bluuebunny/crossref_metadata_2025_split huggingface dataset:
Young-onset colorectal: Emotional and psychosocial effects on patients, survivors, and caregivers.
Authors: Porter Laura Diane , Yarden Ronit , Newcomer Kim Lynn ,   N2Y Advisory Board
Published: June 2021

3592 Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. Young-onset colorectal cancer refers to individuals diagnosed under the age of 50. In recent years, the incidence has increased by 2.2% annually in individuals younger than 50 years, and 1% in individuals 50-64, in contrast to a 3.3% decrease in adults 65 years and older. The Colorectal Cancer Alliance launched the Never Too Young Survey and the Caregiver Survey to assess and better understand the unmet needs of the young-onset population and their caregivers. Methods: A cross-sectional study, conducted in the form of an online survey, was launched to better understand the experiences around YO-CRC patients and caregivers. YO-CRC patients and survivors (N = 885) and caregivers (N = 204) completed an online questionnaire that was based on established instruments including PROMIS, EORTC-QOL-30, and EORTC-CR-29. The final survey instrument and study plan were reviewed and approved by the Aspire Inc. Institutional Review Board. Results: Nearly 75% of patients/survivors shared that they have been concerned about their mental health, and 64% responded that they have needed help for their depression. Further, 67% of caregivers surveyed responded that they were also concerned about their mental health, and 68% responded that they needed help with their depression. Seventy-one percent of caregivers often felt sadness, and 30% indicated that they had lost hope. Emotional exhaustion was reported by 77% of caregivers, whether they were providing round-the-clock care or caregiving from a distance. The effect was more pronounced in the patient/survivor cohort, with 95% indicating that emotional exhaustion impacted their lives. As a result, 71% of caregivers and 29% of patients/survivors indicated that they had withdrawn from other people. These results indicate the emotional toll that colorectal cancer has on patients/survivors and caregivers and their need for further resources. Conclusions: The Colorectal Cancer Alliance is committed to meeting these needs and providing resources that support patients, survivors and caregivers. Information and services may assist the caregiver in helping the patient make decisions, including shifting roles and routines in response to changing demands of YO-CRC. Further studies should investigate psychological well-being and support strategies.
First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): Expanded efficacy and safety data from CheckMate 649.
Authors: Moehler Markus H. , Shitara Kohei , Garrido Marcelo , Salman Pamela , Shen Lin , Wyrwicz Lucjan , Yamaguchi Kensei , Skoczylas Tomasz , Campos Bragagnoli Arinilda Silva , Liu Tianshu , Schenker Michael , Yanez Patricio Eduardo , Tehfe Mustapha , Li Mingshun , Cullen Dana , Memaj Arteid , Lei Ming , Xiao Hong , Janjigian Yelena Y. , Ajani Jaffer A. 
Published: June 2021

