tbuckley/cabot-search huggingface dataset:
Utility of circulating tumor DNA (ctDNA) versus tumor tissue clinical sequencing for enrolling patients (pts) with advanced non-colorectal (non-CRC) gastrointestinal (GI) cancer to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA combined analysis.
Authors: Akihiro Ohba, Yoshiaki Nakamura, Hiroya Taniguchi, Masafumi Ikeda, Hideaki Bando, Nobumasa Mizuno, Ken Kato, Chigusa Morizane, Tomohiro Nishina, Makoto Ueno, Junji Furuse, Hiroki Hara, Tadamichi Denda, Hisato Kawakami, Taito Esaki, Toshikazu Moriwaki, Hisateru Yasui, Yoshito Komatsu, Takayuki Yoshino, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2020)

3516 Background: We recently reported that clinical assessment of genomic biomarkers using ctDNA had advantages over tumor tissue-based sequencing for enrollment into matched clinical trials across a wide range of GI cancers. Herein we investigated the utility of ctDNA in non-CRC cancers in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue samples of pts with non-CRC were analyzed by a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay, since Feb 2015. In GOZILA, plasma samples of non-CRC pts were analyzed by an NGS-based ctDNA assay, Guardant360, since Feb 2018. Results: As of Apr 2019, 2,952 pts in GI-SCREEN and 633 pts in GOZILA were enrolled. Baseline characteristics between the groups were well matched except that GOZILA included more pancreatic (P &lt; 0.0001) and liver cancers (P = 0.016) but fewer gastric cancers (P &lt; 0.0001) and GIST (P = 0.020) than GI-SCREEN. The success rates of the tests were 86.6% in GI-SCREEN and 87.3% in GOZILA (P = 0.649). Median turnaround time (TAT) was 37 days in GI-SCREEN and 12 days in GOZILA (P &lt; 0.0001). The proportion of cases with actionable alterations detected (tissue vs blood; 29.8% vs 46.8%, P &lt; 0.0001) and enrolled into matched clinical trials (4.8% vs 6.5%, P = 0.286) for each group by cancer type are shown in the Table. Pts with upper GI cancers, especially those in GOZILA, were more often enrolled into matched trials; trial enrollment for those with hepatobiliary and pancreatic (HBP) or other cancers was similar regardless of testing method. Median time from GI-SCREEN or GOZILA enrollment to clinical trial enrollment was 5.0 and 1.0 months (mo), respectively (P &lt; 0.0001). Objective response rates (ORR) and progression-free survival (PFS) were not significantly different (tissue vs. blood; ORR: 14.6 vs. 26.3%, P = 0.30: median PFS: 3.3 vs. 2.6 mo, P = 0.71). Conclusions: Clinical sequencing of ctDNA, with its shorter TAT, contributed to rapid enrollment of non-CRC pts into matched clinical trials compared to those tested by tumor tissue sequencing, particularly for those with upper GI cancer, without compromising efficacy. Clinical trial information: UMIN000029315 . [Table: see text]
Association Between Adverse Childhood Experiences and Dementia in Older Japanese Adults
Authors: Yukako Tani, Takeo Fujiwara, Katsunori Kondo
Journal: JAMA Network Open (2020)

The prevalence of dementia in Japan has been increasing. Childhood poverty has been associated with increased risk of cognitive impairment, possibly mediated by individuals' educational paths. However, the associations between dementia and adverse childhood experiences other than poverty and education have not been well documented.To examine the association between adverse childhood experiences and dementia onset among Japanese individuals born before 1948 who grew up during and after World War II.A 3-year (2013-2016) follow-up was performed of 17 412 participants in the Japan Gerontological Evaluation Study, a population-based cohort study of adults aged 65 years or older. Data were analyzed in December 2019.Dementia onset was assessed through the public long-term care insurance system. Adverse childhood experiences before the age of 18 years were assessed by survey at baseline. Seven adverse childhood experiences were assessed: parental death, parental divorce, parental mental illness, family violence, physical abuse, psychological