tbuckley/cabot-search huggingface dataset:
SEER-Medicare study of early-stage triple-negative breast cancer: Real-world treatment patterns, survival, and expenditures 2010 to 2016.
Authors: Jan Sieluk, Amin Haiderali, Min Huang, Lingfeng Yang, Konstantinos Tryfonidis, Kim M. Hirshfield
Journal: Journal of Clinical Oncology (2020)

e12512 Background: In the US, triple-negative breast cancer (TNBC) represents about 10–20% of breast cancers. Current information about the clinical and economic burden of early-stage TNBC in elderly patients is lacking. Methods: We used the SEER-Medicare database to identify patients with continuous Medicare Parts A/B enrollment, ≥66 years old, newly diagnosed between 2010 - 2015 (followed until 2016) with stage II-III TNBC, who initiated systemic neoadjuvant and/or adjuvant (including chemotherapy and radiation) therapy. Overall survival (OS) and event-free survival (EFS) from diagnosis were estimated using Kaplan-Meier (KM). Healthcare costs were determined during neoadjuvant and adjuvant periods. Results: Of 1569 patients ( &gt; 99% women), 94 (6%) received neoadjuvant therapy, 1162 (74%) received adjuvant therapy, and 313 (20%) received both (neo/adj; Table). Age and race/ethnicity distributions were comparable in the three cohorts. Primary tumor T stage was T1c/T2 for 43%, 83%, and 58% in neoadjuvant, adjuvant, and neo/adj, respectively, and T3 for 14%, 10%, and 15%, respectively. The most common systemic regimens in both neoadjuvant and adjuvant periods were a taxane +/- anthracycline; 21% and 67% of patients in adjuvant and neo/adj cohorts received radiation therapy after surgery. Most claims were for outpatient treatment; hospitalizations were uncommon. The total mean expenditures per patient per month were US$10,620 and $24,408 during neoadjuvant and adjuvant periods, respectively. Conclusions: This study provides insights into patient characteristics, as well as clinical and economic outcomes for elderly patients with early-stage TNBC, treated from 2010-2016 in the US, highlighting the high monetary burden of TNBC and poor outcomes associated with stage III patients. [Table: see text]
Rathke’s cleft-like cysts arise from Isl1 deletion in murine pituitary progenitors
Authors: Michelle L. Brinkmeier, Hironori Bando, Adriana C. Camarano, Shingo Fujio, Koji Yoshimoto, Flávio S. J. de Souza, Sally A. Camper
Journal: Journal of Clinical Investigation (2020)

The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke's cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene-expression program in the cysts. We confirmed expression of FOXA1, FOXJ1, and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development.
A phase II study of anti-PD1 monoclonal antibody (Nivolumab) administered in combination with anti-LAG3 monoclonal antibody (Relatlimab) in patients with metastatic melanoma naive to prior immunotherapy in the metastatic setting.
Authors: Anjali Rohatgi, Ryan Campbell Massa, William E. Gooding, Tullia C. Bruno, Dario Vignali, John M. Kirkwood
Journal: Journal of Clinical Oncology (2020)

