bluuebunny/crossref_metadata_2025_split huggingface dataset:
Staged resection versus simultaneous resection for conversion surgery for initially unresectable colorectal liver metastasis: A prospective cohort study.
Authors: Chen Yijiao , Zhu Dexiang , Xu Jianmin 
Published: June 2024

3582 Background: Patients with initially unresectable colorectal liver metastasis (CRLM) who undergo successful conversion therapy have two treatment options to consider for surgery: simultaneous resection or staged resection. Numerous studies have conducted comparisons between both strategies in cases of initially resectable CRLM. However, almost were retrospective and conclusions were contradictory. Moreover, there have been no research studies that have directly compared the safety and effectiveness of these two approaches in patients with initially unresectable CRLM who are undergoing conversion surgery. Methods: We recruited prospectively patients undergoing conversion surgery for initially unresectable CRLM on the basis of completed randomized controlled trials (RCT) and ongoing multicenter RCT studies. The major outcomes included the rate of perioperative complications within 60 days following surgery, overall survival (OS), and relapse-free survival (RFS). Results: A total of 351 CRLM patients were recruited. Three-hundred-ten eligible patients (203 and 107 in the staged- and simultaneous-resection groups, respectively) were analyzed. In comparison to the staged-resection group, the simultaneous-resection group exhibited a significantly higher percentage of perioperative complications (37.4% VS. 50.5%, P=0.027). The start of adjuvant chemotherapy was significantly later in simultaneous-resection group (the percentage of time to start adjuvant chemotherapy >4 weeks: 14.8% VS. 28.0%, P=0.010). In the staged-resection group, two (1.0%) patients did not reach the liver resection stage, and this was due to disease progression. As compared with simultaneous-resection group, the staged-resection group showed a significantly improved RFS (HR=0.762, 95%CI 0.600-0.969, P=0.024) and liver-specific RFS (HR=0.709, 95%CI 0.554-0.908, P=0.005). The OS analysis did not differ between groups after a median follow-up of 49.7 months (HR=0.798, 95%CI 0.580-1.098, P=0.163). Conclusions: Among patients undergoing conversion surgery for initially unresectable CRLM, simultaneous resection of the primary tumor and liver metastases was associated with an increased incidence of postoperative complications and impaired relapse-free survival.
Genomic alterations in early-onset versus average-onset stage IV colorectal cancer.
Authors: Lander Eric Michael , Rivero-Hinojosa Samuel , Aushev Vasily N. , Jurdi Adham A , Liu Minetta C. , Eng Cathy 
Published: June 2024

3586 Background: The etiology of the rising incidence of early-onset colorectal cancer (EOCRC), defined as in patients aged <50, remains unknown. EOCRC is diagnosed at advanced pathologic stages compared to average-onset colorectal cancer (AOCRC; age >60). We previously reported data for Stages I-III disease. In this analysis, we evaluated tumor genomic differences in stage IV EOCRC versus AOCRC. Methods: The cohort included 3212 patients diagnosed with stage IV colon or rectal cancer who had whole exome sequencing (WES) as part of clinical tumor-informed ctDNA testing (Signatera, bespoke mPCR NGS assay, Natera, Inc.). Tumor mutational burden (TMB) and microsatellite instability (MSI) status were derived from tumor WES analysis. The prevalence of somatic variants, gene mutations and mutational signatures were compared between EOCRC and AOCRC groups, stratified by TMB and MSI status. Fisher’s exact test was used to test significance between age groups and p-values were adjusted using the FDR method for multiple test correction. Results: A total of 1070 patients with EOCRC (75.8% colon, 22.2% rectal, 2% unknown) and 2141 patients with AOCRC (80.2% colon, 18.3% rectal, 1.5% unknown) were included. No significant differences were found in the frequency of MSI and TMB status between age groups. In the TMB-Low/MSS group (EOCRC N=982; AOCRC N=1930), TP53 mutations were more common in EOCRC (62% vs. 54.5%, p=0.0036), but APC gene mutations were less common in EOCRC (59% vs. 65%, p=0.02). In the TMB-High/MSI-H group (EOCRC N=64; AOCRC N=182), BRAFand BEND4 mutations were less common in EOCRC (6.2% vs. 59.3%, p<0.001 and 6.2% vs 31.9%, p=0.036), but KRASgene mutations were more common in EOCRC (54.7% vs. 17%, p<0.001). BRAF V600E was the only significant single variant (0% vs 59.3% p<0.001). No significant differences were found in the TMB-High/MSS group (EOCRC N=24; AOCRC N=29). In the mutational signature analysis for the TMB-Low/MSS group, the clock-like signature was less frequent in EOCRC (76.9% vs. 85.4%, p< 0.001). In the TMB-High/MSI-H group, MMR deficiency signature was the most frequent signature, however no significant differences were found between EOCRC and AOCRC (81.25% vs. 85.71, p=0.42). In the TMB-High/MSS group, POLE exonuclease domain mutations signature was 2.2 times more frequent in EOCRC (62.5% vs. 27.6%, p<0.024). MMR deficiency signature was also less common in EOCRC vs. AOCRC (33.33% vs. 55.17%; p<0.10). Conclusions: Tumors in EOCRC harbored unique genomic alterations that varied between the TMB-Low/MSS, TMB-High/MSI-H, and TMB-High/MSS subpopulations. In TMB-Low/MSS tumors, similar gene mutations and genomic signatures were observed. However, the TMB-High/MSI-H and TMB-High/MSS subgroups harbored gene mutations and signatures that differed between age groups, suggesting that EOCRC may arise from uniquely different mutagenic processes in these subgroups.
