bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flow cytometric micronucleus assay and TGx-DDI transcriptomic biomarker analysis of ten genotoxic and non-genotoxic chemicals in human HepaRG™ cells
Authors: Buick Julie K. , Williams Andrew , Gagné Rémi , Swartz Carol D. , Recio Leslie , Ferguson Stephen S. , Yauk Carole L. 
Published: February 2020

Abstract
Background
Modern testing paradigms seek to apply human-relevant cell culture models and integrate data from multiple test systems to accurately inform potential hazards and modes of action for chemical toxicology. In genetic toxicology, the use of metabolically competent human hepatocyte cell culture models provides clear advantages over other more commonly used cell lines that require the use of external metabolic activation systems, such as rat liver S9. HepaRG™ cells are metabolically competent cells that express Phase I and II metabolic enzymes and differentiate into mature hepatocyte-like cells, making them ideal for toxicity testing. We assessed the performance of the flow cytometry in vitro micronucleus (MN) test and the TGx-DDI transcriptomic biomarker to detect DNA damage-inducing (DDI) chemicals in human HepaRG™ cells after a 3-day repeat exposure. The biomarker, developed for use in human TK6 cells, is a panel of 64 genes that accurately classifies chemicals as DDI or non-DDI. Herein, the TGx-DDI biomarker was analyzed by Ion AmpliSeq whole transcriptome sequencing to assess its classification accuracy using this more modern gene expression technology as a secondary objective.

Methods
HepaRG™ cells were exposed to increasing concentrations of 10 test chemicals (six genotoxic chemicals, including one aneugen, and four non-genotoxic chemicals). Cytotoxicity and genotoxicity were measured using the In Vitro MicroFlow® kit, which was run in parallel with the TGx-DDI biomarker.

Results
A concentration-related decrease in relative survival and a concomitant increase in MN frequency were observed for genotoxic chemicals in HepaRG™ cells. All five DDI and five non-DDI agents were correctly classified (as genotoxic/non-genotoxic and DDI/non-DDI) by pairing the test methods. The aneugenic agent (colchicine) yielded the expected positive result in the MN test and negative (non-DDI) result by TGx-DDI.

Conclusions
This next generation genotoxicity testing strategy is aligned with the paradigm shift occurring in the field of genetic toxicology. It provides mechanistic insight in a human-relevant cell-model, paired with measurement of a conventional endpoint, to inform the potential for adverse health effects. This work provides support for combining these assays in an integrated test strategy for accurate, higher throughput genetic toxicology testing in this metabolically competent human progenitor cell line.
MRI measurement of optic nerve sheath diameter using 3D driven equilibrium sequence as a non-invasive tool for the diagnosis of idiopathic intracranial hypertension
Authors: Abdelrahman Ahmed S. , Barakat Mai M. K. 
Published: February 2020

Abstract
Background
The idiopathic intracranial hypertension is a disease that is represented by high intracranial pressure of unknown reason. The visual disturbance presents the main medical problem of this syndrome. This study was conducted to assess the diagnostic value of the optic nerve sheath diameter (ONSD) measured using MRI 3D DRIVE in the diagnosis of idiopathic intracranial hypertension.

Results
The mean value of the ONSD measured using 3D DRIVE sequence in the patient group (5.81 ± 0.33) was significantly higher than the mean value of the normal control group (4.95 ± 0.45) (p < 0.001). The optimal optic nerve sheath diameter cut-off value for diagnosing idiopathic intracranial hypertension was > 5.31 mm, with 94.12% sensitivity and 93.3% negative predictive value.

