bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of childhood maltreatment on prevalence, onset, and persistence of psychiatric comorbidities and suicide attempts in bipolar disorders
Authors: Grillault Laroche D. , Godin O. , Dansou Y. , Belzeaux R. , Aouizerate B. , Burté T. , Courtet P. , Dubertret C. , Haffen E. , Llorca P. M. , Olie E. , Roux P. , Polosan M. , Schwan R. , Leboyer M. , Bellivier F. , Marie-Claire C. , Etain B. ,   The FACE-BD Collaborators
Published: January 2022

AbstractBackgroundPsychiatric comorbidities and suicide attempts are highly prevalent in Bipolar Disorders (BD). We examined the associations between childhood maltreatment, psychiatric comorbidities, and suicide attempts, in terms of lifetime prevalence, sequence of onset, and current symptoms.MethodsWe assessed 3,047 individuals with BD for suicide attempts, anxiety disorders, substance use disorders, and eating disorders. Participants completed a self-report for the assessment of childhood maltreatment. Associations between childhood maltreatment and characteristics of comorbidities (lifetime prevalence, current symptoms, and age at onset) were examined using logistic regressions and network analyses.ResultsPsychiatric comorbidities were frequent with a mean number per individual of 1.23 (SD = 1.4). Most comorbidities occurred prior to the onset of BD. Participants who reported higher levels of childhood maltreatment had more frequent and multiple comorbidities, which were also more currently active at inclusion. Childhood maltreatment did not decrease the age of onset of comorbidities, but was associated with a faster accumulation of comorbidities prior to the onset of BD. Logistic regression and network analyses showed that emotional abuse and sexual abuse might play a prominent role in the lifetime prevalence of psychiatric comorbidities and suicide attempts.ConclusionsChildhood maltreatment was associated with suicide attempts, and with frequent, multiple, and persistent psychiatric comorbidities that accumulated more rapidly prior to the onset of BD. Hence, childhood maltreatment should be systematically assessed in individuals with BD, in particular when the course of the disorder is characterized by a high comorbid profile or by a high suicidality.
TRAIL Score: A Simple Model to Predict Immunochemotherapy Tolerability in Patients With Diffuse Large B-Cell Lymphoma
Authors: Harris Will , Bataillard Edward J. , Choi Yoonha , El-Galaly Tarec C. , Cuchelkar Vaikunth , Henneges Carsten , Kwan Antonia , Schneider Daniel J. , Paulson Joseph N. , Nielsen Tina G. 
Published: January 2022

PURPOSE Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) represents the standard of care for first-line treatment of diffuse large B-cell lymphoma (DLBCL). However, many patients are unable to tolerate R-CHOP and have inferior outcomes. This study aimed to develop a practical tool to help physicians identify patients with newly diagnosed DLBCL unlikely to tolerate a full course of R-CHOP. METHODS We developed a predictive model (Tolerability of R-CHOP in Aggressive Lymphoma [TRAIL]) on the basis of a training data set from the phase III GOYA trial (obinutuzumab with CHOP v R-CHOP in 1L DLBCL) using a composite binary end point, identifying patients who prematurely stopped or required reductions of R-CHOP. Candidate predictive variables were selected on the basis of known baseline characteristics that contribute to patient frailty, comorbidity, and/or chemotherapy toxicity. TRAIL was developed using an iterative trial-and-error modeling process to fit a logistic regression model. The final model was evaluated for robustness using a GOYA holdout data set and the phase III MAIN (R-CHOP with or without bevacizumab in 1L DLBCL) R-CHOP-21 data set as external validation. RESULTS TRAIL includes four simple predictors available in the routine clinical setting: Charlson Comorbidity Index, presence of cardiovascular disease or diabetes, serum albumin, and creatinine clearance. Model generalization performance estimated by the area under the curve was around or above 0.70 across GOYA training, GOYA holdout, and MAIN data sets. Classifying patients into low-, intermediate- and high-risk categories, the proportion of patients experiencing a tolerability event was 3.3%, 12.4%, and 32.9%, respectively, in GOYA holdout, and 9.7%, 9.7%, and 34.2%, respectively, in MAIN. CONCLUSION TRAIL may be useful as a clinical decision support tool for treatment decisions in patients with DLBCL who may not tolerate standard chemoimmunotherapies.
Microorganospheres as a novel precision oncology platform in colorectal cancer.
Authors: Hsu Carolyn , Wang Zhaohui , Oh Sehwa , Rupprecht Gabrielle , Pittman Kelly , Smith Amber , Delubac Daniel , Shen Xiling , Jia Jingquan , Hsu Shiaowen David 
Published: January 2022