Artemin and immune checkpoint inhibitor (ICI) efficacy in metastatic colorectal cancer (mCRC): A correlative analysis of the Canadian Cancer Trials Group (CCTG) CO.26 trial.
Authors: Ma Lucy Xiaolu , Titmuss Emma , Jonker Derek J. , Kennecke Hagen Fritz , Berry Scott R. , Couture Felix , Ahmad Chaudhary E. , Goffin John R. , Kavan Petr , Harb Mohammed , Colwell Bruce , Samimi Setareh , Samson Benoit , Abbas Tahir , Aubin Francine , Koski Sheryl L. , Tu Dongsheng , O'Callaghan Christopher J. , Loree Jonathan M. , Chen Eric Xueyu 
Published: June 2024

3587 Background: ICIs have limited efficacy in microsatellite stable (MSS) mCRC. The mechanisms of resistance to ICI remain incompletely understood. Recent findings suggest that erythyroid progenitor cells (EPCs) in the tumour microenvironment can exert immunosuppressive properties and promote tumour progression through the secretion of artemin, a neurotrophic factor. We conducted this post-hoc analysis of the Phase II CCTG CO.26 trial (NCT02870920) to investigate the relationship between artemin and ICI treatment outcomes in MSS mCRC. Methods: The CO.26 trial randomized patients (pts) with refractory mCRC to durvalumab plus tremelimumab (D+T) and best supportive care (BSC) compared to BSC alone in a 2:1 fashion. Serum artemin concentrations were determined from pre-treatment and serial on-treatment blood samples. The median artemin value (1.051ng/ml) was used to stratify pts into high versus low artemin groups. Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazard models were used to analyze prognostic and predictive impacts of artemin on PFS and OS. Results: Of 180 pts enrolled in CO.26, blood samples were available for 161 pts (N= 114 D+T, 47 BSC) at baseline, 94 at week 8 and 69 at progression. In the BSC arm, OS was lower for pts with high artemin at baseline compared to low pts (mOS 3.17 vs. 5.65 months, HR 1.74 [0.94-3.25], p=0.080). In artemin high pts, D+T improved OS compared to BSC (mOS 6.44 vs. 3.17 months, HR 0.54 [0.33-0.91] p=0.020). There was no difference in OS between D+T and BSC arms in artemin low pts (mOS 6.64 vs. 5.65 months, HR 0.87 [0.53-1.43], p=0.58, multivariable p-interaction=0.061). In the D+T arm, pts with progressive disease had significant increases in artemin levels at week 8 compared to baseline (p=0.026), while there was no significant change in week 8 artemin levels in pts with stable disease (p=0.14). Conclusions: High baseline artemin may be a poor prognostic marker in MSS mCRC and increase in artemin level during treatment can be indicative of progressive disease. High baseline artemin may predict benefit from ICI treatment. Studies are warranted to better understand and explore targeting the EPC-artemin axis to enhance efficacy of ICI in MSS mCRC.
Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX).