neglect, and psychological abuse. Participants were classified according to whether they had 0, 1, 2, or 3 or more adverse childhood experiences. Cox regression models were used to estimate hazard ratios for the risk of dementia.Among 17 412 participants (9281 women [53.3%]; mean [SD] age, 73.5 [6.0] years), dementia occurred in 703 participants (312 men and 391 women) during a mean follow-up of 3.2 years (range, 2.4-3.3 years). Among all participants, 6804 (39.1%) were older than 75 years; 10 968 (63.0%) reported 0 adverse childhood experiences, 5129 (29.5%) reported 1 adverse childhood experience, 964 (5.5%) reported 2 adverse childhood experiences, and 351 (2.0%) reported 3 or more adverse childhood experiences. Participants who experienced 3 or more adverse childhood experiences had a greater risk of developing dementia compared with those who grew up without adverse childhood experiences, after adjustment for age, sex, childhood economic hardship, nutritional environment, and education (hazard ratio, 2.18; 95% CI, 1.42-3.35). After successive adjustment for adult sociodemographic characteristics, social relationships, health behavior, and health status, this hazard ratio was attenuated but remained statistically significant (1.78; 95% CI, 1.15-2.75; P = .009).This study found that having 3 or more adverse childhood experiences was associated with increased dementia risk among older Japanese adults.
Baseline liver function and outcomes in the phase III REFLECT study in patients with unresectable hepatocellular carcinoma (uHCC).
Authors: Arndt Vogel, Catherine Frenette, Max W. Sung, Bruno Daniele, Ari David Baron, Stephen Lam Chan, Jean-Frédéric Blanc, Toshiyuki Tamai, Min Ren, Howard John Lim, Daniel H. Palmer, Yuko Takami, Masatoshi Kudo
Journal: Journal of Clinical Oncology (2020)

524 Background: Lenvatinib (LEN) is approved for first-line treatment of uHCC. Baseline (BL) liver function (Child-Pugh score [CPS] and albumin-bilirubin grade [ALBI]) was prognostic in uHCC patients (pts) who received sorafenib (SOR) but has not been assessed with LEN in uHCC. Here, we report post hoc analysis of BL liver function and efficacy/safety outcomes from the phase 3 REFLECT study. Methods: Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were stratified by BL ALBI or CPS. OS and PFS were estimated by Kaplan–Meier method. Independent radiologic review utilized mRECIST criteria for ORR. Safety was assessed using NCI-CTCAE, version 4.0. Results: Liver function measured by ALBI and CPS seemed to be prognostic for OS and ORR. Median OS was longer in ALBI grade 1 (ALBI-1) vs grade 2 (ALBI-2) pts or for CPS-5 vs CPS-6 on either treatment arm and was longer for LEN vs SOR. ORR was higher in pts with better ALBI or CPS and for LEN vs SOR. Rates of treatment-emergent adverse events grade ≥3 were lower with better BL liver function (ALBI-1 vs ALBI-2: 70% vs 86%; CPS-5 vs CPS-6: 72% vs 86%). Study-drug withdrawal, dose reduction, and dose interruption occurred more often in pts with worse BL liver function. Conclusions: This post hoc analysis suggests ALBI (by OS, PFS and ORR) and CPS (by ORR) may be prognostic in uHCC pts and that BL liver function may be linked with efficacy/safety outcomes. This analysis also found that LEN provided benefit vs SOR for uHCC, regardless of BL liver function. The benefit of LEN may be underestimated, as more ALBI-2 pts and fewer ALBI-1 pts received LEN vs SOR. Clinical trial information: NCT01761266. [Table: see text]
<i>In Vivo</i>Tracking of Adoptively Transferred Natural Killer Cells in Rhesus Macaques Using 89Zirconium-Oxine Cell Labeling and PET Imaging
Authors: Noriko Sato, Kate Stringaris, Jan K. Davidson-Moncada, Robert Reger, Stephen S. Adler, Cynthia Dunbar, Peter L. Choyke, Richard W. Childs
