bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prophylactic hyperthermic intraperitoneal chemotherapy in T4 colorectal cancer: Can it improve the oncologic prognosis?
Authors: Sun Lifeng , Zheng Yuyan , Chen Chao , Gong Zhiyuan 
Published: June 2023

3619 Background: Previous studies have shown that T4 stage was one of the risk factors for peritoneal metastasis (PM) of colorectal cancer (CRC). However, there is paradoxical data to prove that prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) treatment is beneficial for CRC patients. Methods: In this cohort study, 220 consecutive CRC patients with T4N0-2M0 were enrolled and recorded from November 2014 to November 2018 with a 3-year follow-up following surgery. A propensity score matching (PSM) approach was applied to balance the clinicopathological characteristics. Finally, 180 patients were matched successfully to further analyze. The 3-year disease-free survival (DFS) was set as the primary outcome, and the PM rate between the two groups after PSM was analyzed. Results: Before PSM, of 220 CRC patients enrolled, the 3-year DFS was 83.9% in the HIPEC group, which was better than 67.2% in the control group. The cumulative PM incidence was 2.2% in the HIPEC group and 12.6% in the control group (p = 0.047). After PSM, 180 matched patients were formed for further analysis. The DFS and the cumulative PM rate of the patients in the HIPEC group were also better than that in the control group (p = 0.034 and 0.047, respectively). For laparoscopic surgery subgroup analyses, PM rate of the patients with laparoscopic surgery was 13.8% in the No HIPEC group, and 2.6% in the HIPEC group (p = 0.070). Through multivariable analysis, it was found that prophylactic HIPEC correlated to better DFS [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.19-0.95; p = 0.037], and N2 stage correlated to worse DFS [HR 1.97, 95% CI 1.09-3.56; p = 0.025]. Besides, no post-operative death occurred, the anastomotic leakage rate was 2.2% in the HIPEC group and 0.7% in the control group (p = 0.439). Conclusions: Prophylactic HIPEC may improve the prognosis in the patients with T4N0-1M0 CRC, but not in the T4N2M0 CRC, and it does not significantly increase the surgery-related complications. Laparoscopic surgery followed by HIPEC for T4 stage CRC is relatively safe, which does not increase the risk of PM.
Molecular profiling and characterization of the tumor immune microenvironment (TME) in appendiceal carcinoma (AC).
Authors: Rehman Muneeb , Baca Yasmine , Xiu Joanne , Walker Phillip , Lou Emil , El-Deiry Wafik S. , Lenz Heinz-Josef , Shields Anthony F. , Marshall John , Johnston Curtis , Oberley Matthew James , Goel Sanjay , Weinberg Benjamin Adam , Holowatyj Andreana Natalie 
Published: June 2023

3622 Background: The rarity of AC presents challenges in understanding disease pathogenesis. We previously showed that AC has higher rates of mutations in KRAS and GNAS and lower rates of TP53, APC, and PIK3CA than CRC. The appendix also has many lymphoid clusters and regulates IgA production in the large bowel, suggesting that AC may be subject to more lymphocytic regulation than CRC. We sought to characterize the molecular profile and TME across AC histopathological types. Methods: AC samples were analyzed by DNA sequencing (592 genes, NextSeq, or whole exome sequencing, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq), and immunohistochemistry (IHC) for molecular profiling, including microsatellite instability (MSI), mismatch repair (MMR), PD-L1 (SP142), and tumor mutational burden (TMB). Microenvironment Cell Population-counter Quantiseq was used to quantify tumor immune contexture using WTS. AC histopathology was derived from pathology reports. Mann-Whitney U and ChiSquare tests were applied as appropriate, with P-values adjusted for multiple comparisons using Benjamini-Hochberg. Results: AC (N = 731) were grouped by histology: 5% goblet cell (GC), 6% high-grade adenocarcinoma (HGA), 14% low grade mucinous (LGM), 33% mucinous adenocarcinoma (MA), 1% pseudomyxoma peritonei (PMP), 6% signet ring cell carcinoma (SRC), and 35% adenocarcinoma not otherwise specified (NOS) (see Table). Age at collection and PD-L1+ (0-5.2%) did not differ by histopathology. Seven patients