Authors: Pollom Erqi L. , Fisher George A. , Shelton Andrew , Johnson Tyler Paul , Chen Christopher , Jackson Scott , Shaheen Shagufta , Holden Thomas , Bien Jeffrey , King Daniel , Morris Arden M. , Kin Cindy , Dawes Aaron , Kirilcuk Natalie , Gahagan John , Vitzthum Lucas , Sheth Vipul , Brown Eleanor , Pratapneni Aniket , Chang Daniel Tandel 
Published: June 2024

3600 Background: Patients (pts) with rectal cancer who achieve a clinical complete response (cCR) after neoadjuvant therapy may be safely observed and spared the long-term sequela of total mesorectal excision (TME). We hypothesized that a novel neoadjuvant regimen (short-course radiation with boost and FOLFOXIRI chemotherapy) would achieve higher cCR rates than historical controls. Methods: We conducted a single-arm, phase II study of short-course radiation followed by FOLFOXIRI for pts with >T2N0 or low T2N0M0 rectal adenocarcinoma (NCT04380337). Pts underwent radiation (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by 8 cycles of FOLFOXIRI. Pts were assessed for primary endpoint (cCR) at 8 weeks following chemotherapy. Those who achieved a cCR or near cCR were surveilled. cCR required no tumor on MRI, endoscopy, and if applicable, digital rectal exam. A Simon 2-stage design addressed our primary objective, with interim analyses for futility and toxicity. Assuming a one-sided type 1 error of 0.1, power of 0.9, a null cCR of 0.2 versus an alternate cCR of 0.4, our sample size was 37 pts. Results: Between May 2020 and April 2023, 37 pts enrolled (Table). 25 pts (67.5%) had at least one high risk feature (cT4, extramural vascular invasion [EMVI], N2, threatened circumferential resection margin [CRM], positive lateral node). All pts completed radiation; 32 pts (86.5%) completed all 8 cycles of chemotherapy. Criteria for futility and safety were met at interim analysis. At primary outcome assessment, 9 (24.3%) pts achieved a cCR and 8 (21.6%) pts achieved a near cCR. 3 pts who initially had a cCR developed local regrowth and underwent TME. Of the pts who had a near cCR, 5 developed local regrowth and underwent TME while 3 pts achieved delayed cCR. Serious adverse events occurred in 5 (13.5%) pts; 1 patient had non-hematologic grade 4 toxicity at least possibly related to treatment. There were no treatment-related deaths. The12-month TME-free survival for all patients was 37.2%, and for patients with T3 and T4 tumors was 44.3% and 12.5%, respectively. Conclusions: Short-course radiation followed by FOLFOXIRI was feasible and safe. In this high-risk cohort of pts with rectal cancer, 24.3% of pts had a cCR at time of primary assessment. Clinical trial information: NCT04380337 . [Table: see text]
T cell receptor and immune gene expression pharmacodynamics for durvalumab monotherapy and in combination with tremelimumab or bevacizumab in unresectable hepatocellular carcinoma (uHCC).
Authors: Kelley Robin Kate , Lee Young S , Conway James , Kurland John F , Negro Alejandra , McCoon Patricia 
Published: June 2024

4022 Background: Study 22 (NCT02519348), a Phase 2 trial of immune checkpoint inhibitor (ICI) monotherapy and combination regimens in uHCC, showed higher rates of objective response (ORR) with STRIDE (Single Tremelimumab [T] Regular Interval Durvalumab [D]) or D plus bevacizumab (B) than with D (1,2). Pharmacodynamic analyses showed that improved efficacy with STRIDE versus D was associated with increased expansion of T cell clones at the end of cycle 1 (C1) versus D (3). We performed further T cell clone analyses to include D+B and compared gene expression signatures (GES) associated with each treatment arm to explore commonalities and differences in mechanistic biomarkers underpinning the efficacies associated with STRIDE and D+B. Methods: Participants (pts) with uHCC and no prior ICI therapy received STRIDE (T 300 mg + D 1500 mg [1 dose during C1] then D 1500 mg once every 4 weeks [Q4W]), T75+D (T 75 mg + D 1500 mg Q4W [4 doses] then D 1500 mg Q4W, D (1500 mg Q4W), T (750 mg Q4W [7 doses] then Q12W), or D+B (D 1120 mg + B 15 mg/kg Q3W). DNA and RNA were isolated from PAXgene-preserved whole blood collected at baseline and at the end of C1. CDR3 sequencing of T cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA) and RNA sequencing (Q Squared Solutions, Morrisville, NC) were performed. ImmunoSeq results and immunologic gene expression changes were reported with ORR across treatment arms. Results: ImmunoSeq did not show significant differences in baseline T cell clonality across treatment arms. In contrast to STRIDE versus D, the number of expanded T cell clones at the end of C1 for D+B versus D was unchanged, and no association between expanded T cell clones and ORR was observed (Table). While increases in Type I and II interferon and mitotic GES were seen for both STRIDE and D+B, more changes in immune-related peripheral GES, with greater magnitude of change, were associated with STRIDE. Significant changes in CD8 T cell, M1 macrophage, and Treg GES were only observed for STRIDE. Conclusions: While STRIDE and D+B both had higher ORRs than D monotherapy in uHCC, only STRIDE was associated with an increased expansion of T cell clones versus D. This, in addition to the differences in magnitude and type of GES changes, suggest that STRIDE and D+B have distinct and potentially complementary mechanisms of action. 1. Kelley, et al. J Clin Oncol 2021. 2. Lim, et al. J Clin Oncol2022, A436. 3. McCoon, et al. J Clin Oncol2021, A4087. Clinical trial information: NCT02519348 . [Table: see text]
Non-colorectal GI malignancies in the young: Incidence trends, demographic disparities, and survival analysis.
