, CrCl ≥30 to ̃60 mL/min, grade ≥2 peripheral neuropathy/hearing loss, NYHA class III heart failure), and had not previously received chemotherapy for advanced/metastatic disease. Patients received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. PD-L1 status was determined by combined positive score (CPS, number of PD-L1–staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of viable tumor cells, multiplied by 100); PD-L1–positive was CPS ≥10. The primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points were duration of response (DOR), OS, and safety. Results: Among 370 enrolled patients, median age was 74 y, 315 (85.1%) had visceral disease, and 43 (11.6%) completed 24 mo of therapy. Median time from enrollment to data cutoff (Sep 26, 2020) was 56.3 mo (range, 51.2-65.3) for all patients and 56.0 mo (range, 51.4-65.2) for the 110 patients (29.7%) with CPS ≥10. Confirmed ORR for all patients was 28.9% (95% CI, 24.3-33.8); complete response, 9.5% (n=35); partial response, 19.5% (n=72). Median DOR was 33.4 mo (range, 1.4+ to 60.7+); 44.8% and 39.4% of patients had DOR ≥36 and ≥48 mo, (Kaplan-Meier estimates). Median OS was 11.3 mo (95% CI, 9.7-13.1); 24- and 36-mo OS rates were 31.5% and 22.1%. Patients with CPS ≥10 had better outcomes than patients with CPS &lt;10 (Table). Treatment-related adverse events (AEs) occurred in 67.3% of patients; 21.1% of treatment-related AEs were grade ≥3, including 1 death (myositis). Conclusions: After up to 5 y of follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible patients with advanced UC. These effects were more pronounced in patients with CPS ≥10. Clinical trial information: NCT02335424. [Table: see text]
INTENSIVE: InterNaTional rEgistry oN Sars-cov-2 posItiVe nEuroendocrine neoplasm patients.
Authors: Francesca Spada, Lorenzo Gervaso, Anna La Salvia, Rocio Garcia-Carbonero, Jorge Hernando, Jaume Capdevila, Johannes Hofland, Wouter de Herder, Anna Koumarianou, Maura Rossi, Sabrina Boselli, Darina Tamayo, Vincenzo Bagnardi, Alice Laffi, Manila Rubino, Mohamad Bassam Sonbol, Nicola Fazio, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2021)

e16205 Background: Data about neuroendocrine neoplasms (NENs) patients with SARS-CoV-2 are scanty and specific indications for clinical practice are missing. Our aim is to create an international registry about NENs patients affected by SARS-CoV-2 positivity to give a worldwide representation of the situation. Methods: This is an observational retrospective/prospective multicenter survey based on a direct email invitation. All types of NEN are eligible except SCLC and MiNEN. Patients fulfilling the inclusion criteria from March 1st, 2020 up to the end pf pandemic will be recruited. Electronic CRFs are filled out using the REDCap database. Local Institutional Review Board approval is required before data entry. Results: Eighty-one centers, 24 in and 57 outside Italy, representing 39 countries and 5 continents, were contacted. Fourteen centers did not respond and 15 declined the invitation. Among the remaining 52, 6 centers are currently recruiting and 8 are active but not recruiting yet. As of the current abstract submission deadline, 67 patients have been included, mostly GEP-NET (75%), non-functioning (86%), metastatic (85%) and on active treatment [47% somatostatin analogs (SSAs), 10% everolimus, 12% tirosin-kinase inhibitors (TKIs), 10% peptide receptor radionuclide therapy (PRRT), 15% chemotherapy]. Median age at NEN diagnosis was 57 years whilst the median age at SARS-CoV-2 diagnosis was 62 years. Almost all patients reported COVID-19-related symptoms, more commonly fever (67% of patients), cough (55%) and dyspnea (51%), in 28% of cases exertional and in 22% at rest. More than one third of patients (n, 24) had a pneumonia. The most common therapies for COVID-19 were antibiotics, steroids and hydroxychloroquine. Eleven patients (16%) needed oxygen therapy, three (4%) sub-intensive care and none intensive care. Fifty-six patients (84%) clinically recovered, six (9%) with sequelae, whereas five (7%) died. Among these latter 4 had a NET and 1 a NEC, and no patients have been receiving chemotherapy. With regard to the anti-tumor therapy no change occurred in 66% of patients, temporary interruption in 30%, and definitive discontinuation in 3%, 2% missing. Conclusions: Most of the NEN patients completely recovered from COVID-19, in many cases without any anti-tumor therapy adjustment. No clear correlations were observed with type, primary site and treatment of NEN. The recruitment is ongoing.
