tbuckley/cabot-search huggingface dataset:
Modified FOLFIRINOX versus sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced pancreatic adenocarcinoma: A real-world analysis.
Authors: Shun Tezuka, Makoto Ueno, Satoshi Kobayashi, Manabu Morimoto, Shuhei Nagashima, Yusuke Sano, Hiroyuki Asama, Kuniyuki Kawano, Satoshi Tanaka, Taito Fukushima
Journal: Journal of Clinical Oncology (2020)

711 Background: Therapy options for second-line treatment of advanced pancreatic adenocarcinoma (PDAC) are limited and preferred regimens have not been established. This study compared the efficacy and safety of modified FOLFIRINOX (mFFX) and sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced PDAC. Methods: This was a retrospective single-center analysis of all patients who received mFFX or sequential chemotherapy between December 2014 and May 2019 as second-line treatment for advanced PDAC. The sequential arm included all patients intended to be treated with sequential chemotherapy even if finished with either FOLFIRI or FOLFOX. For efficacy analysis, progression-free survival (PFS), overall survival (OS), and response rate (RR)of all the patients, excluding those with locally advanced pancreatic cancer (LAPC), were evaluated. For safety analysis, we evaluated the incidence of grade ≥3 adverse events in all the patients. Results: Seventy-four patients (mFFX 44; sequential 30) were included.The patients characteristics (mFFX/sequential) are as follows:median age 64/67 years, performance status (ECOG) 0 50%/53%, and LAPC 16%/13%. In contrast to sequential therapy, the mFFX group showed better OS and RR. However, there was no significant difference between mFFX and sequential therapy in PFS (median 4.4 [95% confidence interval (CI) 1.8-7.9] vs. 4.6 [95% CI 2.0-6.2] months; hazard ratio [HR] 0.88 [95% CI 0.51-1.56]; p = 0.657), OS (median 10.6 [95% CI 5.9-13.8] vs. 8.5 [95% CI 5.0-12.2] months; HR 0.71 [95% CI 0.37-1.41]; p = 0.318), and RR (8.1% vs. 3.8%; odds ratio 1.94 [95% CI 0.19-19.87]; p = 1.000). In the safety analysis, grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 36.4%, 6.8%, and 16.0%, respectively, with mFFX and 0%, 0% and 3.3%, respectively, with sequential chemotherapy. Conclusions: Whereas certain trends were observed, there were no significant differences in efficacy between mFFX and sequential chemotherapy. Considering the incidence of grade ≥3 adverse events with mFFX, sequential chemotherapy could be considered as one of the second-line treatment options for advanced PDAC.
Association of socioeconomic disparities with underutilization of palliative care in patients with metastatic foregut cancer.
Authors: Michelle Ju, Matthew R. Porembka
Journal: Journal of Clinical Oncology (2020)