Authors: Vadehra Deepak , Advani Shailesh M , George Anthony , Attwood Kristopher , Brown Timothy J , Siromoni Beas , Sonti Sahithi , Mukherjee Sarbajit 
Published: June 2024

4023 Background: The incidence of gastrointestinal (GI) cancers is rising within the younger populations. Previously, we have detailed the increasing incidence of colorectal cancer (CRC) in the adolescent/young adult (AYA) population, defined as 15-39 years old. In this analysis, we seek to further describe incidence, mortality, and demographic differences in the AYA population for non-CRC GI malignancies compared to their older counterparts (≥50 years old). Methods: We queried the Surveillance, Epidemiology, and End Results Program (SEER) database from 2000-2020. The demographic, clinical, and secondary cancer characteristics were summarized in the overall sample (and within racial subgroups) by disease site. The summary statistics were reported for baseline covariates, with comparisons made using the Kruskal-Wallis or chi-square test. Overall survival (OS) and disease-specific survival (DSS) were reported using the Kaplan-Meier method and comparisons were made using the log-rank test. Univariate and multivariate Cox regressions assessed the association between baseline covariates and time-to-event. Changes over time were assessed by annual percentage change (APC). Results: We identified 21,677 AYA patients with non-CRC GI malignancies (esophageal, stomach, small intestine, anal, hepatobiliary, pancreas, and primary peritoneal) from 2000-2020. Most were male (58%), White (47%), and living in metro areas (90%). The median age of diagnosis was 38 years. The AYA population had a higher percentage of Black, Asian, and Hispanic patients (14%, 12%, and 25%, respectively) affected compared to the ≥50 group (11%, 10%, and 14%). The most common non-CRC GI malignancies in the AYA group were stomach, pancreas, and liver (27%, 20%, and 19 %, respectively). Stomach cancer was found to be much higher in the AYA group compared to the ≥50 group (27 vs 17%). More patients in the AYA group underwent surgery (46 vs 30%) and chemotherapy (54 vs 42%) compared to the ≥50 group. More patients in the AYA group began treatment within 1 month (35 vs 22%). OS and DSS were significantly better in the AYA group (Median OS 24 vs 9 months, Median DSS 52 vs 13 months, p<0.001). Overall, the incidence of non-CRC GI cancers significantly increased from 2000-2019 based on APC (p < 0.05). Specifically, the incidence of small bowel, anal, and liver cancer increased during this period. Univariate and multivariate analysis revealed that male sex, African American race, income <$45k/year, no surgery, and delayed time to treatment were all predictors of worse OS and DSS (p<0.01). Conclusions: Non-CRC GI malignancies are increasing within the AYA population, and specific socio-demographic disparities notably affect survival in this age group. Further study is needed to define the underlying mechanisms of these findings and to ultimately reverse these observed trends.
Circulating immune protein biomarkers of early response and resistance in patients with metastatic HER-2–negative esophagogastric cancer (mEGC) treated with pembrolizumab and chemotherapy.