149 Background: Patient-derived organoids (PDO) have been shown to have a high degree of similarity to the original patient tumors. PDO have also been used to perform high throughput drug screens and shown to correlate with patient response to therapy. Unfortunately, PDO require too much tissue, take too long to establish and are too inefficient and costly for adoption into the clinic. The ideal assay for clinical use would be one that could be performed in less than14 days from a core biopsy to minimize delay in therapy. We have now circumvented these barriers by leveraging recent technological advances in emulsion microfluidics and droplet generators to develop MicroOrganoSpheres (MOS) that can be established and used to predict drug sensitivity within 14 days of obtaining a biopsy. Methods: 18-gauge core biopsy specimens from patients with colorectal cancer liver metastasis who subsequently received an oxaliplatin based therapy were first obtained. Biopsy specimens were minced, enzymatically digested and mixed with components necessary to generate MOS. The mixture was then processed through a custom fabricated flow-focusing droplet microfluidic chip in our MOS Generator Device to generate MOS. After culturing for 8-10 days, MOS were then used to perform drug screen with oxaliplatin. Results: A total of twelve CRC biopsies from liver metastasis were obtained and processed to generate MOS with a success rate of 12/12 (100%). Furthermore, drug screens with oxaliplatin were performed on all twelve samples with an average time to drug screen of 10.1 days. We next wanted to determine if there was a correlation between MOS drug sensitivity and patient clinical outcome (ie. time on treatment). For the first eight patients, MOS was used to predict sensitivity to oxaliplatin and using a drug sensitivity cut-off of 1 uM, four patients were predicted to be sensitive to oxaliplatin and four patients were predicted to be resistant. Three of the four patients predicted to be sensitive to oxaliplatin continue to be on treatment (> 6 months), whereas 3 of the four patients predicted to be resistant to oxaliplatin progressed on oxaliplatin based therapy within 8 weeks (sensitivity = 80%, specificity = 100%, positive predictive value = 100%, negative predictive value = 75%). Conclusions: MOS can be generated from core biopsies and correlates to time on treatment. Although further studies will need to be conducted, the ability to generate MOS and perform a drug screen in < 14 days will allow for the development of a precision oncology platform that can be rapidly used in the clinic to guide therapy.
The role of genetic variants involved with ferroptosis regulator genes in predicting outcomes in patients (pts) with RAS-mutant metastatic colorectal cancer (mCRC): Data from MAVERICC and TRIBE trials.
Authors: Wang Jingyuan , Millstein Joshua , Arai Hiroyuki , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Wu Zhang , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef 
Published: January 2022

197 Background: Ferroptosis, an iron-dependent programmed cell death, is one of the anti-tumor mechanisms of anti-angiogenesis drugs. RAS mutation can confer ferroptosis in colorectal cancer (CRC). Previous studies suggested that polymorphisms of ferroptosis regulator genes are associated with the increased risk of CRC. Therefore, we hypothesized that genetic variants in the ferroptosis regulator genes may predict first-line treatment outcome in RAS-mutant mCRC pts treated with bevacizumab (bev)-based chemotherapy. Methods: Genomic DNA from blood samples of mCRC pts enrolled in two independent randomized trials, MAVERICC (FOLFIRI+bev arm: discovery cohort, RAS-mutant, n = 56; control-1: RAS-wildtype, n = 87) and TRIBE (FOLFOXIRI+bev arm: validation cohort, RAS-mutant, n = 57; control-2: RAS-wildtype, n = 34), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 13 selected SNPs in 5 main ferroptosis regulator genes (ACSL4, LPCAT3, SLC3A2, SLC7A11, ALOX15) was analyzed. Results: In the MAVERICC bev cohort, pts with RAS-mutant tumors carrying ALOX15 rs7217186 any C allele (n = 35) showed significant longer overall survival (OS) than carrier of T/T allele (n = 5) in both univariate (24.97 vs. 12.22 months, hazard ratio [HR] = 0.23; 95% confidence interval [CI]: 0.06-0.9; p = 0.02) and multivariate (HR = 0.06; 95%CI 0.007-0.5; p = 0.009) analysis. In the TRIBE bev cohort, RAS-mutant carriers of any C allele (n = 30) showed numerically longer progression-free survival (PFS), compared to carriers of T/T allele (n = 13) in both univariate (11.91 vs. 9.47 months, HR = 0.45; 95%CI 0.2-1.02; p = 0.05) and multivariate (HR = 0.42; 95%CI 0.16-1.1; p = 0.09) analysis. Conversely, RAS-wildtype carriers of any C allele (n = 17) showed significant shorter PFS than T/T carriers in the TRIBE bev cohort (8.91 vs. 15.59 months, univariate HR = 3.39, 95%CI: 1.03-11.18, p = 0.04). Conclusions: Our study demonstrated for the first time that ALOX15 polymorphisms may have different predictive values for the bev-based treatment in mCRC patients based on RAS mutational status. These findings may provide novel insights for the combination of ferroptosis inducers and anti-VEGF treatment.
Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for patients with advanced ESCC: A multicenter, single-arm, open-label phase Ⅱ clinical trial.
Authors: Wang Junsheng , Wu Tao , Luo Suxia , Li Ning , Hong Yonggui , Guo Yanzhen , Cheng Yufeng , Li Baosheng 
Published: January 2022