502 Background: Metastatic foregut cancers (MFC) are frequently associated with debilitating symptoms that have significant negative impact on patients’ quality of life. Palliative care (PC) is effective in mitigating disease-, psychosocial-, and treatment-related effects. However, PC remains heavily underutilized. The aim of our study was to characterize the rate of PC utilization in MFC and determine the impact of various clinicopathologic and socioeconomic factors associated with the receipt of PC. Methods: We conducted a retrospective review of 277,957 National Cancer Database patients diagnosed with MFC between 2004-2013. Chi-squared tests were used to analyze differences between groups. Logistic regression was performed to assess the impact of factors on the likelihood of receiving PC. Results: PC utilization increased among all groups over time (12.3% 2004-2006 vs. 14.7% 2007-2010 vs. 16.4% 2011-2013 for all cancers). Female sex, Medicaid, median income &lt; $46,000/year, higher education level, higher Charlson/Deyo Score, and pancreatic or biliary cancers were associated with increased likelihood of PC interventions. Additionally, patients treated at an academic center or integrated network cancer program were more likely to receive PC than patients treated in the community setting. When receipt of PC was stratified by race, Hispanics were significantly less likely to have undergone palliative interventions compared to non-Hispanic Whites (OR 0.70, 95% CI 0.66-0.73). Patients with Medicare or private insurance were less likely to receive PC than uninsured patients (OR 0.92, 95% CI 0.87-0.97 and 0.81, 95% CI 0.77-0.89, respectively). Conclusions: Differences in palliative care receipt rates exist with regards to racial/ethnic and socioeconomic factors such as insurance status, median household income, and education level. Patients receiving care in the community setting were also less likely to receive palliative care than those treated at academic or integrated network cancer program centers. Further studies are needed to delineate why these disparities exist with regards to palliative care utilization.
PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: a first-in-human, randomised, double-blind, placebo-controlled study
Authors: Sodiomon B Sirima, Laura Richert, Arnaud Chêne, Amadou T Konate, Cécilia Campion, Sébastien Dechavanne, Jean-Philippe Semblat, Nadine Benhamouda, Mathilde Bahuaud, Pierre Loulergue, Alphonse Ouédraogo, Issa Nébié, Moïse Kabore, Désiré Kargougou, Aïssata Barry, San Maurice Ouattara, Valérie Boilet, Florence Allais, Gwenaelle Roguet, Nicolas Havelange, Elvira Lopez-Perez, Alexis Kuppers, Eleine Konaté, Caroline Roussillon, Myriam Kanté, Linda Belarbi, Amidou Diarra, Noelie Henry, Issiaka Soulama, Amidou Ouédraogo, Helene Esperou, Odile Leroy, Frederic Batteux, Eric Tartour, Nicola K Viebig, Rodolphe Thiebaut, Odile Launay, Benoît Gamain
Journal: The Lancet Infectious Diseases (2020)
Young-onset pancreas cancer (PC) in patients less than or equal to 50 years old at Memorial Sloan Kettering (MSK): Descriptors, genomics, and outcomes.
Authors: Anna M. Varghese, Isha Singh, Ritu Raj Singh, Marinela Capanu, Joanne F. Chou, Winston Wong, Zsofia Kinga Stadler, Erin E. Salo-Mullen, Christine A Iacobuzio-Donahue, David Paul Kelsen, Wungki Park, Kenneth H. Yu, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2020)

774 Background: For individuals ≤ 50 years old, cancer incidence is increasing, particularly gastrointestinal and obesity related cancers (Sung, Lancet Public Health 2019). Limited details are known about young onset PC. Herein, we report the epidemiologic, pathologic, and molecular characteristics of PC in patients (pts) ≤ 50 years. Methods: MSK institutional database was queried for medical and treatment history, genomics, and outcomes in pts ≤ 50 years old diagnosed with PC between January 2008 and July 2018. Neuroendocrine cancers were excluded. Overall survival (OS) from date of PC diagnosis was estimated using Kaplan-Meier methods. Results: N = 450 pts ≤ 50 years old with a diagnosis of PC were identified. Ninety-six percent had adenocarcinoma, and 4% had acinar cell carcinoma/other histologies. Table summarizes demographics. Median OS was 16 months in the entire cohort and 11.3 months in stage IV disease. For N = 236 pts diagnosed after 2014, 119 (50%) underwent successful somatic testing with at least one alteration identified, and 21/119 tumors were RAS wild-type with identification of several actionable alterations (NRG1 fusions (n=2), NTRK fusions (n=2), IDH1 R132C (n=1), and microsatellite unstable tumors (n=1) ). N = 114 pts had germline testing (routine after 2015), and 33/114 (29%) had pathologic germline alterations, including BRCA1/2 (n=18), CHEK2 (n=3), PALB2 (n=3), ATM (n=2), MLH1 (n=1), and MSH3 (n=1). Conclusions: Pathogenic germline alterations are present in a substantial percentage of pts with young onset PC, and actionable somatic alterations were seen frequently in the subgroup of young onset PC RAS-wild type tumors. These observations underpin the need for germline and somatic profiling in PC. [Table: see text]
Declining Use of Primary Care Among Commercially Insured Adults in the United States, 2008–2016
Authors: Ishani Ganguli, Zhuo Shi, E. John Orav, Aarti Rao, Kristin N. Ray, Ateev Mehrotra
Journal: Annals of Internal Medicine (2020)