TPS10085 Background: Novel checkpoint inhibitors are a promising treatment for advanced melanoma, as only a fraction of patients have durable responses to current FDA-approved immunotherapy. Lymphocyte activation gene 3 (LAG3) is an inhibitory checkpoint receptor on CD4+ and CD8+ T cells, where engagement results in suppression of T cell activation and proliferation. LAG3 and PD1 are co-expressed on T cells during T cell receptor signaling and are down-regulated after antigen clearance. Persistent stimulation leads to prolonged LAG3 and PD1 expression and to T cell exhaustion, a possible mechanism of resistance to immunotherapy. Both LAG3 and PD1 are expressed on tumor-infiltrating T cells in melanoma. Murine tumors treated with both anti-LAG3 and anti-PD1 have demonstrated increased tumor regression than tumors in mice treated with either single agent. Further, a phase I trial has demonstrated safety of combined anti-LAG3 monoclonal antibody, relatlimab and anti-PD1 monoclonal antibody, nivolumab. Methods: This phase II, single-center clinical trial is designed to enroll treatment naive patients with unresectable or metastatic melanoma to ultimately receive combined relatlimab and nivolumab after a lead-in arm where patients are randomized to receive relatlimab, nivolumab, or the combination for the first 4 week cycle. For the lead-in phase, patients will have baseline and post-treatment blood and tumor sampling. Disease assessment by imaging will occur after the lead-in phase at 4 weeks. After completion of the lead-in phase, all patients proceed to combination therapy with disease assessment at 12-week intervals. The primary endpoint for the lead-in phase is to evaluate changes in immune cell populations in peripheral blood and tumor with the single agents and combination treatment. The primary endpoint for the combination phase is best overall anti-tumor response. Secondary clinical endpoints include progression-free survival, overall survival, duration of response and toxicity. Exploratory endpoints are to determine the mechanistic effects of anti-LAG3 and anti-PD1 on the blood and tumor microenvironment, cytokine signatures, and correlation of these with clinical response. The study is currently accruing with enrollment of 9 out of 42 patients. Clinical trial information: NCT03743766.
Core limitations in clinical trials leading to anticancer drug approvals by the U.S. Food and Drug Administration.
Authors: Talal Hilal, Miguel Gonzalez-Velez, Vinay Prasad
Journal: Journal of Clinical Oncology (2020)

2057 Background: To date, a comprehensive evaluation of core limitations in clinical trials leading to anti-cancer drug approvals by the US Food and Drug Administration (FDA) has not been undertaken.The aim of this analysis was to assess the percentage of clinical trials with core limitations, defined as lack of randomization, lack of overall survival data, inappropriate use of crossover, and use of sub-optimal control arms that led to FDA approvals from 2014 to 2019. Methods: This observational analysis included all approved anti-cancer drug indications by the FDA from July 2014 through July 2019. All indications were investigated and each clinical trial evaluated for design, enrollment period, primary endpoints, and presence of core limitations. The standard of care therapy was determined by evaluating the literature and published guidelines 1-year prior to start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. We then calculated the percentage of approvals based on clinical trials with any or all core limitations. Results: A total of 187 anti-cancer approvals were evaluated. The number of anti-cancer drug approvals doubled over time with 68 in first half of study period (June 2014 to December 2016) to 119 in second half of study period (January 2017 to July 2019). Of those, 125 (67%) were based on a clinical trial with at least one core limitation. 64 (34%) approvals were based on a single-arm clinical trial. Of the remaining 123 approvals based on randomized trials, 60 (32%) had a core limitation. Of all randomized trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a sub-optimal control, and 17 (14%) used crossover inappropriately. Conclusions: The majority of cancer drugs are approved based on clinical trials with core limitations. Efforts to minimize core limitations at the time of clinical trial design are essential to ensure that new anti-cancer drugs being marketed truly improve patient outcomes over current standards.
Molecular mechanism(s) of resistance to vandetanib in medullary thyroid carcinoma.
Authors: Brittany Glassberg, Sophia Khan, Alex Pemov, Robert Hawley, Brigitte C. Widemann, Javed Khan, John Glod
Journal: Journal of Clinical Oncology (2020)