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Trials of adoptive natural killer (NK)-cell immunotherapy for hematologic malignancies have thus far shown only marginal effects, despite the potent in vitro antitumor activity of these cells. Homing of infused cells to tumor microenvironments is critical for efficacy, but has not been well characterized. We established a novel method to track and quantify the distribution of adoptively transferred NK cells using rhesus macaques (RM) as a clinically relevant preclinical model. Experimental Design: RM NK cells were expanded ex vivo for 14–21 days, labeled with 89Zr-oxine complex, and assessed for phenotype, function, and survival. Trafficking of 89Zr-labeled ex vivo–expanded NK cells infused into RMs was monitored and quantitated by serial positron emission tomography (PET)/CT (n = 3, 2.05 ± 0.72 MBq, 23.5 ± 2.0 × 106 NK cells/kg) and compared with that of 89Zr-labeled nonexpanded NK cells, apoptotic NK cells, and hematopoietic stem and progenitor cells (HSPC). Results: NK cells retained sufficient levels of 89Zr for accurate in vivo tracking for 7 days. 89Zr labeling did not alter cellular phenotype, viability, or function. PET/CT showed NK cells initially localized in the lungs, followed by their migration to the liver, spleen, and, at low levels, bone marrow. One day following transfer, only 3.4% of infused NK cells localized to the BM versus 22.1% of HSPCs. No clinical side effects were observed, and dosimetry analysis indicated low organ radioexposures of 6.24 mSv/MBq (spleen) or lower. Conclusions: These data support translation of this technique to humans to track the distribution of adoptively infused cells and to develop novel techniques to improve immune cell homing to tumor microenvironments.
Gamma-synuclein as a potential novel prognostic marker promoting tumor cell migration in biliary tract carcinoma.
Authors: Yusuke Takemura, Hidenori Ojima, Go Oshima, Masahiro Shinoda, Minoru Kitago, Hiroshi Yagi, Yuta Abe, Shutaro Hori, Yoko Nishimura, Naoto Kubota, Yuki Masuda, Taizo Hibi, Michiie Sakamoto, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2020)

577 Background: Biliary tract carcinoma (BTC) is a highly malignant tumor, but the detailed pathological mechanism of its development and progression remain ill-defined. Gamma-synuclein (SNCG) promotes invasive behavior in pancreatic cancer and a range of other cancers, and SNCG expression is reportedly a prognostic factor. However, the role of SNCG in BTC remains unknown. Consequently, we investigated the clinicopathological significance and function of SNCG in BTC. Methods: Using surgically resected BTC specimens from 149 patients with adenocarcinoma [extrahepatic cholangiocarcinoma (ECC) (n =98); intrahepatic cholangiocarcinoma (ICC) (n =51)], we immunohistochemically evaluated SNCG positivity and checked for correlations with clinicopathological factors and outcomes. Furthermore, cell lines with high expressions of SNCG were selected from 17 BTC cell lines by using immunohistochemistry and qPCR. Cell proliferation and migration assays were then performed in the presence and absence of SNCG (silenced using). Results: SNCG expression was found in 32 of 149 (21.4%) BTC patients. SNCG expression was significantly correlated with poorly differentiated tumor ( P = 0.001) and lymph node metastases ( P = 0.001). SNCG positivity was also correlated with poorly differentiated tumor in both ECC and ICC ( P = 0.008 and P = 0.03, respectively), but was correlated with lymph node metastases only in ECC ( P = 0.003). Multivariate analyses identified SNCG expression as an independent prognostic factor of poor overall survival ( P = 0.008) and poor recurrence-free survival (RFS) ( P = 0.006). SNCG expression in both ECC and ICC was significantly associated with poor prognosis in univariate analysis, and multivariate analysis identified SNCG as an independent prognostic factor of poor RFS for ECC (P = 0.03). High SNCG expression was found in 3 BTC cell lines (NCC-BD1, NCC-BD3, and NCC-CC6-1). Functional analysis revealed that SNCG silencing by siRNA suppressed cell migration significantly in NCC-BD1 and NCC-CC6-1 and downregulated cell proliferation in NCC-CC6-1. Conclusions: Our results suggest that SNCG may promote tumor cell activity and is potentially a novel prognostic marker in BTC.