Primary care is known to improve outcomes and lower health care costs, prompting recent U.S. policy efforts to expand its role. Nonetheless, there is early evidence of a decline in per capita primary care visit rates, and little is understood about what is contributing to the decline.To describe primary care provider (PCP) visit trends among adults enrolled with a large, national, commercial insurer and assess factors underlying a potential decline in PCP visits.Descriptive repeated cross-sectional study using 100% deidentified claims data from the insurer, 2008-2016. A 5% claims sample was used for Poisson regression models to quantify visit trends.National, population-based.Adult health plan members aged 18 to 64 years.PCP visit rates per 100 member-years.In total, 142 million primary care visits among 94 million member-years were examined. Visits to PCPs declined by 24.2%, from 169.5 to 134.3 visits per 100 member-years, while the proportion of adults with no PCP visits in a given year rose from 38.1% to 46.4%. Rates of visits addressing low-acuity conditions decreased by 47.7% (95% CI, -48.1% to -47.3%). The decline was largest among the youngest adults (-27.6% [CI, -28.2% to -27.1%]), those without chronic conditions (-26.4% [CI, -26.7% to -26.1%]), and those living in the lowest-income areas (-31.4% [CI, -31.8% to -30.9%]). Out-of-pocket cost per problem-based visit rose by $9.4 (31.5%). Visit rates to specialists remained stable (-0.08% [CI, -0.56% to 0.40%]), and visits to alternative venues, such as urgent care clinics, increased by 46.9% (CI, 45.8% to 48.1%).Data were limited to a single commercial insurer and did not capture nonbilled clinician-patient interactions.Commercially insured adults have been visiting PCPs less often, and nearly one half had no PCP visits in a given year by 2016. Our results suggest that this decline may be explained by decreased real or perceived visit needs, financial deterrents, and use of alternative sources of care.None.
Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia
Authors: Hui Wei, Ying Wang, Robert Peter Gale, Dong Lin, Chunlin Zhou, Bingcheng Liu, Shaowei Qiu, Runxia Gu, Yan Li, Xingli Zhao, Shuning Wei, Benfa Gong, Kaiqi Liu, Xiaoyuan Gong, Yuntao Liu, Guangji Zhang, Zhen Song, Yang Wang, Wei Li, Yingchang Mi, Jianxiang Wang
Journal: Clinical Cancer Research (2020)

Cytarabine, 100-200 mg/mE+2/day, is commonly used in induction therapy of acute myelogenous leukemia (AML). Whether a higher dose of cytarabine would be more effective is unknown. Also, there is controversy whether high-dose cytarabine is better than an intermediate-dose combined with other drugs for post-remission therapy. In this open-label, randomized controlled, parallel group study, roles of intermediate-dose cytarabine were investigated.Subjects with AML age 15-55 years were randomized to receive daunorubicin, omacetaxine mepesuccinate, and conventional- or intermediate-dose cytarabine. Subjects achieving complete remission were randomized to receive 3 courses of high-dose cytarabine or 2 courses of intermediate-dose cytarabine with daunorubicin in the 1st and mitoxantrone in the 2nd course. The primary endpoint was disease-free survival (DFS).591 subjects were randomized to intermediate- (N = 295) or conventional-dose (N = 296) cytarabine group. Three-year DFSs were 67% [95% confidence interval (CI), 61-73] in the intermediate-dose cohort compared with 54% (95% CI, 48-61) in the conventional-dose cohort [Hazard Ratio (HR), 0.67; 95%CI, 0.51-0.89; P = 0.005). Three-year survivals were 68% (95%CI, 63-74) and 59% (95%CI, 53-65; HR, 0.720; 95%CI, 0.56-0.94; P = 0.014). Two courses of intermediate-dose cytarabine with daunorubicin or mitoxantrone resulted in similar DFS and survival as three courses of high-dose cytarabine when used for post-remission therapy.Induction therapy with intermediate-dose cytarabine with daunorubicin and omacetaxine mepesuccinate increases DFS and survival in persons with AML ages 15-55 years compared with conventional-dose cytarabine.See related commentary by Watts and Bradley, p. 3073.
Regulation of gene expression by DNA methylation with cytotoxic T lymphocytes evaluation in consensus molecular subtypes of colorectal cancer.
Authors: Yuanyuan Shen, Justin Hummel, Isabel Cristina Trindade, Christos Papageorgiou, Chi-Ren Shyu, Jonathan B. Mitchem
Journal: Journal of Clinical Oncology (2020)