Authors: Nixon Andrew B. , Howard Lauren , Kar Amrita , Liu Yingmiao , Brady John C. , Niedzwiecki Donna , Strickler John H , Rucevic Marijana , Uronis Hope Elizabeth 
Published: June 2024

4024 Background: Immune checkpoint inhibition (ICI) in combination with chemotherapy is standard of care for first line HER2- mEGC. Tissue-based biomarkers can improve patient selection for ICI therapy, but these biomarkers require invasive biopsy, and the optimal cutoff for treatment benefit is controversial. Longitudinal plasma samples were collected from patients (pts) enrolled in the KeyLargo trial (NCT03342937), a single-arm phase II study of pembrolizumab (pembro) combined with oxaliplatin and capecitabine in first line HER2- mEGC, to identify novel prognostic and predictive circulating protein biomarkers. Methods: We employed large scale Next generation multiplex proteomics (Olink Explore) to evaluate 1536 functional protein biomarkers in 36 pts, including markers known to drive tumor biology and immune response. Samples at baseline (n=36), one week of pembro monotherapy (C1D8) (n=28), C2D1 (n=25), first restaging (n=26), and progression (n=20) were analyzed. Cox models assessed univariable associations between each marker and outcome at baseline. Markers that changed from baseline to C1D8 with effect size >0.5, and to other time points with effect size >1, were deemed most important, all with p<0.05 (paired t-test). Results: At baseline, high PREB, EPHA10, GHRHR, BAMBI and GDF15 levels were associated with worse progression-free survival (PFS) (p<0.001); high SPINK1, S100P, LDLR, GDF15 and PM20D1 levels were associated with worse overall survival (OS) (p<0.003). On-treatment analyses revealed that circulating PDL1 levels were significantly elevated in the presence of pembro at all time points (p<10-16). After one week of pembro monotherapy (C1D8), 6 immune-related biomarkers (TNFRSF8, CXCL9, CCL19, IFNγ, IL10, CXCL10) exhibited significant change (effect size >0.5). At C2D1 and first restaging, the addition of chemotherapy to IO revealed a shift as key metabolic and hormone-regulating proteins (KRT19, GCG, ARG2) were most significantly altered (effect size >1). However, at progression an immune-related phenotype re-emerged as IL10, IL17A and GPA33 significantly changed (effect size >1). Subsequent pathway analyses aligned with the individual markers, highlighting the impact of immune cell signaling after IO monotherapy while cell signaling pathways, hormone-controlled pathways, and extracellular matrix degradation were activated at later times. Conclusions: Multiple prognostic biomarkers were identified that implicate proteins related to hormone metabolism and TGFβ biology in mEGC, including GDF15, a key molecule regulating obesity, tumor metastasis, immunomodulation, and cachexia. Significant changes in immune-related cytokines were seen early (C1D8) as well as at progression, highlighting a potential role for circulating immune protein biomarkers in mEGC.
Clinical impact of oncogenic KRASdosage variation in pancreatic cancer.
Authors: Jung Kwangrok , Lee Jong-Chan , Kim Jaihwan , Hwang Jin-Hyeok 
Published: June 2024

4027 Background: Some studies have reported that KRAS oncogenic dosage variation plays a critical role in the biology and phenotype diversification of pancreatic ductal adenocarcinoma (PDA). However, this has not been confirmed in large-scale data. Therefore, this study aims to validate the clinical impact of oncogenic KRAS dosage variation using a large Korean clinico-genomic dataset. Methods: We conducted whole exome sequencing (WES) in 205 human PDA tissues. Tumor cellularity, ploidy, and allele-specific copy number (CN) were derived from WES data using the SEQUENZA software. Subsequently, allele-specific CN for both of mutant and wild-type KRAS was assigned based on tumor cellularity and variant allele fraction (VAF) of mutant KRAS. Finally, we defined mutant KRAS allelic imbalance as a condition where the mutant KRASCN exceeded that of the wild-type KRAS and assessed its clinical significance. Results: Out of 205 PDA patients, 183 (89.3%) patients harbored KRAS mutation and 166 (81.0%) patients were evaluable for mutant KRAS allelic imbalance. Among 166 patients, mutant KRAS allelic imbalance was identified in 62 (37.3%) patients. There was no significant difference in the proportion of stage IV PDA between the imbalance and balance group (59.7% vs. 51.0%, p = 0.353). Nevertheless, a significant disparity was noted in the metastatic pattern, indicating a higher incidence of liver metastasis in the imbalanced group compared to the balanced group (81.1% vs. 52.8%, p = 0.011). In the survival analysis, the imbalance group exhibited significantly shorter progression-free survival and overall survival compared to the balance group (4.6m vs 8.0m, p = 0.009 and 12.5m vs. 17.9m, p = 0.002, respectively). This statistical significance persisted even after adjusting for several variables such as age, sex, stage, and treatment course. Conclusions: Our findings underscore the role of oncogenic KRAS dosage variation, as assessed by mutant KRAS allelic imbalance, in shaping clinical phenotypes and prognosis in PDA. [Table: see text]