tbuckley/cabot-search huggingface dataset:
High-Intensity Strength Training, Knee Pain, and Knee Joint Compressive Forces in Adults With Knee Osteoarthritis—Reply
Authors: Stephen P. Messier
Journal: JAMA (2021)

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Efficacy and safety of KN046 plus paclitaxel/cisplatin as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).
Authors: Jianming Xu, Rongrui Liu, Yanqiao Zhang, Nong Xu, Qingxia Fan, Shegan Gao, Hongming Pan, Mingquan Cai, Dong Yan, Qianqian Liang, Qiong Wu, Baohong Guo, Yakun Qi, Ting Xu
Journal: Journal of Clinical Oncology (2021)

4062 Background: The prognosis of pts with advanced esophageal squamous cell carcinoma (ESCC) remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. Recently, the combination of PD-1/PD-L1 pathway blockades with chemotherapy has shown synergistic efficacy in a few clinical trials. KN046 is the world's first dual immune checkpoint inhibitor, which can block PD-1/PD-L1 and CTLA-4 pathways at the same time. The purpose of this ongoing phase II trial (NCT03925870) in China was to evaluate the efficacy and safety of KN046 monotherapy or combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC. Methods: This trial included 3 cohorts, one of which enrolled systemic treatment naïve pts with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1. Eligible subjects were given paclitaxel (135-175mg/m 2 , iv, d1, q3w) and cisplatin (75mg/m 2 , iv, d2-4, q3w) plus KN046 (5mpk, iv, d1, q3w) for 4̃6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with KN046 monotherapy (5mpk, iv, q2w) until progression or unacceptable toxicity. Tumour response was assessed according to RECIST 1.1 every 6 weeks. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DCR, safety, PK profile, and immunogenicity. Results: As of December 14, 2020, 15 pts were enrolled, all of them were male, 52.3% ≥60 years, 64% ECOG 1, 80% with distant metastasis. Median exposure time to KN046 was 11.4 wks and average KN046 treatment was 2.4 cycles. 12 pts were included in the efficacy analysis and 15 pts in the safety analysis. The overall response rate (ORR) and disease control rate (DCR) were 58.3% and 91.6%, respectively. 7 pts (58.3%) had partial response (PR) including one complete response of target lesion. 4 pts (33.3%) had stable disease (SD) with 3 pts showing more than 20% of tumor burden reduction. The overall incidence of KN046 related adverse events was 80.0%, with 13.3% Gr 3 or above TRAE. Infusion-related adverse events occurred during 7.8% and most were mild. Immune related adverse events（irAE）were seen in 53.3% and the most common Gr 3 irAE were nausea (n＝1, 6.7%) and rash (n＝1, 6.7%). Conclusions: KN046 plus paclitaxel/cisplatin demonstrated clinical efficacy and acceptable safety as first-line treatment, and might be a favorable option for pts with advanced ESCC. Clinical trial information: NCT03925870. Research Sponsor: Jiangsu Alphamab Biopharmaceuticals Co., Ltd. Clinical trial information: NCT03925870.
Dihydropyrimidine dehydrogenase deficiency in patients treated with 5FU or capecitabine based regimens: A single center experience from South India.
Authors: Keechilat Pavithran, Prasanth Ariyannur, Hridya Jayamohanan, Arun Philip, Wesley Mannirathil Jose, Sumi Soman
Journal: Journal of Clinical Oncology (2021)