25 Background: Low cytotoxic T lymphocyte (CTLs) infiltration in colorectal cancer (CRC) tumors is a challenge to treatment with immune checkpoint inhibitors. Consensus molecular subtypes (CMS) classify patients based on tumor attributes, and CMS1 patients include the majority of patients with high CTL infiltration and “inflamed” tumors. Epigenetic modification plays a critical role in gene expression and therapy resistance. Therefore, in this study we compared DNA methylation, gene expression, and CTL infiltration of CMS1 patients to other CMS groups to determine targets for improving immunotherapy in CRC. Methods: RNA-seq (n = 511) and DNA methylation (n = 316) from The Cancer Genome Atlas databases were used to determine gene expression and methylation profiles based on CMSs. CMS1 was used as a reference and compared to other subtypes (CMS2-4). Microenvironment Cell Populations- counter (MCPcounter) was used to determine tumor CTL infiltration. Genes with significantly different expression (p &lt; 0.01, LogFC≥|1.5|) and difference of mean methylation β value ≥|0.25| were integrated for Pearson correlation coefficient analysis with MCPcounter score (r &gt; |0.7|). Results: Comparing CMS1 and CMS2, ARHGAP9, TBX21, and LAG3 were differentially methylated and correlated with CTL scores. ARHGAP9 and TBX21 were decreased and hypomethylated in CMS2. Comparing CMS1 and CMS3, ARHGAP9, TBX21, FMNL1, HLA-DPB1, and STX11 were downregulated in CMS3 and highly correlated with CTL scores. ARHGAP9, FMNL1, HLA-DPB1, and STX11 were hypomethylated in CMS3 and TBX21 was methylated in both, but had a higher methylation ratio in CMS1. Comparing CMS1 and CMS4, TBX21 was the only gene downregulated, hypomethylated, and highly correlated with CTL scores in CMS4 patients. Conclusions: We found six genes differentially expressed, differentially methylated, and highly correlated with CTL infiltration when comparing CMS1 to other CMS groups. Specifically, TBX21 was the only gene highly correlated with CTL scores with differential gene expression and methylation in CMS2-4 when compared to CMS1. Thus, T-bet may be a critical regulator of T cell responses in CRC.
Integrating multiple “omics” analyses, on a triage concept, for effective case selection followed by diagnostic colonoscopy.
Authors: Sheeno P. Thyparambil, Jin You, Kang Liu, Hui Sun, Junjie Peng, Sanjun Cai, Yaqi Li, Pingping Bao, Qing Li, Yani Zhang, Zheng Li, Jingzhi Yang, Ziyu Yin, Xiaoming Yao, Xiurui Zhu, Shiying Hao, Robert Heaton, James Schilling, Karl G. Sylvester, Xuefeng B. Ling
Journal: Journal of Clinical Oncology (2020)