4002 Background: CheckMate 649 is the largest randomized, global phase 3 study of 1L programmed death (PD)-1 inhibitor–based therapy in GC/GEJC/EAC. 1L NIVO + chemo demonstrated superior overall survival (OS) vs chemo, with progression-free survival (PFS) benefit and an acceptable safety profile in pts whose tumors expressed PD-ligand (L)1 at combined positive score (CPS) ≥ 5 and ≥ 1, and in all randomized pts (Moehler et al. Ann Oncol 2020). We report additional data for all randomized pts. Methods: Eligible pts had previously untreated, unresectable advanced or metastatic GC/GEJC/EAC. Known HER2-positive pts were excluded. Pts were randomized to receive NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded central review in PD-L1 CPS ≥ 5 pts. Hierarchically tested secondary endpoints were OS in PD-L1 CPS ≥ 1 and all randomized pts. Results: At 12-month minimum follow-up for 1581 randomized pts, NIVO + chemo had a statistically significant OS benefit vs chemo (HR 0.80 [99.3% CI 0.68–0.94; P = 0.0002]) in all randomized pts; PFS benefit was also seen (HR 0.77 [95% CI 0.68–0.87]). OS benefit was observed in multiple prespecified subgroups, consistent with the primary population. Grade 3–4 treatment-related adverse events (TRAEs) were reported in 59% (NIVO + chemo) and 44% (chemo) of pts. TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) are shown in the table. Pts in the NIVO + chemo arm had decreased risk of symptom deterioration on treatment vs those in the chemo arm (HR 0.77 [95% CI 0.63–0.95; P = 0.0129]). Tolerability as measured by the FACT-Ga GP5 item was similar in both treatment groups. Conclusions: The addition of NIVO to chemo demonstrated improved OS and PFS benefit in all randomized pts, along with an acceptable safety profile and maintained tolerability as well as QoL, providing further support for NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116. [Table: see text]
Neo-AEGIS (Neoadjuvant trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Preliminary results of phase III RCT of CROSS versus perioperative chemotherapy (Modified MAGIC or FLOT protocol). (NCT01726452).
Authors: Reynolds John V. , Preston Shaun R. , O'Neill Brian , Lowery Maeve Aine , Baeksgaard Lene , Crosby Thomas , Cunningham Moya , Cuffe Sinead , Griffiths Gareth Owen , Roy Rajarshi , Falk Stephen , Hanna George , Bartlett Frederick R. , Parker Imelda , Alvarez-Iglesias Alberto , Nilsson Magnus , Piessen Guillaume , Risum Signe , Ravi Narayanasamy , McDermott Raymond S. 
Published: June 2021

4004 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) is unknown. A key question is whether neoadjuvant multimodal therapy, specifically CROSS (carboplatin/paclitaxel, 41.4Gy radiation therapy), is superior to optimum peri-operative chemotherapeutic regimens including modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) and more latterly FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin). Neo-AEGIS was designed as the first randomised controlled trial to address this question. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5%. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 24.5 (1-92) months, at the second futility analysis (60% of planned events), there were 143 deaths, 70 CROSS and 73 MAGIC/FLOT arm, with 3-year estimated survival probability of 56% (95% CI 47,64) and 57% (95% CI 48,65), respectively [(HR 1.02 (95%CI. 0.74-1.42))]. Based on the absence of futility evidenced in this data the DSMB recommended closure of recruitment in December 2020. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy, notwithstanding greater proxy markers of local tumour response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in decision making in modern practice. Clinical trial information: NCT01726452. [Table: see text]
Hepatic arterial infusion chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase 3 trial (The FOHAIC-1 study).
Authors: Lyu Ning , Zhao Ming 
Published: June 2021

