tbuckley/cabot-search huggingface dataset:
An improved method for detection of methylated circulating tumor DNA in colorectal cancer.
Authors: Nicky Boulter, Gregor Tevz, Betty Yu, Michelle Chan, David Murray, Erin L. Symonds, Graeme P. Young, Susanne Kartin Pedersen
Journal: Journal of Clinical Oncology (2019)

e15120 Background: Assays detecting methylated circulating tumor DNA (ctDNA) hold promise for colorectal cancer (CRC) screening, but there is a need to develop more accurate assays for early stages. In this study, we examined modifications to COLVERA (an IKZF1 and BCAT1 methylation marker qPCR assay) that added a third biomarker (IRF4) as well as introducing double stranded detection. Methods: Bisulfite converted DNA extracted from plasma collected from subjects undergoing diagnosis for CRC was assayed using either a double-stranded (ds) specific multiplexed qPCR for BCAT1 and IKZF1 detection (Assay 1) and/or a single-stranded (ss) specific BCAT1/IRF4, ds-specific IKZF1 multiplexed qPCR (Assay 2). The unmodified COLVERA test (Clinical Genomics) was used for comparison. Detection of any marker was considered positive. Results: Assay 1 performance evaluated against COLVERA on bisulfite converted DNA from 1453 samples showed an improved sensitivity for CRC detection (93/134 (69.4%) vs 79/134 (59.0%) COLVERA, p = 0.02), but specificity was suboptimal (no neoplasia: 861/1023 (84.2%) vs 946/1023 (92.5%) COLVERA, p &lt; 0.0001). The decrease in specificity resulted primarily from modifications in the BCAT1 assay component (1023 no neoplasia: 60 positive with ss- BCAT1 vs 146 positive with ds- BCAT1, p &lt; 0.0001). Thus, a novel configuration, Assay 2 (ss- BCAT1, ss- IRF4 and ds- IKZF1) was compared to Assay 1 using 189 previously untested specimens. Assay 2 showed a notable improvement in specificity (99/104 (95.2%) vs 93/104 (89.4%) Assay 1; p = 0.0351). Both assays exhibited comparable sensitivities for CRC (41/49 (83.7%) vs 39/49 (79.6%), Assay 1, p = 0.3633). Assay 2 was positive in: adenomas, 9/36 (25.0%); Stage I, 3/7 (42.9%); Stage II, 17/19 (89.5%); Stage III, 6/6 (100%); Stage IV, 7/7 (100%) and 8/10 (80%) unstaged CRCs. Prior COLVERA sensitivity estimates were 9% adenoma, 41% Stage I and 76% Stage II. Conclusions: Targeting both of the non-complementary bisulfite converted strands of selective regions of interest markedly improve ctDNA assay sensitivity for cancer including early lesions while achieving good specificity. Prospective evaluation in a true CRC screening population is now underway. Clinical trial information: 12611000318987.
Phase I study of irinotecan/5-fluorouracil/leucovorin (FOLFIRI) with sunitinib for advanced gastroesophageal cancers (EGC).
Authors: Sarbajit Mukherjee, Christos Fountzilas, Patrick McKay Boland, Kristopher Attwood, Wei Tan, Nikhil I. Khushalani, Renuka V. Iyer
Journal: Journal of Clinical Oncology (2019)

e15569 Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]
Change in Mortality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time
Authors: Aidan Neligan, Alastair John Noyce, Tushar Divakar Gosavi, Simon D. Shorvon, Sebastian Köhler, Matthew C. Walker
Journal: JAMA Neurology (2019)