244 Background: Implementation of population screening for colorectal cancer (CRC) before colonoscopy can reduce the challenge of the overall capacity of bowel examination and improve survival. Blood based CRC assessment biomarkers, on a triage concept, can lead to improved selection to colonoscopy and cost-effective CRC care. Methods: Innovative multi-omics approaches, with global and targeted LCMS data production (metabolomics, lipidomics, and 2D proteomics) and integrative data analytics, were applied to discover serological biomarkers to assess nonadvanced adenoma and identify stage I/II colorectal bowel lesions. A cohort of 2396 normal, 660 adenoma, 953 stage I, and 101 stage II blood samples, was constructed to discover screening biomarkers to support case finding of patients at high risk for nonadvanced adenoma and stage I/II cancer for subsequent diagnostic colonoscopy. Results: A three-analyte mProbe panel was constructed which outperformed the commercial assays of plasma methylated septin 9 and fecal Cologuard tests. Sensitivity: (1) nonadvanced adenoma–Cologuard 17.2%, mProbe 76.0%; (2) stage I-III-Cologuard 93.3%, stage I-II Septin 9 (ARUP laboratories) 77%, stage I-II mProbe: 92.3%. Specificity–Cologuard 89.8%, Septin 9 (ARUP laboratories) 88%, mProbe 90.7%. Conclusions: mProbe triage concept of a blood-based protein biomarker panel promises the precision to allow future CRC screening, and reduce the low-risk utilization of unnecessary, unpleasant and risk-associated bowel examinations.
Correlation of heart dose with lymphopenia in esophageal cancer patients treated with chemoradiation.
Authors: Amber Post, Stephen R. Bowen, Bao-Ngoc Nguyen, William Logan, Jing Zeng, Smith Apisarnthanarax
Journal: Journal of Clinical Oncology (2020)

346 Background: Lymphopenia has been associated with survival and disease progression in esophageal cancer patients treated with chemoradiation (cRT). We previously published on our posterior-only proton therapy approach that maximally spares the heart and lungs, but at the cost of increased dose to the bone marrow in the vertebral bodies (VBs). We assessed hematologic toxicity in proton (PT) and IMRT treated patients and studied dosimetric parameters associated with hematologic toxicity. Methods: 35 patients treated with PT and 46 patients treated with IMRT for esophageal cancer between 2011-2018 were analyzed. Most patients were treated concurrently with carboplatin/paclitaxel to a median dose of 50.4 Gy. Lymphocyte, neutrophil and total leukocyte values while under treatment were recorded and graded per the CTCAE v4.03 toxicity scale, and the neutrophil-to-lymphocyte ratio (NLR) was computed. Mean dose and volumes (cc) receiving 5-50 Gy were calculated for the heart and VBs. A receiver-operator characteristic analysis was performed for univariate correlation between incidence of grade ≥3 hematotoxicity and dose-volume parameters. Results: Median follow-up was 36.1 months for all patients and the overall survival at 3 years was 57.5%. The rates of grade 3 or 4 hematologic toxicity in the PT group were 37.1% (leukopenia), 22.9% (neutropenia), and 80.0% (lymphopenia) versus 41.3%, 15.2% and 87.2%, respectively, for IMRT patients. There was a significant correlation between grade 4 lymphopenia and the heart V5, V10 and V20, but no significant correlation between VB doses with any hematotoxicity. Median NLR values and heart dose were higher in the IMRT group (9.17 vs 3.86 with PT, p = 0.0048; 10.5 vs 23.5Gy, p&lt; 0.0001, respectively). There was a correlation between survival and NLR with a hazard ratio of 1.025 (CI 1.006 - 1.044). Conclusions: Low doses to the heart mediate severe lymphopenia in esophageal cancer patients treated with cRT. These data confirm the safety of the posterior-only proton approach without concern for increased hematologic toxicity despite higher vertebral body doses compared to IMRT. They also suggest that the blood pool is more important as a source of severe lymphopenia.
HucMSC-Derived Exosomes Mitigate the Age-Related Retardation of Fertility in Female Mice
Authors: Weijie Yang, Jing Zhang, Boqun Xu, Yuanlin He, Wei Liu, Jiazhao Li, Songying Zhang, Xiaona Lin, Dongming Su, Tinghe Wu, Jing Li
Journal: Molecular Therapy (2020)