had dMMR (4 NOS and 3 MA). Median TMB was significantly higher in NOS vs. GC (4 mutations/megabase vs 2, q < 0.001), NOS vs. LGM (4 vs 3, q = 0.048), MA vs. GC (4 vs 2, q < 0.001), and MA vs. LGM (4 vs 3, q = 0.037). Distinct TME patterns were observed in NOS vs. MA (median cell fraction: dendritic cells 0.07 vs 0, q < 0.01; M2 macrophages 0.055 vs 0.042, q = 0.030; natural killer cells 0.034 vs 0.031, q = 0.011; CD4 T cells 0.006 vs 0, q = 0.044) and GC vs. MA (M1 macrophages 0.039 vs 0.057, q = 0.021; dendritic cells 0.012 vs 0, q < 0.01; B cells 0.061 vs 0.050, q = 0.013; M2 macrophages 0.074 vs 0.042, q < 0.01; natural killer cells 0.041 vs 0.031, q = 0.01; and neutrophils 0.017 vs 0.038 q = 0.045). T cell inflamed signature (TIS) and immune-oncology (IO) marker gene expression were higher in HGA and lower in LGM and MA. Somatic mutation rates differed by histopathology (see Table). Conclusions: There is significant heterogeneity in TMB, TME, and mutational profiles across AC histologies. MA has a particularly immune-cold TME shown by lower infiltration of lymphocytes, TIS, and IO gene expression. These findings are critical to identify novel biomarkers and develop new therapeutic strategies for AC. [Table: see text]
Health-related quality of life (HRQoL) in the phase 3 KEYNOTE-966 study of pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) versus placebo plus gem/cis for advanced biliary tract cancer (BTC).
Authors: Yoo Changhoon , Finn Richard S. , Klümpen Heinz-Josef , Kelley Robin Kate , Vogel Arndt , Furuse Junji , Ren Zhenggang , Yau Thomas , Chan Stephen Lam , Ozaka Masato , Oh Sang Cheul , Gu Shanzhi , Park Joon Oh , Valle Juan W. , Edeline Julien , Kamble Shital , Norquist Josephine M , Yu Li , Malhotra Usha , Ueno Makoto 
Published: June 2023

4003 Background: In the randomized, double-blind, phase 3 KEYNOTE-966 trial (N = 1069; NCT04003636), pembro + gem/cis significantly improved OS versus placebo + gem/cis (HR 0.83; 95% CI 0.72-0.95; P = 0.0034) and had an expected and manageable safety profile as first-line therapy for unresectable locally advanced or metastatic BTC. We present the protocol-specified exploratory patient-reported outcomes (PROs) from KEYNOTE-966. Methods: PROs were assessed using the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L questionnaires. The analysis population included all treated patients (pts) who completed ≥1 HRQoL assessment for the specific endpoint. A constrained longitudinal analysis model (covariates: treatment, time, treatment by time interaction, and stratification factors) was used to compare least squares mean (LSM) score changes from baseline (BL) to wk 18 (ie, latest timepoint that completion was ≥60% and compliance was ≥80%) in QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and role functioning (RF), QLQ-BIL21 jaundice and pain, and EQ-5D-5L visual analogue scale (VAS). A stratified Cox proportional hazards model was used to assess the magnitude of the between-arm difference in time to deterioration (TTD) in GHS/QoL, PF, RF, jaundice, and pain (ie, time to first onset of ≥10-point deterioration from BL in each scale/subscale confirmed by ≥10-point deterioration from BL at the next visit; established as clinically relevant). Results: Questionnaire compliance was >87% from BL to wk 18 in both arms. LSM changes from BL to wk 18 in QLQ-C30 GHS/QoL, PF, and RF, QLQ-BIL21 jaundice and pain, and EQ-5D-5L VAS were similar between arms. Time to deterioration was also similar between arms: median not reached (NR) vs 21.2 mo for GHS/QoL (HR 0.86, 95% CI 0.70-1.07), NR vs 12.0 mo for PF (HR 0.95, 95% CI 0.78-1.17), 6.5 mo vs 5.8 mo for RF (HR 0.98, 95% CI 0.81-1.18), NR vs NR for jaundice (HR 1.20, 95% CI 0.94-1.54), and NR vs NR for pain (HR 0.79, 95% CI 0.59-1.05). Conclusions: HRQoL was maintained when pembro was added to gem/cis. Together with the efficacy and safety data, these results support pembro + gem/cis as a new first-line treatment option for advanced BTC. Clinical trial information: NCT04003636 . [Table: see text]
Results from the MORPHEUS-liver study: Phase Ib/II randomized evaluation of tiragolumab (tira) in combination with atezolizumab (atezo) and bevacizumab (bev) in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC).