Status epilepticus (SE) is associated with significant morbidity and mortality. Since the late 1990s, a more aggressive management of prolonged convulsive seizures lasting longer than 5 minutes has been advocated.To determine if convulsive SE mortality has decreased during a time of increasing advocacy for out-of-hospital treatment and escalating and earlier treatment protocols for prolonged seizures and SE.This systemic review and meta-analysis on studies focused on the mortality of convulsive status epilepticus was conducted by searching MEDLINE, Embase, PsychINFO, CINAHL Plus, and the Cochrane Database of Systematic Reviews between January 1, 1990, and June 30, 2017.Studies were excluded if they had fewer than 30 participants (<20 for refractory SE), were limited to SE of single specific etiology or an evaluation of a single treatment modality, or were studies of nonconvulsive SE.Data were abstracted and their quality was assessed via a modified Newcastle-Ottawa scale independently by 2 reviewers (A.N. and T.D.G.) using the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using a random-effects model.The main outcome measure was in-hospital mortality or 30-day case fatality expressed as proportional mortality.Sixty-one studies were included in the analysis. The pooled mortality ratios were 15.9% (95% CI, 12.7-19.2) for adult studies, 13.0% (95% CI, 7.2-19.0) for all-age population studies, 3.6% (95% CI, 2.0%-5.2%) for pediatric studies, and 17.3% (95% CI, 9.8-24.7) for refractory SE studies, with very high between-study heterogeneity. We found no evidence of a change in prognosis over time nor by the definition of SE used.The mortality of convulsive SE is higher in adults than in children and there was no evidence for improved survival over time. Although there are many explanations for these findings, they can be explained by aetiology of SE being the major determinant of mortality. However, there are potential confounders, including differences in case ascertainment and study heterogeneity. This meta-analysis highlights the need for strict international guidelines for the study of this condition.
ET140202 t-cells: A novel therapy targeting AFP/MHC complex, that is both safe and effective in treating metastatic hepatocellular carcinoma.
Authors: Chang Liu, Hong Liu, Yun Wang, Xiaogang Zhang, Fengling Fan, Ruitao Wang, Kai Qu, Bijan Nejadnik, Bingyin Shi, Cheng Liu
Journal: Journal of Clinical Oncology (2019)

e15614 Background: CAR-T cells has emerged as novel cancer treatment, particularly for hematologic malignancies. However, treatment of solid tumors using redirected T-cells remains challenging. We developed a novel T-cell platform ET140202 targeting AFP/MHC complex enhanced by GPC3-guided co-stimulation. Herein we report a case study of ET140202 for a male subject with 3 liver HCC lesions, multiple lung metastases and with no response to sorafenib and regorafenib. Methods: The schedule and dose of ET140202 T cell infusion was summarized in Fig 1a. The subject received 16 i.v. infusions of ET140202 T cells at doses ranging from 0.42-6 ×10 6 cells/kg, totaling 2.461×10 9 cells. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 3, 5, 9 and 12. Results: T-cell expansion was observed shortly after each infusion. No treatment-related Grade 3 or higher AEs observed. Grade 1 or 2 events that were possibly attributable to therapy included dry mouth, dry skin peeling from hand and foot, and voice hoarseness and oral mucosal ulceration. All events resolved in 3-5 days with symptomatic treatment. At Day 40, the subject developed Grade 2 mucositis, which improved in 5 days following vitamin C treatment and oral hygiene care. The subject did not experience any signs of CRS or neurotoxicity. Cytokines including IL-2, IL-6, GM-CSF, INFg and TNFa were below detection at most time points post-infusion. All 3 liver lesions regressed at month 5 and the regression persisted to the last follow-up timepoint at month 12. All 4 lung nodules appeared to slightly increase in size at month 1, which may be attributed to pseudo-progression and substantially decreased at month 5. The decrease of the lung lesions also persisted to month 12. AFP levels were increased above the baseline shortly after T-cell infusion, possibly due to the lysis of tumor and gradually decreased to the normal level of 10 ng/mL on Day 135 and persisted to the last follow-up on day 365. Conclusions: ET140202 T cells has the potential to be used safely and effectively in AFP+/HLA-A2+ HCC to induce regression of primary and metastatic lesions.
Implementation of complex perioperative intervention in older patients with cancer (IMPROVED program).
Authors: Elena Paillaud, Frederique Peschaud, Tristan Cudennec, Philippe Caillet, Mathilde Gisselbrecht, Laure De Decker, Nicola De Angelis, Pierre Cattan, Benoit Plaud, Christophe Tournigand, Thomas Aparicio, Sandrine Touzet, David Moszkowicz, Marie Laurent, Florence Canoui-Poitrine, Etienne Brain
Journal: Journal of Clinical Oncology (2019)