e15517 Background: DPYD deficiency is present in 3-5% of patients. The risk of treatment-related death in DPYD mutation carriers who receive fluoropyrimidine chemotherapy has been estimated at 3-10%. There is growing data in support of widespread screening for DPYD deficiency prior to fluoropyrimidine chemotherapy. The purpose of our study was to identify the prevalence of DPYD deficiency among patients receiving 5-fluorouracil (5FU) or capecitabine based combination chemotherapy, and to analyse the toxicity profile among the DPYD deficient group. Methods: The study involved patients who have received 5FU and capecitabine based chemotherapy for the treatment for gastrointestinal, breast and head and neck cancers between 2019-2020. Four DPYD variants were checked using real-time PCR based Genotyping assay. Three common DPYD variants recommended by the CPIC guidelines (IVS14+1 G&gt;A (*2A), c.1679T&gt;G (*13), c.2846A&gt;T) and a common variant in Asian population (c.496A&gt;G), based on previous studies, was included in our analysis. These variants were assessed prior to the initiation of the chemotherapy and dose was modified based on the activity score and the toxicity profile was assessed. Descriptive statistics was performed using SPSS version 20. Results: 375 patients were included in this analysis. The median age of the cohort was 61years (21-84 years). 51.3% were males and 49.7% females. Among the 375 patients, 47 patients had DPYD mutation (12.5%). The median age of the DPYD mutated patients were 68 years; 29 (61.7%) males and 18 (38.2%) females. 32 (68.8%) had deleterious mutation in DPYD variant c.496A&gt;G (rs2297595) and 15 (31.9%) showed mutation IVS14+1 G&gt;A (rs3918290). 35 out 47 patients had grade II-III toxicity even after dose reduction during the first cycle of chemotherapy. The commonly seen adverse events were hand and foot syndrome in 18 (38.3%), mucositis in 7 (14.9%), diarrrhoea in 15 (31.9%) and neutropenia in 25 (31.9%) patients. Four patients had febrile neutropenia. One patient experience myocardial infarction. There was no mortality. Chi square analysis showed DPYD mutation had significant association with presence of severe adverse reaction (74.5%, p-value. 0.002). Conclusions: Prevalence of DPYD mutation in our patients was 12.5%. They experienced more toxicities while receiving 5-FU/Capecitabine even after dose modification. c.496A&gt;G (rs2297595) was the most common variant seen in our patients. Screening of patients for DPYD mutations prior to administration of 5-FU/capecitabine using pharmacogenetic methods may help identify those patients who are at risk for adverse effects, allowing a more individualized approach to their chemotherapy management. c.496A&gt;G (rs2297595) variant should also be in included routinely in DPYD screening among South Asian population.
TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy
Authors: Allison C. Ostriker, Yi Xie, Raja Chakraborty, Ashley J. Sizer, Yalai Bai, Min Ding, Wen-Liang Song, Anita Huttner, John Hwa, Kathleen A. Martin
Journal: Circulation (2021)

Background: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. Methods: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle–specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. Results: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. Conclusions: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.
A phase 3, randomized, double-blind, placebo-controlled study of ruxolitinib plus parsaclisib in patients with JAK- and PI3K-inhibitor treatment-naïve myelofibrosis.
Authors: Abdulraheem Yacoub, Susan Erickson-Viitanen, Feng Zhou, Albert Assad
Journal: Journal of Clinical Oncology (2021)

TPS7058 Background: Ruxolitinib (JAK1/JAK2 inhibitor) significantly improves outcomes in patients with myelofibrosis (MF); however, a subset of patients may experience a suboptimal response. Recent phase 2 data showed that addition of PI3Kδ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub. EHA2020. S216). This phase 3, randomized, double-blind study (INCB 50465-313; NCT04551066), evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naïve to Janus kinase (JAK) and PI3K inhibitor therapies. Methods: Eligible patients are aged ≥18 years with a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) risk category of at least Intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin; total symptom score ≥10 at screening, ECOG PS 0–2, and life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF ≤3 months of first study dose and/or lack of recovery from all toxicities related to previous therapies to grade ≤1, have recent history of inadequate bone marrow reserve (eg, platelet count = 50×10 9 /L) or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg QD or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×10 9 /L vs 50 to = 100×10 9 /L inclusive). Treatment will begin on Day 1, with starting ruxolitinib dose level determined by baseline platelet count, and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to crossover to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at Week 24 for patients who received ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability for ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Sites are opening across the United States, Europe, Asia, and New Zealand. Clinical trial information: NCT04551066.
NHS must prioritise tackling ethnic health inequalities “at every level,” says report
Authors: Gareth Iacobucci
Journal: BMJ (2021)

The NHS must give as much priority to tackling ethnic minority health inequalities as other areas such as waiting times and financial targets, a new report1 has urged.