Authors: Finn Richard S. , Ryoo Baek-Yeol , Hsu Chih-Hung , Li Daneng , Burgoyne Adam , Cotter Christopher , Badhrinarayanan Shreya , Wang Yulei , Yin Anqi , Rao Edubilli Tirupathi , Gane Edward 
Published: June 2023

4010 Background: Atezo + bev is the current first-line standard of care for uHCC based on the IMbrave150 study, which demonstrated superior overall survival, progression-free survival (PFS), and objective response rate (ORR) vs sorafenib (Finn, et al. New Engl J Med 2020; Cheng, et al. J Hepatol 2022). TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, such as PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. Here we report data from a cohort of the MORPHEUS-liver study (NCT04524871) evaluating the combination of tira + atezo + bev vs a control arm (atezo + bev) in patients with uHCC. Methods: Patients with previously untreated uHCC were randomized to receive atezo (1200mg IV) + bev (15mg/kg IV) with or without tira (600mg IV) every three weeks. The primary endpoint was investigator-assessed ORR by RECIST V1.1. Secondary endpoints included PFS and safety. Results: A total of 58 patients were randomized (tira + atezo + bev, n=40; atezo + bev, n=18). As of 28 November 2022, median follow up was 14.0 months in the tira + atezo + bev arm and 11.8 months in the control arm. Confirmed ORR was higher in the tira + atezo + bev arm (42.5%) vs the control arm (11.1%). Median PFS was longer with tira + atezo + bev (11.1 months; 95% CI: 8.2–NE) vs control (4.2 months; 95% CI: 1.6–7.4), corresponding to a PFS hazard ratio (HR) of 0.42 (95% CI: 0.22–0.82). A similar pattern of increased ORR and PFS was observed for the treatment arms in both PD-L1+ (n=23) and PD-L1– (n=27) subgroups. For tira + atezo + bev vs control arm, grade 3/4 treatment-related AEs were 27.5% vs 33.3% and AEs leading to any treatment discontinuation were 22.5% vs 22.2%, respectively. Conclusions: The addition of tira to atezo + bev resulted in higher ORR and longer PFS compared with atezo + bev, and no new safety signals were identified. These data suggest that tira + atezo + bev may be a promising novel first-line treatment option for patients with uHCC, and support further study in this setting. Clinical trial information: NCT04524871 . [Table: see text]
Subgroup analysis of double-blind, placebo-controlled Ph. 2 study of nanvuranlat in treatment of pre-treated, advanced, refractory biliary tract cancer (BTC): Patients with high LAT1 expression and response to nanvuranlat.
Authors: Ikeda Masafumi , Ueno Makoto , Furukawa Masayuki , Morizane Chigusa , Takehara Tetsuo , Nishina Tomohiro , Todaka Akiko , Okano Naohiro , Hara Kazuo , Nakai Yousuke , Ohkawa Kazuyoshi , Sasaki Takashi , Sugimori Kazuya , Yokoyama Naoyuki , Yamamoto Kouji , Furuse Junji 
Published: June 2023

4011 Background: L-type amino acid transporter 1 (LAT1, SLC7A5) is overexpressed in cancer cells leading to aggressive proliferation and lymphatic metastases. LAT1 sustains energy resources by supplying essential amino acids to the TCA cycle in chemotherapy-resistant cancer cells. LAT1 is a documented marker of poor prognosis. In a placebo-controlled, randomized trial involving patients with pre-treated, advanced, refractory biliary tract cancer (BTC), monotherapy with nanvuranlat (JPH203), a selective LAT1 inhibitor, demonstrated a significant improvement in progression free survival (PFS) compared to placebo. Subgroup analysis was conducted to determine whether the level of expression of LAT1 affects nanvuranlat efficacy. Methods: Patients with four different subtypes of advanced BTC were enrolled: intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder and ampulla of Vater cancers. All were refractory to or intolerant of standard chemotherapy and other investigational medicines. Our analysis compared efficacy and safety in the subgroup with high LAT1 expression and all patients group. LAT1 expression was immunohistochemically evaluated in tumor specimens of BTC patients at baseline, as defined by Yanagisawa N, et al. (Cancer Med 2014). Results: At data cut-off (Feb 28, 2022), 211 BTC patients consented at 14 centers in Japan, and 104 patients were randomized (2:1) to nanvuranlat (n = 69) or placebo (n = 35) as the full analysis set (FAS) population. Among the samples immunohistochemically evaluable for LAT1, 62.5% had high LAT1 expression. There was no significant difference in background demography between all patient group and the high-LAT1 subgroup. Nanvuranlat met its primary endpoint (FAS by the blinded independent central review (BICR)), demonstrating a statistically significant improvement in PFS by BICR in comparison with the placebo group. The hazard ratios were further improved with nanvuranlat versus placebo, on analysis of the high-LAT1 subgroup of patients in both PFS and OS. Safety was comparable between nanvuranlat and placebo, on analysis of the high-LAT1 subgroup. Conclusions: This subgroup analysis indicates that the efficacy of nanvuranlat in PFS and OS is enhanced in BTC patients with high LAT1 expression, when compared with placebo. Safety profiles were similar for nanvuranlat- and placebo-treated patients in this subgroup analysis. Clinical trial information: UMIN000034080 . [Table: see text]
A randomized study of consolidation chemoradiation (CTRT) vs observation after first-line chemotherapy (CT) in advanced gall bladder cancers (GBC): RACE-GB Study.
