tbuckley/cabot-search huggingface dataset:
4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma
Authors: Hyung‐Don Kim, Seongyeol Park, Seongju Jeong, Yong Joon Lee, Hoyoung Lee, Chang Gon Kim, Kyung Hwan Kim, Seung‐Mo Hong, Jung‐Yun Lee, Sunghoon Kim, Hong Kwan Kim, Byung Soh Min, Jong Hee Chang, Young Seok Ju, Eui‐Cheol Shin, Gi‐Won Song, Shin Hwang, Su‐Hyung Park
Journal: Hepatology (2019)

Background and Aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8 + T cells (CD8 + tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8 + TILs in hepatocellular carcinoma (HCC). Approach and Results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8 + TILs. 4‐1BB expression was almost exclusively detected on CD8 + T cells in the tumor—especially on programmed death 1 (PD‐1) high cells and not PD‐1 int and PD‐1 neg cells. Compared to PD‐1 int and 4‐1BB neg PD‐1 high CD8 + TILs, 4‐1BB pos PD‐1 high CD8 + TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BB pos cells among CD8 + TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1 high CD8 + TILs, 4‐1BB pos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8 + TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8 + TILs, especially in cases showing high levels of T‐cell activation. Conclusion 4‐1BB expression on CD8 + TILs represents a distinct activation state among highly exhausted CD8 + T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.
Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer
Authors: Luca Lazzari, Giorgio Corti, Gabriele Picco, Claudio Isella, Monica Montone, Pamela Arcella, Erika Durinikova, Eugenia R. Zanella, Luca Novara, Fabiane Barbosa, Andrea Cassingena, Carlotta Cancelliere, Enzo Medico, Andrea Sartore-Bianchi, Salvatore Siena, Mathew J. Garnett, Andrea Bertotti, Livio Trusolino, Federica Di Nicolantonio, Michael Linnebacher, Alberto Bardelli, Sabrina Arena
Journal: Clinical Cancer Research (2019)

Patient-derived xenograft (PDX) models accurately recapitulate the tumor of origin in terms of histopathology, genomic landscape, and therapeutic response, but some limitations due to costs associated with their maintenance and restricted amenability for large-scale screenings still exist. To overcome these issues, we established a platform of 2D cell lines (xeno-cell lines, XL), derived from PDXs of colorectal cancer with matched patient germline gDNA available.Whole-exome and transcriptome sequencing analyses were performed. Biomarkers of response and resistance to anti-HER therapy were annotated. Dependency on the WRN helicase gene was assessed in MSS, MSI-H, and MSI-like XLs using a reverse genetics functional approach.XLs recapitulated the entire spectrum of colorectal cancer transcriptional subtypes. Exome and RNA-seq analyses delineated several molecular biomarkers of response and resistance to EGFR and HER2 blockade. Genotype-driven responses observed in vitro in XLs were confirmed in vivo in the matched PDXs. MSI-H models were dependent upon WRN gene expression, while loss of WRN did not affect MSS XLs growth. Interestingly, one MSS XL with transcriptional MSI-like traits was sensitive to WRN depletion.The XL platform represents a preclinical tool for functional gene validation and proof-of-concept studies to identify novel druggable vulnerabilities in colorectal cancer.
Genetic Risk Scores for Diabetes Diagnosis and Precision Medicine
Authors: Miriam S Udler, Mark I McCarthy, Jose C Florez, Anubha Mahajan
Journal: Endocrine Reviews (2019)

Abstract During the last decade, there have been substantial advances in the identification and characterization of DNA sequence variants associated with individual predisposition to type 1 and type 2 diabetes. As well as providing insights into the molecular, cellular, and physiological mechanisms involved in disease pathogenesis, these risk variants, when combined into a polygenic score, capture information on individual patterns of disease predisposition that have the potential to influence clinical management. In this review, we describe the various opportunities that polygenic scores provide: to predict diabetes risk, to support differential diagnosis, and to understand phenotypic and clinical heterogeneity. We also describe the challenges that will need to be overcome if this potential is to be fully realized.
Renal safety of sustained pemetrexed (P)/platinum treatment for advanced malignant mesothelioma (MM)
Authors: M. Karthaus, K. Hornych, U. Wiegand, N. Pfeil, F. Baysal, M. Trapp, K. Tagizadeh
Journal: Journal of Clinical Oncology (2007)