e15628 Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C cells of the thyroid. Pediatric cases of this cancer are associated with the diagnosis of multiple endocrine neoplasia, which is caused by a mutation in the rearranged during transfection ( RET) gene. Vandetanib, an oral receptor tyrosine kinase inhibitor, is approved for the treatment of patients with progressive MTC. While there is a response rate of 50%, the majority of patients eventually develop resistant disease. The goal of this work is to understand genetic and epigenetic underpinnings of sensitivity and resistance to vandetanib, and develop novel synergistic combination therapies in medullary thyroid carcinoma. Methods: The TT cell line (RET mutation p.C634W) was cultured in increasing concentrations of vandetanib in order to generate a vandetanib resistant cell line. Both vandetanib-sensitive and vandetanib-resistant lines were evaluated. Each line underwent exome sequencing, RNA sequencing, and methylation array analysis. In parallel we performed Genome-wide CRISPR knock-out and CRISPR activation of both cell lines using the TKO Version 3 Library, consisting of 71,090 gRNAs targeting 18,000 genes, and the Calabrese P65-HSF activation Library, using 56,762 guides for 18,000 genes. Results: Both whole exome and RNA sequencing demonstrate increased expression of RET C634W in both cell lines, to a significantly greater extent in the drug-resistant line than in the sensitive line. RNA sequencing demonstrates differential expression of transcripts between the vandetanib-sensitive and vandetanib-resistant cell lines, including multidrug-resistance 1 (which confers drug resistance in other cancers) and autotaxin (promotes cell survival). Genome-wide CRISPR knock-out showed enrichment of genes necessary for growth suppression by vandetanib, including MACROD2, GORASP2, and MAP3K genes. Gene set enrichment analysis of the CRISPR knock-out data showed enrichment of the proteasome pathway as a potential candidate of growth suppression by vandetanib, which was validated via exposure of the cell lines to bortezomib (IC 50 = 3.62nM), a molecularly targeted proteasome-inhibitor. Conclusions: DNA mutations and epigenetic modification confer resistance of medullary thyroid carcinoma to tyrosine kinase inhibition. Adding further therapeutic agents to target these genetic alterations is a potential strategy for overcoming resistance.
Donor monocyte–derived macrophages promote human acute graft-versus-host disease
Authors: Laura Jardine, Urszula Cytlak, Merry Gunawan, Gary Reynolds, Kile Green, Xiao-Nong Wang, Sarah Pagan, Maharani Paramitha, Christopher A. Lamb, Anna K. Long, Erin Hurst, Smeera Nair, Graham H. Jackson, Amy Publicover, Venetia Bigley, Muzlifah Haniffa, A.J. Simpson, Matthew Collin
Journal: Journal of Clinical Investigation (2020)

Myelopoiesis is invariably present and contributes to pathology in animal models of graft-versus-host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties, and role in pathogenesis of these cells, we isolated single-cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome, and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and NanoString gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a keratinocyte cell line and mediated pathological damage to skin explants independently of T cells. Together, these results define the origin, functional properties, and potential pathogenic roles of human GVHD macrophages.
Research progress in doctor-patient joint decision making
Authors: Lina Wang, Chunyan Jiang
Journal: BMJ (2020)

In a modern society, with the development of economic status, people′s health consciousness is increasing as well, and the traditional medical model cannot meet the needs of health care. People-oriented medical care model represents the high-quality medical care, and the shared decision making as a new medical culture model, has been widely studied in recent years. This article summarizes the concept, significance, influencing factors and current situation of doctor-patient joint decision making at home and abroad, to provide reference for future study and clinical practice. It is hoped the doctor-patient joint decision making would be promoted in China and it would play a certain role in improvement of doctor-patient relationship.


Key words: 
Shared decision-making; Doctor-patient relationship; Progress
Arthroscopic drilling vs. micro-invasive surgery for the treatment of full-thickness chondral defects
Authors: De-bo Yue, Wan-shou Guo, Wei-guo Wang, Shao-hui Shi, Bai-liang Wang, Zi-rong Li
Journal: BMJ (2009)

This retrospective study was to compare the clinical effects of arthroscopie drilling with arthroscopic microfracture technology on full-thickness chondral defects in 68 patients treated between March 2003 and June 2005. The patients were followed up for an average of (20 ± 5 ) months. Lysholm score and Tegner scale were used to evaluate the efficacy. For the arthrescopic drilling group (n = 15 ) and the microfracture surgery group (n =27) , total effective rates were 12/15 and 85% (23/27), respectively. Our data suggest that those two methods provide simple and effective surgical procedure for the treatment of chondral defects of the knee; the results of arthroscopic microfracture were significantly better than arthroscopic drilling.