Conclusion
The high resolution of 3D DRIVE provides an accurate measurement of ONSD which correlated with elevated cerebrospinal fluid pressure and hence the diagnosis of idiopathic intracranial hypertension.
Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): Results from the multicohort, phase II KEYNOTE-158 study.
Authors: Marabelle Aurelien , Cassier Philippe Alexandre , Fakih Marwan , Guren Tormod Kyrre , Italiano Antoine , Kao Steven Chuan-Hao , Nielsen Dorte , Ascierto Paolo Antonio , Bariani Giovanni M. , Santoro Armando , Shah Manisha H. , Asselah Jamil , El-Khoueiry Anthony B. , Spencer Kristen Renee , Takahashi Shunji , Chatterjee Arkendu , Jin Fan , Norwood Kevin , Delord Jean-Pierre 
Published: February 2020

1 Background: For patients (pts) with ASCC, second-line or later treatment options have been limited. Pembrolizumab (pembro), an anti-PD-1 monoclonal antibody, has demonstrated antitumor activity in several tumor types (including ASCC) in the multicohort phase 1b KEYNOTE-028 study. KEYNOTE-158 (NCT02628067) is an open-label, phase 2, multicohort study that evaluates antitumor activity and safety of pembro in pts with previously treated advanced cancer. Results from the ASCC cohort are presented. Methods: Eligible pts were ≥18 y with histologically/cytologically documented metastatic and/or unresectable ASCC with prior treatment failure on or intolerance to standard first-line therapy, measurable disease per RECIST v1.1, ECOG PS of ≤1, and evaluable tissue sample for PD-L1 and biomarker analysis. PD-L1 expression was assessed by the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). Pts received pembro 200 mg Q3W until disease progression, unacceptable AE, or completion of 35 cycles. The primary endpoint was ORR per RECIST v1.1 (assessed every 9 wk for 12 mo, then every 12 wk thereafter) by independent central review. Secondary endpoints were DOR, OS, PFS and safety. Results: 112 pts with ASCC were enrolled (81.3% women; median age, 61 y [range 32–79]; ≥2 prior therapies, 73.2%). At database cutoff (Dec 6, 2018) 10 pts (8.9%) had completed 35 cycles and 102 discontinued; median follow-up was 12.0 mo (range, 0.8–33.0) Five pts had CR and 8 had PR; ORR was 11.6% (95% CI, 6.3–19.0). Median DOR was not reached (range, 6.0+ to 29.1+ mo). Responses occurred in 11/75 pts (14.7%) with PD-L1 combined positive score (CPS) ≥1 and 2/30 pts (6.7%) with PD-L1 CPS < 1. Among all pts, median OS was 12.0 mo (95% CI, 9.1–15.4), and median PFS was 2.0 mo (95% CI, 2.0–2.1). 68 (60.7%) pts had treatment-related AEs, including 21 (18.8%) who had grade 3–5 events; there were no treatment-related deaths. 4 pts (3.6%) discontinued due to treatment-related AEs. 27 pts (24.1%) had immune-mediated AEs/infusion reactions. Conclusions: Pembro demonstrated antitumor activity and manageable toxicity in pts with heavily pretreated advanced ASCC, regardless of PD-L1 status. Clinical trial information: NCT02628067.
Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with mFOLFOX6 (three versus six months) in the prospective IDEA France cohort study (PRODIGE-GERCOR).
Authors: Pages Franck , Andre Thierry , Taieb Julien , Vernerey Dewi , Henriques Julie , Borg Christophe , Marliot Florence , Ben Jannet Rim , Louvet Christophe , Mineur Laurent , Bennouna Jaafar , Desrame Jérôme , Faroux Roger , Duval Alex , Laurent-Puig Pierre , Svrcek Magali , Hermitte Fabienne , Catteau Aurelie , Galon Jerome , Emile Jean-François 
Published: February 2020