315 Background: Chemotherapy is the standard first-line therapy for advanced Esophageal Squamous Cell Carcinoma (ESCC). However, the poorly 5-year survival rate (4.8%) was unsatisfied. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Here we reported the update results and futhur evaluated the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited. Eligible patients were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60̃75mg/m2, iv, d1̃3, q3w) plus anlotinib (10mg, po, d1̃14, q3w) for 4̃6 cycles as initial therapy. Maintenance treatment was administered to those without disease progression with anlotinib monotherapy (10mg, po, d1̃14, q3w) until progression or unacceptable toxicity. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. The predefined sample size was 47. Tumor response was assessed by investigators according to RECIST version 1.1 criteria using CT scans every two cycles. Results: From Oct 2019 to Mar 2021, a total of 47 pts with ESCC were included and 46 pts were included in intention-to treat analysis, among whom 4 CR (8.7%), 31 PR (67.4%) and 7 SD (15.2%) were observed and 4 patients (8.7%) were not available for efficacy assessment. Consequently, ORR was 76.1% (95%CI: 61.2%-87.4%) and DCR was 91.3% (95%CI: 79.2%-97.6%). At the cut-off date on July 15, 2021, 23 pts discontinued treatment due to PD, the preliminary median PFS of ITT patients was 8.38 months (95%CI: 6.44-10.32). And the median OS was not yet available. Additionally, safety profile exhibited that the common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia. And the common grade ≥3 adverse events were myelosuppression (29.8%), gastrointestinal reaction (10.6%), hypertension (6.3%), fatigue (4.3%) and hypokalemia (4.3%). Conclusions: The update results suggested that paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusion should be validated in more pts with ESCC subsequently. Clinical trial information: NCT04063683.
Conversion of initially unresectable hepatocellular carcinoma (HCC) with triple-combination therapy (lenvatinib, anti-PD-1 antibodies, and transarterial therapy): A retrospective analysis.
Authors: Song Tianqiang , Lang Mengran , Lu Wei , Zhang Ti , Li Huikai , Wu Qiang , Cui Yunlong , Zhang Wei , Li Qiang , Zang Fenglin , Xing Wenge , Ren Shaohua , Gan Leijuan 
Published: January 2022

413 Background: Combination therapy with tyrosine kinase inhibitors and anti-PD-1 antibodies can allow selected patients with initially unresectable HCC to convert to surgical resection. We evaluated conversion therapy with a triple combination of lenvatinib (LEN), anti-PD-1 antibodies and transarterial therapy. Methods: We retrospectively searched medical records from 117 consecutive patients with unresectable/advanced HCC who received triple combination therapy between Dec 2018 and Oct 2020 at Tianjin Medical University Cancer Institute & Hospital. Eligible patients were required to have potentially resectable HCC, defined as meeting ≥1 of the following criteria: 1) estimated future liver remnant after radical (R0) resection of < 40% or < 30% in patients with/without cirrhosis, respectively; 2) R0 resection technically difficult to complete; 3) Child-Pugh score ≥7, ECOG performance status ≥1; 4) tumor thrombus in the main portal vein or inferior vena cava; 5) resectable extrahepatic metastases. The primary endpoint was the proportion of patients who underwent a successful resection (conversion rate). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), 6-month disease-free survival (DFS) and safety. Results: Of 37 patients included in the analysis, all received LEN and anti-PD-1 antibodies with transarterial chemoembolization (TACE, n = 22), hepatic arterial infusion chemotherapy (HAIC, n = 9) or both (n = 6). The conversion rate was 40.5% (15) and the ORR and DCR were 67.7% and 86.5% by RECIST v1.1 and 75.7% and 86.5% by mRECIST, respectively. The median conversion time was 4 months (range: 2-15). After a median postoperative follow-up time of 10 months (95% CI, 6.42-13.58), the 6-month DFS rate was 93%. Overall, 89.2% of patients had ≥1 treatment emergent adverse event (TEAE) and 29.7% experienced a Grade 3/4 TEAE, the most common was hypertension (18.9%, n = 7). Conclusions: A triple combination of LEN, anti-PD-1 antibodies and transarterial therapy was well tolerated and effective at converting potentially resectable HCC to resectable disease. These findings warrant confirmation by future prospective studies.
Early nivolumab addition to regorafenib in patients with hepatocellular carcinoma progressing under first-line therapy (GOING trial), interim analysis and safety profile.
Authors: Sanduzzi Zamparelli Marco , Matilla Ana , Lledó Jose Luis , Martínez Sergio Muñoz , Varela Maria , Iñarrairaegui Mercedes , Perelló Christie , Minguez Beatriz , Llarch Neus , Márquez Laura , Guerrero Antonio , Iserte Gemma , Castaño-García Andrés , Carrión Laura , Rimola Jordi , Garcia-Criado Ángeles , Domenech Gema , Boix Loreto , Bruix Jordi , Reig Maria 
Published: January 2022