Impact of the COVID-19 Pandemic on Administration of Selected Routine Childhood and Adolescent Vaccinations — 10 U.S. Jurisdictions, March–September 2020
Authors: Bhavini Patel Murthy, Elizabeth Zell, Karen Kirtland, Nkenge Jones-Jack, LaTreace Harris, Carrie Sprague, Jessica Schultz, Quan Le, Cristi A. Bramer, Sydney Kuramoto, Iris Cheng, Mary Woinarowicz, Steve Robison, Ashley McHugh, Stephanie Schauer, Lynn Gibbs-Scharf
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

After the March 2020 declaration of the COVID-19 pandemic in the United States, an analysis of provider ordering data from the federally funded Vaccines for Children program found a substantial decrease in routine pediatric vaccine ordering (1), and data from New York City and Michigan indicated sharp declines in routine childhood vaccine administration in these areas (2,3).In November 2020, CDC interim guidance stated that routine vaccination of children and adolescents should remain an essential preventive service during the COVID-19 pandemic (4,5).To further understand the impact of the pandemic on routine childhood and adolescent vaccination, vaccine administration data during March-September 2020 from 10 U.S. jurisdictions with high-performing* immunization information systems were assessed.Fewer administered doses of routine childhood and adolescent vaccines were recorded in all 10 jurisdictions during March-September 2020 compared with those recorded during the same period in 2018 and 2019.The number of vaccine doses administered substantially declined during March-May 2020, when many jurisdictions enacted stay-at-home orders.After many jurisdictions lifted these orders, the number of vaccine doses administered during June-September 2020 approached prepandemic baseline levels, but did not increase to the level that would have been necessary to catch up children who did not receive routine vaccinations on time.This lag in catch-up vaccination might pose a serious public health threat that would result in vaccine-preventable disease outbreaks, especially in schools that have reopened for in-person learning.During the past few decades, the United States has achieved a substantial reduction in the prevalence of vaccine-preventable diseases driven in large part to the ongoing administration of routinely recommended pediatric vaccines.These efforts need to continue even during the COVID-19 pandemic to reduce the morbidity and mortality from vaccine-preventable diseases.Health care providers should assess the vaccination status of all pediatric patients, including * A high-performing immunization information system was defined as a system with vaccine estimates within 10 percentage points of those from the 2018 National Immunization Survey-Child and National Immunization Survey-Teen immunization information systems, and which recorded ≥90% of doses administered to persons aged <19 years that were submitted and processed within 30 days of vaccine administration.
Astrocytic apoE4 and tau: Deadly combination for neurons
Authors: Paramita Chakrabarty, David R. Borchelt
Journal: Cell Reports Medicine (2021)

New data from Wang and colleagues1 suggest that astrocyte-derived apoE4 drives tau-mediated neurodegeneration. This research highlights how a genetic risk factor for Alzheimer's disease is a major determinant of neurodegeneration in tau-expressing neurons by regulating non-cell-autonomous pathways.
Australian real-world outcomes of ribociclib and aromatase inhibitor in hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC): Results from Kisqali Access Registry for Metastatic breast cancer in Australia (KARMA) collected alongside a medicine access program.