18106 Background: MM is a very rare and aggressive neoplasm with a short life expectancy. Standard care of MM is P + cisplatinum (DDP). The optimal duration of chemotherapy(ctx) for MM is undetermined. The feasibility of maintenance with P/DDP has not been reported. A major obstacle to sustained P/DDP for MM is renal safety beside neurotoxicity. At present, there are no data regarding renal safety in pts receiving ≥ 6 cycles of P/DDP in MM. Methods: We evaluated long term renal function of P(500 mg/m2)/DDP(75 mg/m2) for MM prospectively. Ctx on d1 was repeated on d22 until disease progression or toxicity. Pts with impairment of renal function (creatinine-clearance &lt;60 ml/min) switched to P/carboplatin (CP) AUC 5 for further ctx. P ctx was stopped if creatinine-clearance (CrCl) &lt;45 ml/min. Routine folinic acid and vitamine B12 was administered to prevent AE. Study endpoint was long term renal function for sustained therapy of P/DDP followed by P/CP and/or P-mono. Results: Between 12/02 and 05/06 86 consecutive MM pts were treated. Staging revealed peritoneal MM in 19, and pleural MM in 67 pts. Five pts did not receive ctx. First-line ctx was P/DDP in 66 pts (prior s-crea 0.85; SD 0.17) given a mean of 4.9 cyles (range 1–11) for a mean of 120 d (21–397 d) and a mean of 138 mg DDP/cycle. 28 pts received CP/P sequentially for further maintenance up to 27 cycles (mean 6.4). A change from P/DDP to P/CP was necessary due to a worsening renal function in all of those pts. Mean s-crea/CrCl prior to DDP ctx in those pts was 0.87 mg/dl (SD 0.17)/96.0 ml/min (SD 26) and 1.01 mg/dl (SD 0.29)/73.4 ml/min (SD 22) at the end of P/DDP. Mean given CP dose was 425 mg/cycle (range 175 - 725 mg). Pts subsequently receiving P/CP had a s-crea of 1.16 mg/dl (CrCl 73.4 ml/min) prior to ctx that did not change during P/CP (1.13 mg/dl/CrCl 73.2 ml/min). 13 pts received P- mono with a mean of 8 cycles (1–26) subsequently. Renal function showed a s-crea(CrCl) of 1.13 mg/dl (71.2 ml/min) prior and 1.11 mg/dl (70.8 ml/min) at the end of P ctx. Conclusions: Long term maintenance P/DDP of MM is limited by renal impairment due to DDP, while subsequent P/CP or P-mono was feasible and not associated with further deterioration of renal function. Further trials with sustained P/CP or P ctx for MM are warranted to evaluate the efficacy of maintenance for advanced MM. No significant financial relationships to disclose.
Improving the Assessment of Screen Exposure in Children
Authors: Kieran Jian Peng Chen, Eri Fujitake, Roshni Vinda
Journal: JAMA Pediatrics (2019)

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HDR brachytherapy combined with hypofractionated EBRT for intermediate-high risk prostate cancer
Authors: T. Akimoto, K. Hiroyuki, K. Shirai, K. Harada, T. Ebara, K. Ito, T. Yamamoto, T. Nakano
Journal: Journal of Clinical Oncology (2006)