Key words: 
Knee joint;  Arthroscopy
Randomized phase II study of canakinumab (CAN) or pembrolizumab (PEM) as monotherapy or in combination as neoadjuvant therapy in patients (Pts) with surgically resected (Stage IB-IIIA) non-small cell lung cancer (NSCLC): CANOPY-N.
Authors: Tony S. K. Mok, Pilar Garrido Lopez, Edward S. Kim, Cagatay Arslan, Jean-Louis Pujol, Yuanbo Song, Cecile Blin, Vanessa Rodrik-Outmezguine, Bijoyesh Mookerjee, Vanessa Q. Passos, Jay M. Lee
Journal: Journal of Clinical Oncology (2020)

TPS9626 Background: Complete surgical resection is the standard treatment (tx) for pts with stage I-IIIA NSCLC. 5-year survival rates range from 19-50%, with most pts dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival (OS) by only 5% in pts with NSCLC, and new tx options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy has shown major pathologic responses (MPR) or pathologic complete responses (pCR) in pts with early stage NSCLC. CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with CAN (IL-1β inhibitor) versus placebo, in a dose-dependent manner for pts with atherosclerosis. In pre-clinical NSCLC humanized models, tx with CAN±anti PD-1 inhibitor could lead to anti-tumor activity. Combination of CAN and PEM is expected to enhance the efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in tumor microenvironment. Based on available evidence, CANOPY-N study was designed to evaluate effect of CAN and PEM as monotherapy or in combination as neoadjuvant tx for pts with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a phase II, randomized, open-label study evaluating effect of CAN or PEM monotherapy or in combination as neoadjuvant tx in resectable NSCLC pts. Histologically confirmed stage IB-IIIA, tx-naive, ECOG PS 0-1 NSCLC pts eligible for surgery and with a planned surgical resection in approximately 4-6 weeks (after 1 st dose of study tx), are eligible to participate. An archival (if obtained up to 6 months before 1 st day of tx) or new biopsy is required. Approximately 110 pts will be randomized in 2:2:1 ratio (stratified by histology [squamous/non-squamous]) to one of the tx arms to receive a total of 2 doses (200 mg Q3w) of CAN alone (n = 44) or in combination with PEM (n = 44) or PEM (n = 22) with safety follow-up up to 130 days from last study drug dose. Primary endpoint is to determine MPR rate (≤10% of residual viable tumor cells at time of surgery), secondary endpoints include determination of ORR, MPR rate based on local review, surgical feasibility rates, anti-drug antibodies incidence and PK parameters. Clinical trial information: NCT03968419 .
Prognostic and predictive effects of circulating and disseminated tumor cells in breast cancer: A National Cancer Database (NCDB) analysis.
Authors: Nadeem Bilani, Leah Elson, Rafael Arteta-Bulos, Elizabeth Blessing Elimimian, Hong Liang, Zeina A. Nahleh
Journal: Journal of Clinical Oncology (2020)

1029 Background: Alongside other biomarkers, circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) could contribute to our growing understanding of the breast cancer (BC) “liquid biopsy”. This study evaluated 1) clinicopathologic factors associated with CTCs and DTCs, 2) the prognostic value of CTCs and DTCs by disease stage, 3), the efficacy of chemotherapy by CTC and DTC status. Methods: We conducted a retrospective analysis of BC using the 2004-2016 National Cancer Database (NCDB). The NCDB defines CTCs as isolated tumor cells (ITCs) found in the blood (using assays such as reverse transcriptase polymerase chain reaction or immunohistochemistry) distant from the breast. DTCs are ITCs found in the bone marrow or other non-regional tissues. To evaluate variables associated with CTCs or DTCs, we used chi-squared and Wilcoxon rank-sum tests (univariate), followed by multivariate logistic regression. Consequently, we included CTC or DTC status in a multivariate, stage-by-stage Cox regression analysis for overall survival (OS). After adjusting for receptor status and staging, we used the Kaplan-Meier method to explore chemotherapy efficacy in CTC- or DTC-positive vs. CTC- or DTC-negative subsets. Results: 4,846 cases reported CTC-status, 1,454 (21.1%) of which were positive. 4,993 cases reported DTC-status, 1,400 (20.3%) of which were positive. Factors associated with positive CTC status were HER2-positivity, progesterone receptor-positivity, lobular histology and N-staging. Factors associated with positive DTC status were being White, HER2-positivity, lobular histology and N-staging. Positive CTC-status was associated with poor OS overall in late-stage (III and IV) (HR 1.477, 95% CI: 1.129-1.931, p = 0.004) but not early-stage BC (0, I, II) (p = 0.110) disease. DTC-status was not associated with OS in early-stage or late-stage subsets. In hormone receptor (HR)-positive disease, chemotherapy was associated with better OS when CTC-status was also positive both in early-stage (p = 0.003) and late-stage (p = 0.023) disease. In a subset of the same BC subtype with negative CTC-status, however, chemotherapy conferred no survival benefit (p = 0.638 for early-stage, p = 0.501 for late-stage). DTC status was not a significant predictor of chemotherapy efficacy in early or late-stage, HR+ disease. Conclusions: This study suggests that CTC-status is a stronger prognostic factor at later stages of BC; yet it can also help guide management of early-stage disease as it appears predictive for chemotherapy benefit.
Comparison of Nutritional Risk Screening-2002 and Subjective Global Assessment in nutritional assessment for patients with maintenance hemodialysis
Authors: Xiao-li Han
Journal: BMJ (2012)