428 Background: Regorafenib (Rego) improves survival in patients with hepatocellular carcinoma (HCC) (RESORCE trial) while nivolumab (Nivo) is also safe and active in terms of radiologic response (15-20% objective response) in second-line. The GOING trial (NCT04170556) is an investigator-initiated phase I/IIa study assessing the safety of Rego plus Nivo in HCC patients who progress and tolerate sorafenib (Cohort A) or who discontinue atezolizumab plus bevacizumab (Cohort B). Methods: Patients from cohort A receive Rego as monotherapy for the first 2 cycles (starting dose 160 mg/day, 3 weeks on/1 week off and adjusted for adverse events [AEs]) and Nivo is added at day 1 of cycle 3 (the first 10 patients at 3 mg/kg; since they did not present serious-AE (SAE), the final dose is 240 mg every two weeks). Treatment continues until unacceptable AEs, symptomatic tumor progression, patient decision or death. Safety is measured by the rate of AEs, rate of treatment related-AEs (Tr-AE), rate of AEs leading to treatment discontinuation and rate of death. Severity of AEs are evaluated according to CTCAE v.5.0. A futility analysis using the non-binding Lan & DeMets beta-spending functions with a boundary of p=0.814 is mandated when 32.8% of cohort A has data of tumor assessment at least at week 16 by RECIST 1.1. Results: Fifty-one patients have been enrolled in cohort A as of May 15, 2021. The first 30 (BCLC-C 73%) were considered in this safety analysis. All patients developed at least one AE, 29 (96.7%) had Tr-AEs of any grade and 10 (33.3%) had grade 3 (no grades 4 or 5 have been reported). Ten (33.3%) patients had a Rego-related AE, 4 (13.3%) Nivo-related, and 4 (13.3%) Tr-AE grade 3 of special interest. The table describes the profile Tr-AE occurring in > 10% of patients. Only 4 (13.3%) patients developed Tr-SAE, 3 (10 %) Rego-related and 3 (10 %) Nivo-related. Four patients discontinued the study due to physician decision, 2 for progression, and 2 for AEs (one related to study treatment). One patient had surgical resection after treatment discontinuation and a complete necrosis was observed at pathology. Conclusions: The sequential combination of Rego-Nivo has a manageable safety profile. Less than one third of the patients developed grade 3/4 Tr-AE and there was no treatment-related death. Futility analysis allowed to continuing recruitment. Clinical trial information: NCT04170556. [Table: see text]
Phase II study of combination pembrolizumab and olaparib in patients with advanced cholangiocarcinoma: Interim results.
Authors: Yin Chao , Armstrong Samantha Ann , Agarwal Seema , Wang Hongkun , Noel Marcus Smith , Weinberg Benjamin Adam , Marshall John , He Aiwu Ruth 
Published: January 2022