Authors: Vanessa Wong, Richard de Boer, Sally E. Baron-Hay, Robert helmut Blum, Benjamin Carl Forster, Susan Li Ling Chua, Katharine Cuff, Michael Green, Elgene Lim, Kelly Mok, Louise M. Nott, Michelle K. Nottage, Ali Tafreshi, Daphne T. F. Tsoi, Belinda Yeo, Peter Gibbs, Sheau Wen Lok
Journal: Journal of Clinical Oncology (2021)

e13018 Background: International guidelines recommend a combination of CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for HR+, HER2- MBC. Results from MONALEESA-2 demonstrate improved progression free survival (PFS) with ribociclib (CDK4/6 inhibitor) and ET as compared to ET alone. Prior to Australia’s Pharmaceutical Benefits Scheme funding, ̃800 patients participated in the ribociclib Medicine Access Program (MAP) from May 2017 to June 2018. Methods: KARMA is a secondary data use, non-interventional study of Australian patients who received first line treatment with ribociclib and aromatase inhibitor (AI), obtained via a MAP, for HR+, HER2- MBC. The aim was to capture comprehensive patient and treatment data to reflect real world practice and outcomes. Direct comparisons were made with the ribociclib/letrozole cohort in MONALEESA-2 given that the eligibility criteria were similar for both studies. Results: Data from 160 patients at 17 sites was analysed with a median follow up of 36.5 months. Baseline characteristics are shown in the table. 63 of 160 (39%) patients remain on ribociclib/AI at time of analysis. 58% of patients had at least 1 dose reduction, with the majority (77%) requiring only a single dose reduction. The most common reasons for dose reductions were neutropenia (68%) and abnormal liver enzymes (17%). 16 of 160 (10%) discontinued treatment due to toxicity, including 1 patient with QTc prolongation &gt; 600ms. There were no deaths due to toxicity. Median duration of treatment and PFS were 24.5 (95% CI 17.8-33.3) and 36.3 months (95% CI 29.9- NR) respectively, compared to 20.2 and 25.3 months in MONALEESA-2. Landmark PFS was 76% at 12 months, 67% at 18 months and 64% at 24 months. Conclusions: This is the first real world study of ribociclib and AI developed alongside a MAP. The combination treatment was well tolerated with similar rates of dose reductions (58% in both) and treatment discontinuation due to toxicity (10% vs 8%) when compared to MONALEESA-2. This real-world cohort achieved a superior PFS, potentially explained in part by a younger population with more favourable baseline disease characteristics, including fewer disease sites and higher rates of bone only metastases. It is encouraging to see drug tolerability and efficacy replicated in real world patients.[Table: see text]
Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
Authors: Marcia Bellon, Izabela Bialuk, Veronica Galli, Xue-Tao Bai, Lourdes Farre, Achilea Bittencourt, Ambroise Marçais, Michael N. Petrus, Lee Ratner, Thomas A. Waldmann, Vahid Asnafi, Antoine Gessain, Masao Matsuoka, Genoveffa Franchini, Olivier Hermine, Toshiki Watanabe, Christophe Nicot
Journal: Molecular Cancer (2021)

Abstract Background Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.
Neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy for locally advanced anal canal squamous carcinoma patients: Antitumor efficacy, safety and biomarker.
Authors: Weiwei Xiao, Yan Yuan, SuiHai Wang, Peiqiang Cai, BaoQing Chen, Rong Zhang, ZhiFan Zeng, Yuanhong Gao
Journal: Journal of Clinical Oncology (2021)

e15500 Background: Efficacy and safety of PD-1 inhibitors have been approved for the treatment of metastatic anal squamous cancer patients, but the efficacy of neoadjuvant treatment with PD-1 in anal squamous cancer patients has not yet been defined. We report results for the cohort of patients with locally advanced anal canal squamous carcinoma treated with neoadjuvant PD-1 inhibitor toripalimab and chemotherapy followed by concurrent immunoradiotherapy. Methods: Five locally advanced anal canal squamous carcinoma patients received 4 cycles of neoadjuvant PD-1 inhibitor toripalimab and Docetaxol and Cisplatin chemotherapy followed by concurrent immunoradiotherapy. Whole exome sequencing (WES) and mIHC were performed with the pretreatment tumor tissue for biomarker analysis. Results: Complete clinical response (cCR) was achieved in 4 patients after neoadjuvant treatment before radiotherapy while the other patient achieved near cCR. cCR was achieved in all the 5 patients 3 months after definitive immunoradiotherapy. Grade 3 toxicity was noted in 1 patient. Molecular testing revealed that PD-L1 expression (≥1%) in tumor and CD4/CD163 expression in tumor and paracancerous tissue were positively correlated with tumor shrinkage in the neoadjuvant treatment phase while TMB didn’t appear to significantly impact the response. Conclusions: PD-1 inhibitor combined with chemoradiotherapy has quite promising effect in locally advanced anal canal squamous carcinoma patients, with very mild toxicity. Pretreatment PD-L1 expression is positively correlated with tumor response to PD-1 inhibitor toripalimab and chemotherapy. It is worthy of further investigation in prospective clinical trial.