The nutritional status of 162 patients with maintenance hemodialysis (MHD) was screened by Nutritional Risk Screening 2002 (NRS-2002) and assessed by Subjective Global Assessment (SGA) at the next day of admission.Among 150 MHD patients who met the study requirement,the nutritional risk was 29.3％ as screened with NRS-2002,and the rate of nutrition deficiency was 41.3％ with SGA assessment,there was no difference between two methods (x2 =18.155,P =0.109) ; According to BMI,the incidence of nutrition deficiencies,overweight and obesity in MHD patients was 13.3％,30.7％ and 29.3％.NRS-2002 and SGA are applicable to nutritional deficiencies assessment in MHD patients,but NRS-2002 is more comprehensive and feasible than SGA.

Key words: 
Malnutrition; Renal dialysis
The shift in therapies for the treatment of chronic lymphocytic leukemia (CLL) patients in the US Veterans Health Administration (VHA) from 2013-2018.
Authors: Zohra Nooruddin, Hannah Le, Daniel McHugh, Kellie Ryan, Xavier Jones, Obiageri O Obodozie-Ofoegbu, Chengwen Teng, Alyssa C Eaves, Christopher R Frei
Journal: Journal of Clinical Oncology (2020)

e19339 Background: The first novel agent for use in CLL was approved in 2014; however, the extent of novel agent uptake in the VHA is largely unknown. Objective: This study described the pharmacoepidemiology of three novel agents (ibrutinib, idelalisib, venetoclax), and traditional chemotherapies/chemoimmunotherapies (CT/CIT) in the VHA. Methods: This was a retrospective study of 26,879 adults with CLL in the VHA from 10/01/2013 to 5/31/2018. All were followed for at least 6 months. Data were extracted from the VHA electronic health record. Patients came from all 18 Veterans Integrated Service Networks, spanning all 50 states and US territories. Descriptive statistics were used to summarize baseline characteristics, CLL treatments, next therapies, and secondary complications. Results: A total of 3670 patients received at least one of 12 CLL therapies of interest. Patients had a median age of 69 years (47% were 65+ and 26% were 75+), a median age-adjusted Charlson comorbidity score of 6, and 6% had a history of exposure to Agent Orange. Ibrutinib accounted for 89% of the novel agent use. Ibrutinib use across all lines of therapy (LOTs) increased sevenfold over the study period (Table). Venetoclax (42%) and idelalisib (30%) were the most common therapies for the next LOT after ibrutinib. Across all LOTs, traditional CT/CIT use declined steadily over the study period. However, in fiscal year (FY) 2018, there were still 17% of patients receiving CT/CIT. Ibrutinib was the most common therapy for the next LOT in these patients (43–74%). Incidence of diffuse large B cell lymphoma post-index was 2–6 times higher in patients on CT/CIT than those on ibrutinib. Other secondary complications were similar between ibrutinib and CT/CIT. Conclusions: To our knowledge, this is the largest study looking at CLL treatment patterns among VHA patients in the real world. There has been a major shift in the treatment of CLL, with fast adoption of novel agents in the VHA from 2013 to 2018. The impact of this shift on healthcare resource use and cost burden in the VHA will need to be examined. [Table: see text]