Pharmacogenomic blood-based assay to predict chemotherapy response and survival in pancreatic cancer.
Authors: Kenneth H. Yu, Brian McCarthy, William H. Isacoff, Brandon Cooper, Andrew Bartlett, Jennifer Park, Fay Purcell, Devan McCarthy, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2020)

738 Background: Pancreatic adenocarcinoma (PDAC) is for most patients a refractory disease. Modern cytotoxic chemotherapeutics (C) are not yet optimal for inducing responses and extending life. We are developing a blood-based pharmacogenomic (PGx) assay profiling circulating tumor and invasive cells (CTICs) to predict sensitivity and resistance to C. Methods: The PGx assay was studied in two cohorts of patients (pts) presenting for frontline C therapy of metastatic PDAC. Cohort 1 is from an ongoing prospective study (planned n=80); pts are enrolled prior to receiving either FOLFIRINOX or gemcitabine (Gem)/nab-paclitaxel (Nab-P). Cohort 2 (n=50) consists of pts enrolled prior to receiving bespoke combinations of C agents informed by the assay. 6 mL of peripheral blood was collected from pts at baseline and while on C therapy. CTICs were isolated by previously described collagen invasion assay, total RNA was extracted and gene-expression analysis was performed. PGx models for seven C agents used in PDAC were applied, and correlated to treatment received. Pts were classified as sensitive if C received were predicted to be effective and resistant if not. Objective endpoints were PFS and OS. Results: Cohort 1 patients who received sensitive first-line C combinations experienced significantly longer time to progression (TTP) v resistant (Table). In Cohort 2, the PGx assay was predictive of TTP and OS when used across multiple lines of therapy, with a two-year survival of 38%. Greater OS was observed in Cohort 2 pts receiving heterogenous C regimens more highly correlated to those predicted by the PGx assay. Conclusions: The PGx assay has promising predictive performance in both standard and personalized C regimens. A prospective, directed trial comparing these approaches is warranted. Clinical trial information: NCT03033927. [Table: see text]
Efficacy of palliative liquid nitrogen spray cryotherapy in curbing progression of dysphagia in esophageal cancer.
Authors: Swathi Eluri, Vivek Kaul, Neil R. Sharma, Stuart R. Gordon, Toufic Kachaamy, George Smallfield, Jason Samarasena, Arvind Trindade, Shivangi Kothari, Jeffrey Weber, Kenneth J. Chang, Petros Benias, Matthew J. McKinley, Nicholas Shaheen
Journal: Journal of Clinical Oncology (2020)

400 Background: Progressive dysphagia in locally advanced esophageal cancer worsens quality of life (QOL). Endoscopic cryoablation may effectively palliate dysphagia. Aim: To study the effect of palliative cryoablation with trūFreeze Spray Cryotherapy (SCT) in patients with esophageal cancer. Methods: This is an interim analysis of a multi-center prospective study of esophageal cancer patients who are non-surgical candidates, not on active systemic therapy, without esophageal stents, or prior SCT. SCT is an endoscopic ablation modality using liquid nitrogen (LN2) delivered by catheter. SCT occurred at 6 week intervals or as indicated at a dose of 2x30 or 3x30 secs/treatment site. Dysphagia and esophageal symptoms were assessed at baseline and after treatment with a 5-point Dysphagia score and the EORTC-QLQ-OES18 (higher score = more symptoms). Results: 39 subjects (mean age 74.4 ±12.2; 87% men, Table) had 182 treatment sessions over a mean follow-up of 206.9 days, and received a median 3 SCT sessions with an average dose of 90 (3x30) secs/site. There was 1 procedure related SAE (2.6% of patients and 0.5% procedures). Mean follow-up dysphagia score was 1.6 ±0.8 and 90% had same or improved dysphagia score after SCT treatment, p&lt;0.01. On average, treated patients maintained the same or improved levels of dysphagia for 117 days. Esophageal QOL was maintained with improvement in “eating problems” (24.4 before treatment to 18.2 after, p=0.01). Only 4 subjects needed an esophageal stent (n=2) or gastrostomy tube (n=2) for nutrition. Conclusions: SCT for palliation of esophageal cancer was effective in limiting progression of dysphagia, while maintaining esophageal QOL. Only 10% required either esophageal stenting or feeding tube at &gt;6 month follow-up. Clinical trial information: NCT03243734. [Table: see text]
The relationship between perioperative markers of the systemic inflammatory response and postoperative complications in patients undergoing curative resection of colon cancer.