TPS11630 Background: Nearly 50% of patients are older than 70 years at diagnosis of digestive cancer. Surgical resection is the first line strategy of treatment. Despite improvement in surgical techniques and development of rehabilitation programs, the rate of postoperative complications remains high. Peri-operative involvement of geriatricians may improve care management older cancer patients. Methods: During a 6 months run-up period (emerging project), we structured a multi-professional network (digestive surgeons, anesthetists, geriatricians, digestive oncologists, epidemiologists), we elaborated a innovative peri-operative geriatric intervention (Improved program) in digestive surgery setting based on evidence-based data. We build a dedicated evaluation plan by determinate the best design for assessing geriatric intervention in this complex context and choose the more appropriate endpoints. Results: We will include 554 patients aged 75 or more with resectable digestive cancer in a stepped wedge cluster randomized trial. The intervention is based on 1/ a preoperative geriatric assessment, focusing on frailty parameters and developing a coordinated program of tailored geriatric interventions 2/ a postoperative shared care with an integrated care model where both surgeon and geriatrician share responsibility for the patient management in surgical ward. This geriatric postoperative management will be focus on prevention and correction of complications, early mobilization, optimal nutritional support. The main endpoint Is is Grade II or higher post-surgical complications rate according Clavien-Dindo classification within 30 days after the surgical procedure. Conclusion: We expected to demonstrate a benefit of a peri-operative shared management model to decrease the risk of post-surgical complications In older patients with digestive cancer.
Fruquintinib or regorafenib as the third-line treatments for metastatic colorectal cancer based on CONCUR and FRESCO trials: A cost-effectiveness analysis.
Authors: Qiu Li, Mengxi Zhang
Journal: Journal of Clinical Oncology (2019)

e15011 Background: Survival benefit of regorafenib and fruquintinib as third-line agents have been respectively demonstrated in patients with treatment-refractory metastatic colorectal cancer. This study tries to explore the cost-effectiveness of the two agents. Methods: A Markov model was performed based on two phase 3 trials, FRESCO and CONCUR. Health outcomes were measured with quality-adjusted life-years (QALYs). The key outcome was incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity and one-way sensitivity analysis were performed to estimate the impact of essential variables on the results of the analysis. Results: No statistical differences were observed in the baseline patient characteristics, except that the CONCUR trial enrolled older patients and higher ratios of prior use of VEGF or EGFR antibodies in comparison with the FRESCO trial.Treatment with fruquintinib was estimated to cost $25,550.15 with an effectiveness gain of 0.54 QALYs, whereas regorafenib resulted in 0.53 QALY at a mean cost of $29,681.52, yielding ICER of $-413,137.00 per QALY. By using treble the Chinese Gross Domestic Product per Capita as willingness-to-pay threshold, the probability for fruquintinib being cost-effective was higher than regorafenib in the probabilistic sensitivity analysis. Conclusions: Fruquintinib provides a more cost-effective option for metastatic colorectal patients compared with regorafenib in the third line treatment.[Table: see text]
Design and implementation of an Internet-based cancer risk assessment tool: Use over 10 years.
Authors: Michael Joseph Lariviere, Hann-Hsiang Chao, Isabella Amaniera, Carolyn Vachani, Margaret K. Hampshire, Christina Bach, Karen Arnold-Korzeniowski, James M. Metz, Christine E. Hill-Kayser
Journal: Journal of Clinical Oncology (2019)