4007 Background: Advanced hepatocellular carcinoma (HCC) with mega liver masses and macrovascular invasion were commonly observed at the first diagnosis, while with less extrahepatic metastases (77.5% vs. 37.9%). However, in clinical trials IMbrave150, SHARP, and Asia-Pacific SHARP, the percentage of extrahepatic metastases reached 63%, 53%, and 68.7%, respectively, while macrovascular invasion only accounted for 38%, 36%, and 36%. Unlike the previous and ongoing phase 3 clinical trials exploring the optimal systemic medication in the first-line treatment of advanced HCC, this study mainly focused on a population with a heavy intrahepatic tumor burden. Methods: In this open-label, phase 3 trial, patients were randomly assigned in a 1:1 ratio to undergo hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimens (HAIC-FO) or sorafenib treatment. Patients in the HAIC-FO group were recommended to receive tumor and normal tissue biopsy to search for the potential genomic biomarkers in predicting the response to treatment. Results: Between May 2017 and May 2020, 551 patients were recruited. Two hundred sixty eligible patients were randomly assigned to receive HAIC-FO (n = 130) or sorafenib (n = 132) and were included in the intention-to-treatment population. Macrovascular invasion with or without extrahepatic metastasis was present in 82.8% of patients (84.6% and 81.1%; P = 0.446). The median tumor diameter was 11.7 cm (IQR 8.3-14.0) of the HAIC-FO group and 10.8 cm (8.7-13.6) of the sorafenib group (P = 0.439). The percentage of patients with > 50% tumor volume involvement of the liver was 41.5% and 39.4%, respectively (P = 0.724). At the time of data cutoff (Oct 31, 2020, at 190 deaths [79 of HAIC-FO and 111 of sorafenib]), patients receiving HAIC-FO had a median overall survival of 13.9 months (95%CI 10.6-17.2), compared with 8.2 months (7.5-9.0) for those receiving sorafenib (HR 0.408 [95%CI 0.301-0.552], P < 0.001). Tumor downstaging occurred in 16 (12.3% of 130) patients of the HAIC-FO group, including 15 (93.8%) receiving curative surgery or ablation and finally achieving a median overall survival (progression-free survival) of 20.8 (16.4) months (95%CI 9.1-32.5 [7.5-25.3]) with a 1-year rate of 93.8% (68.8%). Analyses of predictive biomarkers based on the whole genome sequencing were ongoing in the HAIC-FO group. Conclusions: This randomized phase 3 study proved that HAIC-FO had superior efficacy and survival outcome than sorafenib in the first-line treatment of primary diagnostic, advanced HCC, indicating that patients with heavy intrahepatic tumor burden, HAIC-FO monotherapy might be a better strategy than sorafenib. Clinical trial information: NCT03164382.
Neoadjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of resectable BCLC stage A/B hepatocellular carcinoma patients beyond Milan criteria: An interim analysis of a multi-center, phase 3, randomized, controlled clinical trial.
Authors: Li Shaohua , Zhong Chong , Li Qiang , Zou Jingwen , Wang Qiaoxuan , Shang Changzhen , Cheng Yuan , Cao Mingrong , Huang Huakun , Mei Jie , Lu Lianghe , Zhao Rongce , Lin Wenping , Wen Yuhua , Guo Zhixing , Ling Yihong , Zheng Lie , Wei Wei , Guo Rongping 
Published: June 2021

4008 Background: The efficacy of operation, as the only radical option for resectable BCLC stage A/B hepatocellular carcinoma (HCC) patients beyond Milan criteria, is still unsatisfactory. This study aimed to investigate to efficacy and safety of preoperative neoadjuvant transarterial infusion chemotherapy (TAI) with FOLFOX regimen for these patients. Methods: In this multi-center, prospective, phase 3, randomized, open-labeled, controlled clinical trial, resectable BCLC stage A/B HCC patients beyond Milan criteria were randomly assigned (1:1) before hepatectomy to receive either neoadjuvant TAI (NT group) or operation directly without any neoadjuvant treatment (OP group). The primary endpoint was overall survival (OS), the secondary endpoints are progression-free survival (PFS), recurrence free survival (RFS), and safety. Results: Between March, 2016 and July, 2020, 208 patients enrolled from five Chinese hospitals were randomly assigned to NT group (n=104) or OP group (n=104)， with 99 patients in NT group and 100 patients in OP group included in the efficacy and safety analysis. Clinicopathological characteristics were balanced between the two groups. The 1-, 2-, and 3-year OS rates for NT group were 92.9%, 78.6%, and 63.5%, and were 79.5%, 62.0%, and 46.3% for OP group, respectively. The 6-, 12-, and 18-month PFS rates for NT group were 77.6%, 50.4%, and 47.4%, and were 52.7%, 42.8%, and 34.8% for OP group, respectively. The OS and PFS were significantly better in NT group than in OP group (p=0.016 and 0.017, respectively). The 6-, 12-, and 18-month RFS rates for NT group were 63.8%, 47.3%, and 47.3%, and were 52.7%, 42.8%, and 34.8% for OP group, respectively. The RFS between the two group had no difference (p=0.385). No patients in NT group experienced grade 3 or more severe TAI related adverse events. The operation related adverse events were similar between two groups (p=0.300). Conclusions: Neoadjuvant TAI before hepatectomy may bring survival benefits for resectable BCLC stage A/B HCC patients beyond Milan criteria. Trial number: NCT03851913. Clinical trial information: NCT03851913.
High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.
Authors: Seeber Andreas , Kocher Florian , Pircher Andreas , Puccini Alberto , Baca Yasmine , Xiu Joanne , Zimmer Kai , Haybaeck Johannes , Spizzo Gilbert , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Salem Mohamed E. , Marshall John , Hall Michael J. , Korn Wolfgang Michael , Nabhan Chadi , Battaglin Francesca , Lenz Heinz-Josef , Wolf Dominik Georg Friedrich 
Published: June 2021