452 Background: Unresectable cholangiocarcinoma (CCA) remains a cancer of dismal prognosis as these tumors tend to be highly chemotherapy-refractory, providing patients (pts) a median survival of only around nine months. We herein provide an interim update to this phase II, single-arm, open-label study, where we investigate the safety and efficacy of olaparib plus pembrolizumab in pts with CCA after first-line gemcitabine-based therapy. We hypothesize that olaparib will increase tumoral response to pembrolizumab by inducing DNA damage and increasing tumor antigen number to produce a durable immune response against CCA - thereby increasing the overall response rate (ORR) of pts from 17.5% (historic chemotherapy control) to 35%. Methods: In total, 36 histologically confirmed advanced cholangiocarcinoma pts will be enrolled onto this trial. Pts receive pembrolizumab, 200 mg, on day 1 of each 21-day cycle, and oral olaparib, 300 mg, twice daily. The primary objective is to assess ORR, while a secondary aim is to evaluate safety. Tumor biopsies are collected at baseline, the third week after treatment initiation, and disease progression; the tissue is tested for ERCC1, PD-1/PD-L1 expression, IDH1/2 mutation status, and immune cell (CD3 and CD8) response. CT or MRI is carried out every 6 weeks for the first 6 months and every 9 weeks for the next 6 months to assess clinical response. Results: At the cutoff date of September 26, 2021, 12 pts had been enrolled and received at least one dose of olaparib plus pembrolizumab. The median age is 62 years (range 47-74); most are female (N = 10) and Caucasian (N = 8). Ten pts were diagnosed with cholangiocarcinoma and 2 with gallbladder carcinoma. According to RECIST v1.1, partial response (PR) was seen in one pt (-50%), stable disease (SD) in 4 pts (one with promising ongoing response at 23% tumor shrinkage), and disease progression in 7 pts. Three pts are actively on trial (1 PR and 2 SD). Complete molecular analysis by FoundationOne CDx revealed mutations in ATM (N = 2), SKT11 (N = 1) , ARID1A (N = 2) , and IDH1 (N = 2); the full tumor profile will be presented at the ASCO-GI meeting. Primary grade 3 treatment-related adverse events (AEs) included anemia (N = 2) and diarrhea (N = 1. Grade 1/2 AEs included thrombocytopenia (N = 2), anemia (N = 1), rash (N = 1), and diarrhea (N = 1). Conclusions: Interim trial results indicate that combination olaparib and pembrolizumab has acceptable safety and manageable toxicity in pts with advanced cholangiocarcinoma. Clinical trial information: NCT04306367.
Prognostic ability of the Gustave Roussy Immune Score for patients with advanced pancreatic adenocarcinoma.
Authors: Ma Lucy Xiaolu , Holzapfel Nicholas Timothy , Wang Yifan , Ramotar Stephanie , Allen Michael J , Jang Gun Ho , Zhang Amy , Dodd Anna , Hutchinson Shawn , Tehfe Mustapha , Ramjeesingh Ravi , Biagi James Joseph , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Grant Robert C , Knox Jennifer J. , O'Kane Grainne M. 
Published: January 2022

469 Background: The Gustave Roussy Immune Score (GRIm-S) considers a composite of neutrophil to lymphocyte ratio (> 6 = 1), albumin (< 35 = 1) and LDH (> ULN = 1) and has been established as a prognostic score and may in aid in the selection of patients for phase 1 trials of immune checkpoint inhibitors. Methods: We explored the prognostic impact of the GRIm-S (high > 1) in patients enrolled on the COMPASS trial and correlated the score with genomic and clinical characteristics. Patients in this trial had biopsies for whole genomic and RNA sequencing prior to standard chemotherapy regimens in the advanced setting. Results: 252 patients were included in the analyses with a median follow-up time of 28 months. 16% of patients had a high GRIm-S with significantly shorter median overall survival (OS) of 4.1 months versus 10.0 months in those with a low score (HR 2.18, 95% CI 1.4-3.4, p < 0.0001). In the GRIm-S-high cohort, early progression with non-evaluable disease and disease progression were more common than in the GRIm-S low cohort (56% vs 31%, p = 0.003). In a multivariable analysis, a high GRIm-S was poorly prognostic (HR 1.6 95% CI 1.3-1.9, p < 0.001), whereas the classical RNA subtype (vs. basal-like) (HR 0.41, 95% CI 0.3-0.6, p < 0.001) and a high HRDetect score (HR 0.47 95% CI 0.3-0.7, p < 0.001) associated with superior OS. The GRIm-S did not correlate with RNA subtypes or with specific KRAS mutations. There were no differences in structural variant load or tumour mutational burden between groups. However those with a high GRIm-S did have a higher total target lesion diameter at baseline (p < 0.001). Conclusions: The GRIm-S identifies a subset of patients who have aggressive pancreas cancer and short life expectancy. This information may help clinicians in treatment decision making and selection for clinical trials.