14655 Background: To report on biochemical outcome and late complication in pts with localized prostate cancer (LPC) treated with HDR-brachytherapy (HDR-BT) combined with hypofractionated EBRT. Methods: From 06/2000 to 12/2004, 108 pts with intermediate (37 pts.) or high-risk (63 pts.) LPC were treated with hypofractionated EBRT (3 Gy × 17 fr., thrice a week) followed by HDR-BT (5 Gy × 5; 9 pts, 7 Gy × 3; 15 pts, 9 Gy × 2; 76 pts). HDR-BT was administered a week after the completion of the hypofractionated EBRT. The planning target volume was defined as the prostate gland with a 5-mm margin all around, and the planning was conducted based on CT images. Biologically effective doses (BED) to the prostate was between 83–84 Gy. All patient received androgen ablation. Acute and late toxicities were scored according to the EORTC/RTOG morbidity grading scales. Median follow-up duration was 27 months from HDR-BT and 39 months from initiation of androgen ablation. Results: All pts completed treatment. The 5-year actuarial PSA relapse-free survival rates for intermediate and high-risk pts were 100% and 93% respectively. Acute genitourinary (GU) toxicity was 64% in grade 0–1, 31% in grade 2 and 6% in grade 3. Urethral stricture developed in 3%, with a median time from the completion of HDR brachytherapy to the occurrence of 22 months (19–26 months). Ten pts had grade 2 rectal bleeding, with a median time from the completion of HDR brachytherapy to the occurrence of 11 months (7–14 months). No pts developed grade 3 or more severe rectal complication. The incidence of acute and late toxicity did not differ according to the fractionation schema of HDR-BT. Conclusion: Our data demonstrate the successful feasibility of HDR-BT combined with hypofractionated EBRT as a safe method for escalating the total dose to the prostate without significant increasing risk of acute and late GU and rectal toxicities. No significant financial relationships to disclose.
Abstract #2552: Hsa-miR-122, a tumor suppressor microRNA that regulates intra-hepatic metastasis of hepatocellular carcinoma
Authors: Ann-Ping Tsou, Wei-Chih Tsai, Wei-Che Hsu, Hsien-Da Huang, Gar-Yang Chau, Tsung-Ching Lai, Michael Hsiao Hsiao
Journal: Cancer Research (2009)

MicroRNAs (miRNAs), inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. In this study, we show that liver-specific hsa-miR-122 (miR-122) is significantly downregulated in liver cancers with intra-hepatic metastastasis and negatively regulates tumorigenesis. Restoration of miR-122 in metastatic Mahlavu and SK-Hep1 cells significantly reduced invitro migration, invasion and anchorage-independent growth as well as invivo tumorigenesis, angiogenesis and intra-hepatic metastasis in an orthotopic liver cancer model. Since an inverse expression pattern is often present between a miRNA and its target genes, we used a computational approach and identified multiple miR-122 candidate target genes from two independent expression microarray datasets. Thirty-two target genes were empirically verified and this group of genes was enriched with genes regulating cell movement, cell morphology, cell-cell signaling and transcription. We further showed that one of the miR-122 targets, ADAM17 (a disintegrin and metalloprotease 17) is involved in metastasis. Silencing of ADAM17 resulted in a dramatic reduction of invitro migration, invasion, in vivo tumorigenesis, angiogenesis and local invasion in the livers of nude mice, which is similar to that which occurs with the restoration of miR-122. Our study suggests that miR-122, a tumor suppressor microRNA affecting HCC intra-hepatic metastasis by angiogenesis suppression, exerts some of its action via regulation of ADAM17. Restoration of miR-122 has a far-reaching effect on the cell. Using the concomitant down-regulation of its targets, including ADAM17, a rational therapeutic strategy based on miR-122 may prove to be beneficial for HCC patients.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2552.
Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice
Authors: Ying Zhou, Bingning Dong, Kang Ho Kim, Sungwoo Choi, Zhen Sun, Nan Wu, Yifan Wu, Jessica Scott, David D. Moore
Journal: Hepatology (2019)