Authors: Agrawal Sushma , Rahul Rahul , Singh Ashish , Mishra Prabhakar , Saxena Rajan 
Published: June 2023

4016 Background: CT (gemcitabine plus cisplatin) is the standard of care for patients presenting with unresectable advanced GBC but their prognosis remains poor. The value of CTRT after CT is uncertain. We therefore conducted a randomised trial evaluating consolidation CTRT versus Observation after four cycles of CT in those patients whose disease did not progress during CT (NCT05493956). Methods: Responders (partial response and stable disease) to 4 cycles of CT were randomised to CTRT vs observation (n=135). CTRT was delivered by 3D-Conformal Radiation Therapy along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45 Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. The primary endpoint was overall survival which was calculated from the date of randomisation. The trial is designed to detect an improvement in 2-year OS from 8% in the control arm to 25% in study arm with 80.0% power at a 0.05 significance level. The required sample size was 130 (65 in each arm) over a duration of 4-5 years. CTRT was delivered by 3DCRT along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. Toxicities documented during CT and CTRT were recorded using the CTCAE version 3.0. and RTOG criteria respectively. Chi square test and Survival analysis was performed for the data analysis. Demographic data and CTRT Dose volume data were correlated with side effects and survival. Statistical analysis was performed with SPSS version-23. Results: 67 patients were randomized to observation and 68 to CTRT. Their demographic characteristics were well balanced. 63% were women, 58% had T4 tumours, 42% had N2, 27% needed stenting for obstructive jaundice. The median overall survival in the CTRT arm was 10 months versus 4 months in the observation arm (HR 0.47 [95% CI 0.33-0.68] p=0.001). Adverse events (grade 3 or higher) due to CTRT included the following: Nausea 3%, Anemia 9%, GI bleed 6%, hepatotoxicity 13%. Updated survival data and prognostic factors affecting overall survival will be presented in the meeting. Conclusions: CTRT after 4 cycles of CT significantly prolonged overall survival but was also associated with adverse events. Clinical trial information: NCT05493956 .
Not all treated KRAS-mutant pancreatic adenocarcinomas are equal: KRAS G12D and survival outcome.