e13075 Background: Prevention and early intervention can improve survival and quality of life across all cancers. Patient understanding of risk factors, and associated actionable lifestyle changes and screening programs, is not well understood by clinicians. Methods: The Internet-based OncoLink “Reduce My Risk” tool was created in 2009 to provide information about cancer risk after individuals responded to a comprehensive survey regarding demographics and cancer risk factors. Research related to these data has been IRB-approved. Results: 28,001 surveys were submitted. Median age among respondents ≥18y was 26y (18-101). 60% were female, 87% lived in North America, and 76% were White/Non-Hispanic. 37% had at least a bachelor’s degree, and 22% had household income &gt; $100,000/y; most lived in a city/suburb (81%). 13% were current smokers, 23% previous smokers, 10% used cigars or pipe tobacco (10%), 6% used oral snuff/chew/quid, and 29% reported secondhand smoke exposure. Other substance use included marijuana (22% former users, 10% current users), alcohol (52% current users, 8% of those ≥14 drinks/w), and areca nut, betel leaf, or exotic smoking (1%). BMI was ≥30 in 19%. 74% reported dietary risks and 36% infrequent exercise. Early intercourse and &gt; 10 sexual partners were reported by 43% and 10%, respectively. Excess UV exposure was reported by 19%, and exposure to known carcinogens 14%; 1% were exposed to DES in utero, and &lt; 1% took DES while pregnant. Nonmodifiable risk factors included family cancer history (64%) or genetic syndrome (3%), and cancer-predisposing health condition (26%). 31% of women began menstruating &lt; 12y and 33% gave birth to a first child &gt; 30y. Conclusions: This free, publicly accessible cancer risk assessment tool has a large user population with higher educational status, higher income, and smaller household than the general population. 97% of users report behaviors associated with cancer risk. Another 72% report non-modifiable risks. By understanding detailed characteristics of a large number of respondents, these data have the potential to answer many hypothesis-generating questions, with the ultimate goal of improving educational interventions to reduce cancer risk across the general public.
Abstract 18226: Fibrinolysis Before Percutaneous Coronary Intervention Reduces the Rate of Cardiogenic Shock in Patients Presenting Within 3 Hours After Symptom Onset
Authors: Maarten Vanhaverbeke, Peter Sinnaeve, Frans Van de Werf, Luc Janssens
Journal: Circulation (2015)

Introduction: Primary percutaneous coronary intervention (PCI) has become the standard of care for the treatment of ST-elevation myocardial infarction (STEMI) when it can be performed within 90 to 120 minutes after first medical contact. Whether fibrinolysis given before the intervention reduces the incidence of cardiogenic shock is not known. Methods: We identified randomized trials of fibrinolysis pre-PCI versus primary PCI in STEMI and assessed the incidence of cardiogenic shock in both groups. The Mantel-Haenszel method was used to calculate the weighted relative risk and the Chi-square test to determine the overall effect. Results: The results of the STREAM, FINESSE, WEST, ASSENT-4 PCI and CAPTIM trials were included. The first four trials investigated facilitated or pharmaco-invasive PCI with full or half dose fibrinolysis. In CAPTIM, fibrinolysis was compared to primary PCI and the majority of patients in the fibrinolysis group underwent PCI. In total 3097 patients were randomized to the fibrinolysis pre-PCI group and 3088 to the primary PCI group. The incidence of cardiogenic shock was not different between both groups (4.8% vs. 5.7% respectively, p =0.12). This result is largely driven by the ASSENT-4 PCI trial. In a subgroup analysis of patients presenting within 3 hours after symptom onset, the incidence of cardiogenic shock was significantly lower in patients receiving fibrinolysis pre-PCI (4.1% vs. 6.5%, p =0.002). However, administration of a fibrinolytic agent pre-PCI increased the risk of major bleeding (5.6% vs. 3.7%, p =0.004) and was not associated with an early mortality reduction (5.1% vs. 4.8%, p =0.29). Conclusion: Our analysis suggests that in STEMI patients presenting within 3 hours after symptom onset, early reperfusion with a fibrinolytic agent before PCI reduces the risk of cardiogenic shock when compared with primary PCI alone, at the cost of an increased risk of bleeding. Whether such a strategy improves long-term survival is not known.
Evaluation of controlled IL-12 as monotherapy in subjects with recurrent GBM.
Authors: Rimas Vincas Lukas, E. Antonio Chiocca, Sylvia Christine Kurz, John Yu, Joseph C. Landolfi, Ganesh Rao, John A. Barrett, Jill Y. Buck, Nathan Demars, Amy Smith, John Miao, Qiang (John) Zhou, Arnold Bruce Gelb, Laurence Cooper
Journal: Journal of Clinical Oncology (2019)