The report by the King’s Fund, commissioned by the independent NHS Race and Health Observatory, said that as the biggest employer of minority ethnic staff in Europe, the NHS needed to take a lead in tackling long standing ethnic health disparities and health inequalities.

It has “proved too easy in the past for the system to lose focus on race equality,” either because it is not prioritised by national leaders, or because it falls between the gaps of different organisations, said …
Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation
Authors: Jonas Weiße, Julia Rosemann, Lisa Müller, Matthias Kappler, Alexander W. Eckert, Markus Glaß, Danny Misiak, Stefan Hüttelmaier, Wolfgang G. Ballhausen, Mechthild Hatzfeld, Monika Haemmerle, Tony Gutschner
Journal: Molecular Cancer (2021)

Abstract Background Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy. Methods We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis. Results We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation. Conclusion Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.
AI-based imaging biomarker in mammography for prediction of tumor invasiveness.
Authors: Hyeonseob Nam, Ki Hwan Kim, Chan-Young Ock
Journal: Journal of Clinical Oncology (2021)

1568 Background: The preoperative diagnosis of ductal carcinoma in situ (DCIS) by core needle biopsy (CNB) can be upstaged in the final pathology, and this possibility is linked to the controversy over whether axillary staging is necessary in primary operation. In this study, we developed an artificial intelligence (AI)-powered Imaging Biomarker in Mammography (IBM) that can predict tumor invasiveness in preoperative mammography and evaluated its performance in an external validation cohort. Methods: A total of 151,764 exams of 4-view mammograms were collected from five institutions of three countries to develop the AI algorithm for breast cancer detection, where 31,776 were cancer exams. In previous studies, the performance of this breast cancer detection algorithm has already been evaluated, and in this study, we further developed the AI-powered IBM for predicting tumor invasiveness on top of the AI algorithm for breast cancer detection. To develop the AI-powered IBM for predicting invasiveness, final diagnosis information was collected for 8,251 cancer exams (472 DCIS, 388 ductal carcinoma in situ (DCIS-MI), and 7,391 invasive ductal carcinoma (IDC)), and 886 cancer exams (44 DCIS, 51 DCIS-MI, 791 IDC) were additionally collected for internal validation. The AI-powered IBM was developed via two stages of training – 1) training with diagnosis labels (cancer vs non-cancer), followed by 2) fine-tuning with invasiveness labels (DCIS, DCIS-MI, IDC). The AI-powered IBM also tested in an external validation cohort of 699 cancer exams (68 DCIS, 19 DCIS-MI, 612 IDC) and all the exams were confirmed by surgical biopsy. Results: The AI-powered IBM showed an area under the curve (AUC) values of 0.968 for breast cancer detection and it successfully distinguished IDC from DCIS and DCIS-MI with AUC values of 0.898 and 0.851, respectively (Table). In addition, the AUC value in terms of discriminating between DCIS and DCIS-MI was 0.752. When the AI-powered IBM was tested in the external cohort, it could detect breast cancer with the AUC of 0.952 and, its performance in terms of invasiveness prediction was similar that of the internal validation (IDC vs DCIS, 0.810; IDC vs DCIS-MI, 0.846), which supports the AI-powered IBM is applicable to the unseen mammography exam. Conclusions: The AI-powered IBM can distinguish IDC from DCIS and DCIS-MI in mammography. The results support that the AI-powered IBM can be used as a biomarker to help determine the surgical plan that includes whether or not to perform the axillary dissection.[Table: see text]
CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.
Authors: Neeraj Agarwal, Stephane Oudard, Josep M. Piulats, Michael Thomas Schweizer, Aude Flechon, Teresa Alonso Gordoa, Karim Nacerddine, Andrew Lithio, Erica L. Johnston, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2021)

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 &amp; 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 &amp; 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 &amp; 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 &amp; 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material &lt;12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.