10 Background: In stage III colon cancer patients treated with CAPOX, 3 months of therapy was as effective as 6 months. It was not the case for those receiving mFOLFOX6. We assessed the prognostic and predictive value of the Immunoscore (IS) in the mFOLFOX6 subgroup (90% of patients enrolled) of the IDEA France cohort study. Methods: 1200 patients randomly assigned to 3 months (n = 593) or 6 months (n = 607) of mFOLFOX6, with available tumor sample, were included. Densities of CD3+ and cytotoxic CD8+ T-cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS using the pre-defined cut-off. The IS performance to predict disease-free survival (DFS) was assessed in each arm and adjusted in multivariate Cox models. Results: In a two-category IS analysis, Low and (Int+High) IS were observed in 423 (43.5%) and 550 (56.5%) patients, respectively. Low IS identified patients with higher-risk of relapse or death (HR = 1.60; 95% CI 1.27-2.01, P < 0.0001). The 3-year DFS was 66.34% (95% CI 61.54-70.69) and 77.66% (95% CI 73.86-80.97) for Low and (Int+High) IS, respectively. In multivariate analysis, IS remained independently associated with DFS (P = 0.0007) when combined with T/N stage. A statistically significant interaction was observed for the IS predictive value for treatment duration (3 vs 6 months) in term of DFS in the whole population (P = 0.0566) and TN subgroups (Low-risk T1-3, N1 vs High-risk T4 and/or N2; P = 0.0015). The 3-year DFS of patients with (Int+High) IS in the 3-month arm was 71.5% (95% CI 65.7-76.6) versus 83.8% (95% CI, 78.8-87.8) in the 6-month arm (HR = 0.528; 95% CI 0.372-0.750; log-rank P = 0.0004); the benefit retained in low-risk and high-risk patients (all P≤0.010). 6-month mFOLFOX6 showed no significant benefit for patients with Low IS (HR = 0.836, log-rank P = 0.269). Conclusions: The IS prognostic value in patients treated with mFOLFOX6 was confirmed. Its predictive value for benefit of longer duration treatment, despite a strong statistical signal, needs to be confirmed in an external validation cohort. Clinical trial information: NCT03422601.
Irinotecan, cetuximab, and bevacizumab (CBI) versus irinotecan, cetuximab, and placebo (CI) in irinotecan-refractory metastatic colorectal cancer (mCRC): Results from an ACCRU network randomized phase II trial.
Authors: Lipsyc-Sharf Marla , Ou Fang-Shu , Yurgelun Matthew B. , Rubinson Douglas Adam , Schrag Deborah , Dakhil Shaker R. , Stella Philip J. , Weckstein Douglas Jay , Wender Donald B. , Faggen Meredith Gail , Zemla Tyler , Heying Erica N. , Schuetz Samantha R , Noble Stephanie , Meyerhardt Jeffrey A. , Bekaii-Saab Tanios S. , Fuchs Charles S. , Ng Kimmie 
Published: February 2020

102 Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.
A phase I/II study of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer.
Authors: Monge B. M. Cecilia , Xie Changqing , Steinberg Seth M. , Fioraventi Suzanne , Walker Melissa , Mabry-Hrones Donna , Wood Bradford J. , Kleiner David E , Greten Tim F. 
Published: February 2020

117 Background: The benefit of immune checkpoint inhibition is limited to the small percentage of advanced colorectal cancer (CRC) patients whose tumors present mismatch repair (MMR) gene abnormalities; immunotherapy has not shown benefit in patients with MMR proficient CRC. Oncolytic immunotherapy represents a unique therapeutic platform. This phase I trial tests the safety of the combination of pexastimogene devacirepvec (Pexa-Vec) plus durvalumab (durva) in patients with locally advanced or metastatic CRC. Methods: Eligible patients with advanced proficient mixed match repair (pMMR) CRC received intravenous infusion of Pexa-Vec at dose level 3 x 108 plaque forming units (pfu) (DL1) or at 109 pfu (DL2) every 2 weeks for 4 doses and durva 1500 mg every 28 days. Response was assessed with CT every 8 weeks. Adverse events were recorded and managed. The primary endpoint included safety, tolerability and feasibility of this combination therapy. Samples of tumor and peripheral blood were collected for assessment of immune parameters. Results: Sixteen patients (6 males and 10 females) enrolled with a median age of 52.1 years (range 39-69) from Dec, 2017 to Oct, 2018. Four patients were treated with Pexa-Vec at DL1 and durva;twelve patients were treated with Pexa-Vec at DL2 and durva.The most common treatment related adverse events (TRAE) included fever 15/16 (94 %), hypotension 12/16 (75 %), chills 12/16 (75%), fatigue 8/16 (50%), sinus tachycardia 7/16 (44%) and rash 6/16 (38%). Grade 3/4 TRAEs were reported in 8/16 (50%)patients; the most common were fever 7/16 (44 %), lymphopenia 2/16 (13%), neutropenia 1/16 (6%) and anemia 1/16 (6%). 14 patients were evaluable for response analysis; one patient 1/14 (7 %) achieved a confirmed partial response (lasting 7.1 months) and continues to receive treatment, while 13 patients had progressive disease. The median progression free survival (PFS) was 2.2 months (95% CI: 2.2-2.3 months) and the median overall survival (OS) was 7.5 months (CI: 4.9-10.1 months). Conclusions: Combination therapy of Pexa-Vec with durva ICI issafe, well tolerated and demonstrates possible activity in patients with advanced pMMR CRC. Clinical trial information: NCT03206073.
Oligometastatic colorectal cancer: Prognostic implications of tumor load, role of locoregional treatments, and of first-line therapy intensification—A pooled analysis of TRIBE and TRIBE2 studies by GONO.
Authors: Zucchelli Gemma , Moretto Roberto , Rossini Daniele , Lonardi Sara , Murgioni Sabina , Tonini Giuseppe , Cupini Samanta , Ratti Margherita , Urbano Federica , Libertini Michela , Antoniotti Carlotta , Corallo Salvatore , Buonadonna Angela , Bordonaro Roberto , Ricci Vincenzo , Tamburini Emiliano , Grande Roberta , Aprile Giuseppe , Falcone Alfredo , Cremolini Chiara 
Published: February 2020