Authors: Katrina Knight, Jia Xun Choong, Campbell SD Roxburgh, Paul G. Horgan, Donald C. McMillan
Journal: Journal of Clinical Oncology (2020)

75 Background: Surgical resection remains the mainstay of treatment for patients with potentially curable colorectal cancer (CRC). However, it can be associated with the development of postoperative complications (POC), which are associated with an increased cancer recurrence risk. Neutrophils are important in innate immunity, especially in the immediate postoperative period as part of the systemic inflammatory response (SIR). We aimed to assess the use of perioperative SIR markers as predictors of POC. Methods: Patients undergoing elective curative CRC surgery at one institution between March 2008 and June 2015 were identified from a prospective database. Demographics and clinicopathological data were extracted from medical records. Logistic regression was used to assess the relationship between perioperative blood counts, clinicopathological variables and POCs. Results: Of 443 cases, most were aged 65 years or older (n = 314, 71%), male (n = 245, 55%), smokers (n = 229, 52%), overweight or obese (n = 263, 59%) and had ASA score of 2 or less (n = 267, 60%). The majority underwent open resection (n = 288, 65%). Preoperative factors associated with the development of POC were: ASA grade &gt; 2 (OR 1.48, 95% CI 0.99-2.18, p = 0.05), smoking history (OR 1.99, 95% CI 1.35 – 2.93, p &lt; 0.001), neutrophil count &gt; 7.5x10 9 /L (OR 3.40, 95% CI 1.82-6.36, p &lt; 0.001) and CRP &gt; 10mg/L (OR 1.70, 95%CI 1.12-2.59, p = 0.013). Postoperative factors associated with the development of POC were open surgery (OR 0.47, 95%CI 0.31-0.72, p &lt; 0.001), neutrophil count &gt; 7.5x109/L (OR 2.67, 95%CI 1.75-4.07, p &lt; 0.001) and CRP &gt; 150mg/L (OR 3.97, 95%CI 2.61-6.02, p &lt; 0.001) on postoperative day 3 (POD3). On multivariate analysis, a preoperative neutrophil count &gt; 7.5x10 9 /L (OR 3.65, 95%CI 1.68-7.90, p &lt; 0.001), a neutrophil count &gt; 7.5 x10 9 /L on POD3 (OR 1.69, 95%CI 1.05-2.72, p = 0.029) and CRP &gt; 150mg/L on POD3 (OR 3.66, 95%CI 2.29-5.87, p &lt; 0.001) were related to POC, independent of smoking, ASA and operative approach. Conclusions: Neutrophil count complements the prognostic value of pre and post-operative CRP to predict POC. Further validation work is required.