Phase I result of ICP-192 (gunagratinib), a highly selective irreversible FGFR inhibitor, in patients with advanced solid tumors harboring FGFR pathway alterations.
Authors: Ye Guo, Chunwang Yuan, Jieer Ying, Xu Zhu, Guodong Luan, Bin Zhang, Renbin Zhao, Jin Li
Journal: Journal of Clinical Oncology (2021)

4092 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR activities irreversibly by covalent binding. Preclinical data showed that gunagratinib overcomes the acquired resistance to the first-generation reversible FGFR inhibitors, e.g., infigratinib. ICP-CL-00301 is a phase I, first-in-human, clinical study which includes a dose escalation followed by dose expansion. The safety and tolerability as well as pharmacokinetics/pharmacodynamics (PK/PD) of gunagratinib were evaluated in patients with advanced solid tumors, and the preliminary anti-tumor activity was evaluated by RECIST1.1 in patients with FGF/FGFR gene aberrations. Methods: In the dose-escalation stage, patients with advanced solid tumors with or without FGF/FGFR alterations were treated with escalating doses (2, 4, 8, 10, 12, 14, 16 mg etc.) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. During the dose-expansion stage, patients with cholangiocarcinoma harboring FGFR2 gene fusion/translocation received the treatment of gunagratinib daily at 12 mg continuously. Results: As of February 2021, a total of 30 patients had received the treatment of gunagratinib. The median age of the treated patients was 55.0 (range: 28 to 75 years) with 56.7% male and ECOG performance status between 0-1. The maximum tolerated dose (MTD) had not been reached. The most common treatment-related adverse events (TRAEs) ( &gt; 20%) included hyperphosphatemia, hypercalcemia, increased ALT or AST, diarrhea and hypertriglyceridemia. Hyperphosphatemia is a commonly reported AE from other trials targeting FGFR and here serves as a PD biomarker of FGFR inhibition. This PD biomarker was observed in 73.3% of the patients treated with gunagratinib at all dose levels and was consistently observed at doses of 8 mg QD and above. Hyperphosphatemia was well managed with oral phosphate binders when necessary. The plasma exposure increased proportionally to the oral dosage levels of gunagratinib. Among the 12 patients with FGF/FGFR gene aberrations who have completed at least one tumor assessment, the overall response rate (ORR) was 33.3%, including 1 patient (8.3%) of cholangiocarcinoma with complete response (CR) and 3 patients (25%) with partial response (PR). The disease control rate (DCR) was 91.7% (11 of 12 patients). Conclusions: Gunagratinib is safe and well-tolerated in patients with advanced solid tumors. Anti-tumor activity was demonstrated in patients with FGF/FGFR gene aberrations in multiple tumor types, including cholangiocarcinoma (NCT03758664). Better response is expected with the increase of treatment durations. Clinical trial information: NCT03758664.