Authors: Ardalan Bach , Ciner Aaron , Baca Yasmine , Darabi Sourat , Kasi Anup , Lou Emil , Azqueta Jose Ignacio , Xiu Joanne , Nabhan Chadi , Shields Anthony F. , Aguirre Andrew , Singh Harshabad , Shroff Rachna T. , Pishvaian Michael J. , Goel Sanjay 
Published: June 2023

4020 Background: KRAS is an oncogenic driver in pancreatic ductal adenocarcinoma (PDAC) with mutations identified in > 90% of cases. G12D is the most frequent variant, followed by G12V and G12R. We recently reported on the prognostic impact of distinct KRAS mutations. The current study utilized a large clinical and genomic database, to further explore and characterize the prognostic and molecular differences between KRAS variants, focusing on KRAS G12D and G12R. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Transcriptomic signatures including MPAS (MAPK activation score), T-cell inflamed score and tumor micro environment (TME) characterization were calculated on WTS data. Significance was determined by X2 and Fisher-Exact and p-value was adjusted for multiple comparisons (q). Real-world overall survival (rwOS) obtained from insurance claims data was calculated from tissue collection to last contact (comparison done by Kaplan-Meier test). Results: 5,555 PDAC patients harboring either KRAS G12D (n = 2,671), G12V (n=1,871) G12R (n = 904) or G12C (n = 109) variants were identified. Patients with KRAS G12R mutant tumors had significantly longer OS compared to G12D (396 vs 311 days, HR 0.81, CI 0.74-0.88, p<0.0001). There was no difference among KRAS variants in the rate of TP53, CDKN2A and SMAD4 mutations. ARID1A and KMT2D were more frequently mutated in KRAS G12D vs. G12R. The MPAS gene signature reflecting MAPK pathway activation trended lower in G12R vs. G12D. Expression of multiple genes in this pathway was statistically lower in the G12R cohort. Immune profiling suggested that: PDL1 expression is significantly lower in G12R vs G12D (13% vs 19%), TMB-H and dMMR were comparable in G12D vs G12R and several glucose and glutamine metabolism genes were significantly lower in expression when comparing G12R vs G12D - table. OS was improved within the G12R cohort for those patients on metformin (n=273 patients) (416 vs 388 days, HR 0.84, CI 0.72-0.99, p =0.037) while no difference was seen in those with KRAS G12D based on metformin use. Conclusions: Patients with G12D mutations have significantly lower survival compared to G12R. Significant molecular differences were seen in MAPK pathway gene expression, markers of immune activation, and genes involved in glucose and glutamine metabolism. Intriguingly, metformin use appeared to impact survival in the KRAS G12R subgroup. We aim to further explore distinct vulnerabilities based on MAPK pathway activation and dysregulated metabolism. Based on this data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities. [Table: see text]
Prospective evaluation of the utility of concurrent 18F-FDG PET/CT and 68Ga-DOTA-TOC imaging in gastroenteropancreatic neuroendocrine neoplasms (GEPNENs): The PETNET study.
Authors: Solar Vasconcelos Joao Paulo , Zhou Marilyn , Ravi Pavithraa , Allan Hayley , Saprunoff Heather , Bloise Ingrid , Harsini Sara , Wilson Don , Benard Francois , Martineau Patrick , Loree Jonathan M. 
Published: June 2023

4022 Background: Somatostatin receptor imaging (SRI) is a standard of care for patients with GEPNETs. The additional value of concurrent 18F-FDG PET/CT (FDG PET) remains unclear. We reviewed a prospective functional imaging study to determine the utility of FDG PET in GEPNENs. Methods: PETNET is a prospective study in British Columbia, Canada, which provides all 68Ga-DOTA-TOC (DOTA PET) imaging in the province. Every patient receives a DOTA PET scan and an FDG PET within 30 days. PETNET enrolls all patients with an indication for SRI. Scans are ordered per treating physician discretion at any point in the disease course. This abstract focuses on the WD-GEPNEN population. Only the first dual functional imaging scans were analyzed and FDG was interpreted qualitatively (positive/negative). Results: From 04/2017-01/2023, 375 patients with NEN were enrolled, 165 (44%) with metastatic GEPNENs. Baseline characteristics are described. Median time between scans was 4 days (IQR 1-11). The proportion of patients with positive FDG PET at baseline increased with WHO grade. For patients with well differentiated G1 to G3 GEPNENs (N=161), overall survival was significantly lower with a positive FDG PET (HR: 4.22; 95%CI 1.61-11.02 p=0.001). FDG remained prognostic when G3 tumors were excluded (N=148) (HR 3.52; 95%CI 1.32-9.42 p= 0.007). When analyzing dual tracer PET imaging, patients with DOTA+/FDG- had reduced risk of dying in comparison with DOTA+/FDG+ (HR:0.26; 95%CI 0.09-0.67 p=0.01). After multivariate analysis, FDG positivity remained independently associated with reduced survival (HR 2.87; 95%CI 1.06-7.75 p=0.04) when controlling for grade of tumor and age. Conclusions: In this prospective cohort of metastatic GEPNENs, a positive FDG PET was significantly associated with reduced overall survival. These results provide additional evidence to support dual tracer functional imaging use in metastatic well differentiated GEPNEN’s. [Table: see text]