Germline Mutations in Familial Papillary Thyroid Cancer
Authors: Marta Sarquis, Debora C. Moraes, Luciana Bastos-Rodrigues, Pedro G. Azevedo, Adauto V. Ramos, Fabiana Versiani Reis, Paula V. Dande, Isabela Paim, Eitan Friedman, Luiz De Marco
Journal: Endocrine Pathology (2020)
Defining population response of patient-derived colorectal cancer organoids against prospective clinical outcomes.
Authors: Jeremy D. Kratz, Amani Gillette, Shujah Rehman, Aishwarya Sunil, Katherine Anne Johnson, Cheri Pasch, Kayla Lemmon, Nicole Lassen, Daniel Erik Abbott, Evie Carchman, Eugene F. Foley, Charles Heise, Elise Hanna Lawson, Noelle K. LoConte, Sam Joseph Lubner, Daniel Mulkerin, Kristina A. Matkowskyj, Nataliya Volodymyrivna Uboha, Melissa C. Skala, Dustin A. Deming
Journal: Journal of Clinical Oncology (2020)

177 Background: No current clinical tool can predict the efficacy of cancer therapeutics for patients with colorectal cancer (CRC). We recently demonstrated the feasibility of using patient-derived cancer organoids (PDCOs) to examine therapeutic response and tumor heterogeneity for individual patients with CRC via optical metabolic imaging (OMI). Here we expand these analyses in a cohort of patients with clinical outcomes. Methods: CRC tissue was collected from patients on IRB-approved protocols. PDCOs were matured and treated with chemotherapy regimens concurrent with patient treatment. Previously established effect size response thresholds were used for diameter ( &gt; 1.5) and OMI ( &gt; 0.5) following 48 hours of treatment. OMI measures the intrinsic autofluorescence of NAD(P)H and FAD using 2-photon microscopy without specific reagents or dyes. Clinical outcomes were prospectively collected by manual chart review. Results: 12 CRC PDCOs were established from patients with CRC. PDCOs were collected from initial diagnosis and advanced setting of both primary and metastatic sites by core needle biopsy and surgical resection. Differential growth rates were observed across lines. PDCOs with RAS/RAF alterations had more uniform growth, while PDCOs without these alterations demonstrated more heterogeneous growth and metabolism. Clinical correlation of PDCOs response with recurrence of disease in the adjuvant setting will be presented. Cases with prior 5-FU-based chemotherapy at the time of PDCO collection had intermediate sensitivity. For PDCOs collected pre-treatment, PDCO response predicted clinical response for 5 of 6 cases using predefined sensitivity thresholds. In the case that overall PDCO response did not predict clinical response, a heterogenous response was observed with distinct sensitive and resistant populations. Across PDCOs, greater post-treatment heterogeneity was observed in resistant lines compared to those with treatment sensitivity. Conclusions: Tumor heterogeneity in treatment response can be assessed using PDCOs growth and metabolism. The utility of PDCOs to predict clinical outcomes for patients with CRC deserves further prospective validation.
Imaging growth as a predictor of grade of malignancy and aggressiveness of IDH-mutant and 1p/19q-codeleted oligodendrogliomas in adults
Authors: Alexandre Roux, Arnault Tauziede-Espariat, Marc Zanello, Sophie Peeters, Gilles Zah-Bi, Eduardo Parraga, Myriam Edjlali, Emmanuèle Lechapt, Natalia Shor, Luisa Bellu, Giulia Berzero, Didier Dormont, Edouard Dezamis, Fabrice Chretien, Catherine Oppenheim, Marc Sanson, Pascale Varlet, Laurent Capelle, Frédéric Dhermain, Johan Pallud
Journal: Neuro-Oncology (2020)

We quantified the spontaneous imaging growth rate of oligodendrogliomas. We assessed whether (i) it discriminates between World Health Organization (WHO) grade II and grade III oligodendrogliomas, and (ii) grade III oligodendrogliomas with neo-angiogenesis are associated with more fast growth rates (≥8 mm/y).