12 Background: According to the ESMO guidelines a metastatic spread involving up to 2 or occasionally 3 sites with 5 or sometimes more metastases (mts) is defined as oligometastatic disease (OMD) and the possibility to offer locoregional treatments (LRTs) should be carefully considered. Tumor load and treatment’s objective (cytoreduction vs disease control) are included among factors affecting the choice of the intensity of the upfront chemotherapy (CT). Nevertheless, no data from clinical trials adopting this definition are currently available, so that the prognostic effect of tumor load, the impact of LRTs and the magnitude of benefit from the CT-intensification in OMD remain unclear. Here we assess the effect of FOLFOXIRI/bev compared to doublets (FOLFOX or FOLFIRI)/bev and the impact of LRTs according to tumor load (OMD vs non-OMD) in a pooled analysis of two randomized phase III studies (TRIBE and TRIBE2). Methods: Subgroup analyses for ORR, PFS and OS were performed according to tumor load at baseline. OMD was defined as up to 5 mts, up to 3 mts in one organ, up to 3 affected organs, mts size ≤ 3 cm, absence of ascites and peritoneal, bone and central nervous system mts. Results: Among 1187 patients (pts) enrolled, 1158 were classifiable: 126 as OMD (11%) and 1032 as non-OMD (89%). Pts with OMD had longer PFS (14.3 vs 10.5 months (mos); p < 0.01) and OS (44.3 vs 24.0 mos; p < 0.01) compared with those with non-OMD. These results were confirmed in multivariable models (p < 0.01). Also among pts who underwent LRTs with curative intent during first line (N = 202), those with OMD at baseline (N = 35) reported longer OS than those with non-OMD (59.6 vs 50.6 mos; p = 0.04). The benefit provided by FOLFOXIRI/bev compared to doublets/bev was confirmed in the OMD subgroup with no interaction effect between treatment arm and tumor load in terms of ORR, PFS and OS (p for interaction = 0.10, 0.58 and 0.23, respectively). Conclusions: OMD is confirmed as a positive prognostic factor and is associated with a higher magnitude of long-term benefit from LRTs than non-OMD. The positive impact of the intensification of the upfront CT is independent of tumor load.
First-line durvalumab + monalizumab, mFOLFOX6, and bevacizumab or cetuximab for metastatic microsatellite-stable colorectal cancer (MSS-CRC).
Authors: Wainberg Zev A. , Diamond Jennifer Robinson , Curigliano Giuseppe , Deva Sanjeev , Bendell Johanna C. , Han Sae-Won , Kalyan Aparna , Naidoo Jarushka , Kim Richard D. , Patel Sandip Pravin , Kourtesis Panagiotis , Li Xia , Ascierto Maria , Song Xuyang , Das Mayukh , Segal Neil Howard 
Published: February 2020