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p < 0.0001). CXCR4-high (top quartile: > 59 TPMs), when compared to CXCR4-low (bottom quartile: < 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8+ T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p < 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p < 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p < 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.
Identification and prognostic impact of PBRM1 mutations in biliary tract cancers: Results of a comprehensive molecular profiling study.
Authors: Zimmer Kai , Kocher Florian , Untergasser Gerold , Puccini Alberto , Xiu Joanne , Wolf Dominik , Spizzo Gilbert , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Marshall John , Hall Michael J. , Korn Wolfgang Michael , Nabhan Chadi , Battaglin Francesca , Lenz Heinz-Josef , El-Deiry Wafik S. , Amann Arno , Hsiehchen David , Seeber Andreas 
Published: June 2021

4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p < 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p < 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p < 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p < 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p < 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p < 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.
Multimodal profiling of biliary tract cancers to detect potentially actionable biomarkers and differences in immune signatures between subtypes.
Authors: Mody Kabir , Azad Nilofer Saba , Jain Prerna , El-Refai Sherif , Shroff Rachna T. , Kelley Robin Kate , El-Khoueiry Anthony B. , Lau Denise , Lesinski Gregory B. , Yarchoan Mark 
Published: June 2021

4023 Background: Biliary tract cancers (BTC) are increasingly subtyped by molecular alterations, but little is known about the relationship between gain-of-function mutations and the RNA transcript expression of immune-related pathways. Methods: A sample of retrospective, clinicogenomic and transcriptomic data from de-identified records of patients with BTC in the Tempus database was selected. We then investigated the relationship between the mutational landscape and immune-related RNA signatures of different anatomic and genomic BTC subtypes. Results: The cohort included 455 samples of intrahepatic bile duct (IH) (n=267), gallbladder (GB) (n=153), and extrahepatic bile duct (EH) (n=35) cancer subtypes. Across all subtypes, we detected alterations in TP53 (43.8%), ARID1A (19.8%), KMT2C (18.2%), BAP1 (14.6%), KRAS (12.7%), TERT (12.0%), IDH1 (11.4%), KMT2D (11.0%), LRP1B (11.0%), and PBRM1 (10.7%), along with FGFR2 fusions (2.6%). Potentially actionable biomarkers ( FGFR2 and NTRK1-3 fusions, IDH1 and BRAFV600E mutations, tumor mutational burden [TMB]>10, HER2 expression, and/or microsatellite instability) were identified in 21.1% of all BTC and 28.6% of IH samples. Mutually exclusive alterations observed between subtypes were TP53 & BAP1, KRAS & BAP1, TP53 & IDH1, KRAS & IDH1, and SMAD4 & BAP1 ( P < 0.001 for all). GB was more inflamed based on RNA signatures and classical immune biomarkers, including PD-L1 and TMB. RNA signature analyses revealed a higher expression of immune-related pathways in GB than IH ( P = 0.001) with no differences in comparison with EH. PD-L1 expression and continuous TMB were elevated in GB versus the other anatomical subtypes. Significant associations were noted between particular genetic mutations and immune profiling features (table). Conclusions: BTC subtypes are diverse in DNA alterations, RNA inflammatory signatures, and immune markers. Notably, potentially actionable biomarkers were identified in a sizable portion of the cohort and varied significantly between subtypes. These results provide guidance for targeted therapy development and support the use of multimodal immune profiling for BTC. For example, GB-specific clinical trials may be considered due to the relative increase in immune-related biomarkers observed in GB and the historically limited success of BTC trials.[Table: see text]