2053 Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. It was conditionally produced in Ph1 “main” study (NCT02026271) in subjects with recurrent glioblastoma (rGBM) using a replication-incompetent adenovirus modified to express IL-12 under transcriptional control of the proprietary RheoSwitch Therapeutic System (Ad-RTS-hIL-12, Ad) regulated by dose of veledimex (V). Monotherapy resulted in sustained intra-tumor influx of activated cytotoxic T cells, consistent with immune-mediated anti-tumor effect, improving overall survival (OS). This correlated with increased circulating CD8 + /FoxP3 + T-cell ratio (“cytoindex”), an emerging biomarker of OS. While widely used with neurosurgery, dexamethasone (dex) blunts response to immunotherapies, nevertheless median mOS of subjects who received 20mg V of 12.7 mo (n=15) at 13.1 mo follow-up. However, subanalysis (n=6) showed low-dose dex (total ≤20 mg) during V dosing improved mOS (17.8 mo). We report a 36 subject substudy in rGBM with limited dex, total rGBM treated (n=70+). Methods: Ongoing Phase 1 substudy (NCT03679754) assesses safety and tolerability of local, inducible IL-12 by single intratumoral injection of Ad (2 x 10 11 viral particles) + V (20 mg PO QD x15 doses Days 0-14) in subjects not receiving dex 4 wks prior to Ad. Results: As of 03Jan19, the majority of new subjects received low-dose dex (total ≤20mg Days 0-14). The initial impact of dex on mOS will be reported. As in the main study, Ad+V 20 mg respectively increased (median) serum IL-12 and downstream IFN-g from Days 0-3: 0.8 to 8.8 pg/mL and 0 to 8.6 pg/mL. Between Days 0-14, there was net increase in cytoindex (from 20 to 46). The safety profile was similar to the main study with the main adverse reaction (AR) being mild to moderate cytokine release syndrome (CRS) characterized by flu-like symptoms. No grade 4 CRS was noted; all ARs were manageable and reversable upon holding V. Conclusions: Local, controlled IL-12 production using the Ad + V platform in subjects with rGBM safely activates the immune system and when dex is limited, appears to further improve mOS, which warrants continued investigation. Clinical trial information: NCT03679754.
Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition.
Authors: Jeffrey S. Weber, Hao Tang, Lauren Hippeli, Max Qian, Megan Wind-Rotolo, James M.G. Larkin, Jedd D. Wolchok, Mario Sznol, Caroline Robert, David Michael Woods, Andressa Sodre Laino, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2019)

100 Background: Acute phase reactants including C-reactive protein (CRP), and chronic inflammatory proteins including IL-6, which induces production of CRP from the liver, have been associated with a poor outcome in a variety of cancers. Methods: Sera from the CheckMate 064, 066 and 067 studies were assessed at baseline and on treatment for levels of IL-6 and CRP by Luminex. Associations between IL-6 and/or CRP levels and response or survival were determined. Purified endotoxin- and azide-free CRP was also tested for its immune effects in vitro using human T cells. Results: In patients receiving sequential nivolumab then ipilimumab in CheckMate 064 (cohort A), baseline serum IL-6 was associated with response (p = 0.03); serum IL-6 at week 12 after nivolumab alone (cohort A) or ipilimumab alone (cohort B), was also associated with response (p = 0.004 and 0.006, respectively). Baseline IL-6 above the median was associated with shorter survival in cohort A (p = 0.003) and cohort B (p = 0.0001). Serum CRP above the median was associated with shorter survival in cohort A (p = 0.001). Baseline IL-6 and CRP in cohort A were associated with one another, rho = 0.71 and p &lt; 0.0001 In the randomized CheckMate 067 study, higher baseline serum CRP above the median was associated with shorter survival for ipilimumab, nivolumab or the combination with p &lt; 0.0001, p &lt; 0.11, and p = 0.0034, respectively. In the randomized CheckMate 066 study, higher baseline serum CRP was associated with shorter survival for nivolumab or dacarbazine (p = 0.131 and P &lt; 0.0001 respectively). CRP suppressed T cell immunity and function, and levels above 10 micrograms/mL suppressed T cell proliferation (p = 0.005) and altered T cell signaling as well as calcium flux (p = 0.01), suggesting that CRP affected the earliest steps in T cell signaling and activation. Conclusions: High levels of CRP and IL-6 at baseline were associated with a poor response and shorter survival after nivolumab alone, and CRP with ipilimumab alone or the combination of both drugs. High levels of CRP were also associated with shorter overall survival in the randomized CheckMate 066 study of chemotherapy compared to nivolumab. CRP and IL-6 are prognostic factors for checkpoint inhibition.