Hepatic endoplasmic reticulum (ER) stress, whether triggered by intrinsic or extrinsic factors, can be resolved by the unfolded protein response (UPR). Sustained UPR activation leads to cell death and inflammatory response and contributes to liver disease progression. Hepatic tissue macrophages are key players in orchestrating liver inflammation, and ER stress can enhance macrophage activation. However, it is not well defined how the interplay between ER stress and inflammation is regulated during hepatic stress response.Here we demonstrate that vitamin D receptor (VDR) activation mitigates hepatic ER stress response, whereas VDR knockout mice undergo persistent UPR activation and apoptosis in response to chemical ER stress inducer. Moreover, VDR deficiency promotes hepatic macrophage infiltration and increases gene expression and systematic levels of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor α. VDR expression is induced in hepatic macrophages by ER stress, and VDR plays a dual regulatory role in macrophages by protecting against ER stress and promoting anti-inflammatory polarization. Co-culture with VDR-activated bone marrow-derived macrophages suppresses UPR target genes in primary hepatocytes treated with ER stress inducers. Thus, the immunomodulatory functions of VDR in macrophages are critical in hepatic ER stress resolution in mice.VDR signaling in macrophages regulates a shift between proinflammatory and anti-inflammatory activation during ER stress-induced inflammation to promote hepatic ER stress resolution.
Screening and Stepped Care Targeting Psychological Distress in Patients With Metastatic Colorectal Cancer: The TES Cluster Randomized Trial
Authors: Claudia S.E.W. Schuurhuizen, Annemarie M.J. Braamse, Aartjan T.F. Beekman, Pim Cuijpers, Mecheline H.M. van der Linden, Adriaan W. Hoogendoorn, Hans Berkhof, Dirkje W. Sommeijer, Vera Lustig, Suzan Vrijaldenhoven, Haiko J. Bloemendal, Cees J. van Groeningen, Annette A. van Zweeden, Maurice J.D.L. van der Vorst, Ron Rietbroek, Cathrien S. Tromp-van Driel, Machteld N.W. Wymenga, Peter W. van der Linden, Aart Beeker, Marco B. Polee, Erdogan Batman, Maartje Los, Aart van Bochove, Jan A.C. Brakenhoff, Inge R.H.M. Konings, Henk M.W. Verheul, Joost Dekker
Journal: Journal of the National Comprehensive Cancer Network (2019)

This study evaluated the effectiveness of a screening and stepped care program (the TES program) in reducing psychological distress compared with care as usual (CAU) in patients with metastatic colorectal cancer starting with first-line systemic palliative treatment.In this cluster randomized trial, 16 hospitals were assigned to the TES program or CAU. Patients in the TES arm were screened for psychological distress with the Hospital Anxiety and Depression Scale and the Distress Thermometer/Problem List (at baseline and 10 and 18 weeks). Stepped care was offered to patients with distress or expressed needs, and it consisted of watchful waiting, guided self-help, face-to-face problem-solving therapy, or referral to specialized mental healthcare. The primary outcome was change in psychological distress over time, and secondary outcomes were quality of life, satisfaction with care, and recognition and referral of distressed patients by clinicians. Linear mixed models and effect sizes were used to evaluate differences.A total of 349 patients were randomized; 184 received the TES program and 165 received CAU. In the TES arm, 60.3% of the patients screened positive for psychological distress, 26.1% of which entered the stepped care program (14.7% used only watchful waiting and 11.4% used at least one of the other treatment steps). The observed low use of the TES program led us to pursue a futility analysis, which showed a small conditional power and therefore resulted in halted recruitment for this study. No difference was seen in change in psychological distress over time between the 2 groups (effect size, -0.16; 95% CI, -0.35 to 0.03; P>.05). The TES group reported higher satisfaction with the received treatment and better cognitive quality of life (all P<.05).As a result of the low use of stepped care, a combined screening and treatment program targeting psychological distress in patients with metastatic colorectal cancer did not improve psychological distress. Our results suggest that enhanced evaluation of psychosocial concerns may improve aspects of patient well-being.
Biologic subtypes and first relapse pattern in curative surgery performed breast cancer patients: Study of Anatolian Society of Medical Oncology.
Authors: Muhammet Ali Kaplan, Ülkü Yalçintas Arslan, Abdurrahman Isikdogan, Berna Oksuzoglu, Mevlude Inanc, Tulay Akman, Ali Inal, Havva Yesil Cankir, Mehmet Kucukoner, Burcin Budakoglu, Metin Ozkan, Ugur Yilmaz, Meltem Baykara, Dogan Yazilitas, Ugur Ersoy, Mehmet Bilici, Erdem Cubukcu, Ozan Yazici, Ali Suner, Umut Demirci
Journal: Journal of Clinical Oncology (2013)