Clinical relevance of clonal hematopoiesis in persons aged ≥80 years
Authors: Marianna Rossi, Manja Meggendorfer, Matteo Zampini, Mauro Tettamanti, Emma Riva, Erica Travaglino, Matteo Bersanelli, Sara Mandelli, Alessia Antonella Galbussera, Ettore Mosca, Elena Saba, Chiara Chiereghin, Nicla Manes, Chiara Milanesi, Marta Ubezio, Lucio Morabito, Clelia Peano, Giulia Soldà, Rosanna Asselta, Stefano Duga, Carlo Selmi, Maria De Santis, Karolina Malik, Giulia Maggioni, Marilena Bicchieri, Alessia Campagna, Cristina A. Tentori, Antonio Russo, Efrem Civilini, Paola Allavena, Rocco Piazza, Giovanni Corrao, Claudia Sala, Alberto Termanini, Laura Giordano, Paolo Detoma, Aurelio Malabaila, Luca Sala, Stefano Rosso, Roberto Zanetti, Claudia Saitta, Elena Riva, Gianluigi Condorelli, Francesco Passamonti, Armando Santoro, Francesc Sole, Uwe Platzbecker, Pierre Fenaux, Niccolò Bolli, Gastone Castellani, Wolfgang Kern, George S. Vassiliou, Torsten Haferlach, Ugo Lucca, Matteo G. Della Porta
Journal: Blood (2021)
The prognostic value of cytoskeletal regulation and vesicle trafficking signaling pathway mutation in breast cancer.
Authors: Haiyan Liu, Guanqun Huang, Tanxiao Huang, Ming Liu, Wenting Liao, Bo Yang, Yuanyuan Liu, Shifu Chen
Journal: Journal of Clinical Oncology (2021)

e13068 Background: Breast cancer (BC) is the most commonly diagnosed cancer in 2020, with an estimated 2.3 million new cases and the leading cause of cancer death in women. The cytoskeleton is a dynamic system of protein filaments that is regulated by dozens of proteins which are, in turn, regulated by phosphoinositides. Cytoskeletal regulation and vesicle trafficking (CRVT) signaling pathway is associated with many changes in the structure and movements of cells. Few studies addressing the association between genetic mutation of the CRVT pathway and the disease prognosis have been reported up to now. Here we investigate the genetic status of CRVT pathway as a biomarker for predicting overall survival (OS) and relapse-free survival (RFS) for breast cancer patients. Methods: We used cBioPortal platform to analyze a cohort of 10646 breast cancer samples. Mutations in 7 genes ( APC, BAP1, KEAP1, PAK1, PTEN, SRC, STAT3 ) are the most common indication in the CRVT signaling pathway. We define overall survival (OS) as the time between the procedure date when the tumor specimen was collected and the date of death or last follow-up visit. And we define relapse-free survival (RFS) as the time from surgical resection to relapse of disease. We estimated and compared the survival curves of these two groups using Kaplan-Meier method and log-rank tests. The statistical significance level was set to 5% ( p &lt; 0.05). Results: Genomic alterations of the CRVT-indicator genes were found in 2582 (n = 2582/10646, 24.25%) samples with sorts of alterations identified including variants of non-synonymous mutations, splicing mutations, short in-frame insertion and deletion, short frame shift insertion and deletion, and copy number gain and loss. PTEN was most commonly altered (n = 2329), followed by PAK1 (n = 863), APC (n = 718), STAT3 (n = 341), KEAP1 (n = 317), BAP1(n = 292), and SRC (n = 278). Based on the result, patients were divided into the CRVT and non-CRVT group. The median OS of the CRVT group was 141.57 moth, which was significantly shorter than the OS of the non-CRVT group (log-rank test p= 0.000662). The median RFS of the CRVT group was 167.76 moth, which was also significantly shorter than the RFS of the non-CRVT group (log-rank test p= 0.0169). Conclusions: To the best of our knowledge, this study is the first investigation to evaluate the prognostic value of CRVT pathway mutation in patients with breast cancer. Our investigation shows that CRVT pathway mutation could significantly predict poor prognosis in breast cancer patients. The result of our analysis should be better confirmed with additional relevant research in the future using updated analyses.