In mammals, resting primordial follicles serve as the ovarian reserve. The decline in ovarian function with aging is characterized by a gradual decrease in both the quantity and quality of the oocytes residing within the primordial follicles. Many reports show that mesenchymal stem cells have the ability to recover ovarian function in premature ovarian insufficiency (POI) or natural aging animal models; however, the underlying mechanism remains unclear. In this study, using exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-exos), we found the specific accumulation of exosomes in primordial oocytes. The stimulating effects of exosomes on primordial follicles were manifested as the activation of the oocyte phosphatidylinositol 3-kinase (PI3K)/mTOR signaling pathway and the acceleration of follicular development after kidney capsule transplantation. Further analysis revealed the stimulatory effects of HucMSC-exos on primordial follicles were through carrying functional microRNAs, such as miR-146a-5p or miR-21-5p. In aged female mice, the intrabursal injection of HucMSC-exos demonstrated the recovery of decreased fertility with increased oocyte production and improved oocyte quality. Although assisted reproductive technologies have been widely used to treat infertility, their overall success rates remain low, especially for women in advanced maternal age. We propose HucMSC-exos as a new approach to mitigate the age-related retardation of fertility in women.
A TR3 peptide-based high throughput fluorescence polarization screen for small molecule Bcl-B inhibitors.
Authors: Kenneth Yip, Dayong Zhai, Paulo Godoi, Xochella Garcia, Michael Cuddy, Motti Gerlic, Eduard Sergienko, John Reed
Journal: Cancer Research (2008)

1270  Background/Purpose: TR3 (NR4A1; HMR; NP10; GFRP1; NAK1; NUR77; NGFIB) is an orphan member of the steroid/thyroid/retinoid nuclear receptor superfamily that translocates from cellular nuclei to mitochondria. At mitochondria, TR3 converts several anti-apoptotic Bcl-2 family members (Bcl-B, Bcl-2, Bfl-1) into pro-apoptotic proteins. A poly-arginine-linked 9-mer peptide (TR3-r8) derived from the full length TR3 protein recapitulates TR3’s Bcl-2 family binding selectivity; Bcl-B, which is over-expressed in multiple myeloma and several other types of malignancy, is bound with the highest affinity. The purpose of our work was to utilize TR3-r8 to screen for novel small molecule inhibitors of Bcl-B and other anti-apoptotic Bcl-2-family proteins.  Experimental Procedures: We optimized a fluorescence polarization assay using FITC-labeled TR3-r8 (FITC-TR3-r8) and GST-labeled Bcl-B (with its transmembrane domain deleted; GST-Bcl-B-ΔTM). TR3-r8 was able to displace FITC-TR3-r8 from GST-Bcl-B-ΔTM, thus serving as a positive control for high throughput screening (HTS).  Observations: Approximately 50,000 Chembridge library compounds were screened at 3.75 mg/L, yielding 332 primary hits showing >50% FITC-TR3-r8 displacement. Of these, 145 were reproducible, representing a confirmed hit rate of 0.29%. After dose-response analyses and counter-screening with an unrelated FITC-based fluorescence polarization assay (FITC-ATP and GST-Hsp70), 6 potential compounds remained. Using 1D-NMR, 3 compounds were found to bind to Bcl-B, but not to GST. Interestingly, 1 compound was not able to displace FITC-labeled BH3-peptides from Bcl-B or Bcl-2, indicating that a TR3-based screen might identify potential non-canonical Bcl-2-family inhibitors. Further experiments in Bcl-B-overexpressing (vs. control) HeLa cells found that this compound induced cell death in a Bcl-B-dependent manner.  Conclusions: A Bcl-B inhibitor has been identified using a novel TR3-based screen.
Magnetic resonance imaging of pulmonary arterial compliance after pulmonary endarterectomy
Authors: Stefano Ghio, Gabriele Crimi, Stefania Guida, Adele Valentini, Anna Celentano, Maurizio Pin, Claudia Raineri, Annalisa Turco, Laura Scelsi, Luigi Oltrona Visconti, Robert Naeije, Andrea Maria D'Armini
Journal: European Respiratory Journal (2020)

<b>In CTEPH patients who have undergone pulmonary endarterectomy, exercise capacity is better associated with changes in invasively measured pulmonary arterial compliance than with changes in magnetic resonance imaging of pulmonary artery stiffness</b>http://bit.ly/30DAWUj