e11559 Background: Relapse is one of the most important risk factors in overall survival, and distant recurrence is related to a complex biologic interaction of seed and soil factors. The aim of the study was to investigate the association between the molecular subtypes and patterns of relapse in patients with curative surgery performed breast cancer. Methods: We retrospectively evaluated clinical data from 1126 breast cancer patients with relapses after their curative surgery between 1998 and 2012 from referral centers of Turkey. Study population was divided into four biological subtypes according to their hormone receptor status and HER2 expression.Patients were divided into four biological subtypes according to IHC: triple negative (ER negative, PR negative, and HER2 negative), HER2 overexpressing (ER negative, PR negative, and HER2 positive), luminal B (ER and/or PR positive, HER2 positive), and luminal A (ER and/or PR positive, HER2 negative). Results: The proportion of patients with luminal A, Luminal B, HER2-overexpressing, and triple negative breast cancer was 42.0% (n=473), 23.0% (n=259), 13.3% (n=150), and 21,7% (n=244), respectively. Median time to relapse was 26.6 months. 22.5% of the patients (n=253) had multiple relapse sites. The incidence of first distant recurrence site was significantly different among the subtypes. Liver (31.8% vs. 22.4%, p=0.008), bone (42.2% vs 37.0%, p&lt;0.001), and lung metastases (30.9% vs. 22.2%, p=0.019) were increased in HER2 overexpressing, luminal A and triple negative group as first relapse site compared with other groups, respectively. Brain metastasis was increased in HER2 overexpressing and triple negative groups (17.7%), compared with Luminal A and B groups (8.0%, p&lt;0.001). Conclusions: Organ-specific metastasis may depend on the molecular subtype of breast cancer. Tailored strategies against distant metastasis concerning the molecular subtypes in breast cancer may be considered.
JAK2 V617F Mutation Allele Burden (MAB) and Its Correlation with Hematologic Characteristics in Myeloproliferative Neoplasms
Authors: David Y Kim, Hamza Tariq, Alan F Brown, Kumari Vadlamudi, Yao Wang, Shohei Ikoma, Kenneth N Holder, Russell A Higgins, Hongxin Fan
Journal: Blood (2017)
Evaluation of local control strategies in patients with localized Ewing sarcoma of bone: A report from the Children’s Oncology Group.
Authors: Steven G. DuBois, Mark D. Krailo, Mark C. Gebhardt, Sarah S. Donaldson, Karen Chayt Marcus, John P. Dormans, Robert C. Shamberger, Scott Lee Sailer, Richard W. Nicholas, John H. Healey, Nancy Tarbell, Meenakshi Devidas, James S. Meyer, Linda Granowetter, Richard Womer, Mark L. Bernstein, Neyssa Marina, Holcombe E. Grier
Journal: Journal of Clinical Oncology (2012)

9537 Background: Patients (pts) with Ewing sarcoma (EWS) require local control, either with surgery alone (S), radiation alone (R), or a combination of surgery + radiation (S+R). Optimal choice of local control for disease control remains unclear. Our primary aim was to determine the mode of local control associated with the highest event-free survival (EFS). Methods: Pts with localized EWS of bone treated on INT0091, INT0154, or AEWS0031 phase III trials were included if they had complete local control data, did not have cranial tumors, received local control starting 2-6 months after enrollment, and were randomized to receive standard dose 5-drug chemotherapy every 3 weeks. We used propensity scores to control for differences in age, tumor site, and year of diagnosis between local control groups. We constructed Cox models controlling for local control propensity scores to assess the impact of local control type on EFS and overall survival (OS) from the start of local control. Results: 465 pts were included. Pts selected for S were treated more recently (p &lt; 0.001), more likely to have appendicular tumors (p &lt; 0.001), and younger (p = 0.02). Pts treated with R, compared to S, had higher unadjusted risk of any event (HR 1.70; 95% CI 1.18 - 2.44; p = 0.004) or death (HR 1.84; 95% CI 1.18 – 2.85; p = 0.006). Pts treated with S+R, compared to S, had higher unadjusted risk of death (HR 1.75; 95% CI 1.10 – 2.76; p = 0.02). After adjusting for propensity scores, there was a trend of higher risk of any event for pts treated with R (HR 1.42; 95% CI 0.94 – 2.14; p = 0.10) compared to S, though this was not statistically significant. No other differences in adjusted risk of event or death between local control groups were statistically significant. We confirmed these results with standard Cox models using age, tumor site, and year of diagnosis as covariates. Conclusions: In this large group of uniformly treated pts, investigator choice of local control approach was not significantly related to EFS. These data support current practice of surgical resection when feasible, while validating radiotherapy as a reasonable alternative in selected pts.