128 Background: Targeting multiple immune checkpoint pathways and combining checkpoint inhibition with chemotherapy may enhance response in MSS-CRC. In a Phase 1/2, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was added to monalizumab (M; an anti-NKG2A antibody). In dose-exploration cohorts, D+M was added to chemotherapy and a biologic agent (bevacizumab [DMCB] or cetuximab [DMCC]) for first-line treatment of advanced/metastatic MSS-CRC. Initial data showed DMCB was well tolerated and clinically active. Here we report updated efficacy and safety of DMCB and initial safety of DMCC. Methods: Eligible patients (pts) had MSS-CRC ( RAS/BRAF wt with a left-sided colon primary tumor in the DMCC cohort) and ECOG PS 0–1. They received D 1500 mg Q4W, M 750 mg Q2W, mFOLFOX6 Q2W and bevacizumab 5 mg/kg Q2W or cetuximab 250/400 mg/m2 QW (up to 500 mg/m2 Q2W) for up to 3 yr. The primary endpoint was safety and tolerability; secondary endpoints included antitumor activity. Results: As of Aug 26, 2019, 18 pts received DMCB and 17 pts received DMCC. Treatment-emergent adverse events (AEs) occurred in 100.0% of the DMCB cohort (most commonly fatigue, nausea and peripheral neuropathy) and 94.1% of the DMCC cohort (most commonly peripheral neuropathy, rash and dermatitis acneiform). The AEs were grade 3/4 in 77.8% of pts receiving DMCB and 70.6% of pts receiving DMCC, and were serious in 38.9% and 47.1%, respectively. Response was evaluable in 17 pts receiving DMCB; objective response rate was 41.2% (all PRs; Table). Responses occurred early and the median duration of response has not yet been reached. Conclusions: In advanced/metastatic MSS-CRC, first-line DMCB and DMCC had a manageable safety profile and DMCB showed promising preliminary activity. Clinical trial information: NCT02671435. [Table: see text]
Started dose of regorafenib and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): A systematic review and meta-analysis.
Authors: Fedyanin Mikhail , Polyanskaya Elizaveta , Pokataev Ilya , Tryakin Alexey , Tjulandin Sergei 
Published: February 2020

131 Background: Regorafenib is one of the standards of care in pts with chemorefractory mCRC. However, high toxicity is a common reason of treatment discontinuation, interruption and dose reduction. There are conflicting results how started dose of regorafenib influence OS (REBECCA, ReDOS and ARRANGE trials). Therefore, we performed systemic review and meta-analysis to evaluate association between started dose of regorafenib and OS in pts with mCRC. Methods: We performed a search of all retrospective and prospective studies in PubMed, Embase, and Cochrane library. The search criteria included all articles and abstracts for all years before 20.08.2019. We compared the pts with standard dose (160 mg) and <160 mg at the first cycle. Primary outcome was hazard ratio (HR) for OS and 95% confidence interval (CI). Random effects were used for analysis due to potential heterogeneity of the studies. Meta-analysis was conducted by "Review Manager" Ver. 5.3. Results: We identified 6 trials – 3 prospective and 3 retrospective ones, which included 1955 pts (160 mg – 1584 and <160 mg – 571 pts). Two trials showed worsening OS in pts with dose <160 mg (Adenis et al., 2016 – HR 1.26, 95%CI 1.01-1.56 and Aljubran et al., 2019 – HR 2.25, 95%CI 0.93-5.43). Two studies showed improving OS in pts with dose <160 mg (Bekaii-Saab et al., 2018 – HR 0.72, 95%CI 0.47-1.11; Gotfrit et al., 2017 – HR 0.46, 95%CI 0.17-1.22). And two studies didn’t show any difference (Yamaguchi et al., HR 0.95, 95%CI 0.82-1.1 and Argiles et al., 2019 - HR 0.86, 95%CI 0.65-1.13). According to results of the meta-analysis there was not any difference in OS between groups with the dose 160 mg and <160 mg at the first cycle: HR 0.97, 95% CI 0.78-1.21; p = 0.79; I2 = 64. Conclusions: Started dose of regorafenib <160 mg in the pts with chemorefractory mCRC does not worsen the OS and this approach can be safely used in the daily clinical practice.