bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and molecular presentation of KRAS G12D-mutated pancreatic ductal adenocarcinoma in real-world settings.
Authors: Sturgill Emma G. , Kolli Sahiti , Feustel Kavanya , Luckett Daniel , Jones Carissa , Holt Marilyn Elaine , Hyde Annastasia , Jones Suzanne Fields , Perez Cesar Augusto , Wang Judy S. , Divers Stephen G. , Pelster Meredith , Henry Jason Timothy , Spigel David R. , Burris III Howard A. , McKenzie Andrew Jacob 
Published: January 2023

738 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating diagnosis with an overall 5-year survival rate of ~10%. Therapies targeting KRAS G12D, a prevalent molecular driver of PDAC, represent an active area of investigation with many agents currently in clinical development. This study characterizes the real-world clinico-genomic landscape of patients with KRAS G12D-mutated PDAC to inform ongoing therapeutic development and clinical trial design. Methods: We conducted a retrospective, records-based analysis of 2,805 patients with PDAC from across 299 community-based oncology clinics. All patients had broad-panel next generation sequencing (NGS) from commercial vendors performed as standard of care. Patients were stratified into KRASWT (26%), KRASG12D (31%), and KRASnon-G12D (43%) cohorts according to NGS results and assessed for co-mutations, overall survival, and time to chemotherapy failure. Results: The KRASG12D and KRASnon-G12D cohorts exhibited similar mutational landscapes with frequent alterations in TP53, CDKN2A, and SMAD4 ( > 20% frequency occurrence) and infrequent actionable co-mutations (i.e. ATM, MTAP, BRCA1/2, PIK3CA, and MYC; < 5% frequency occurrence). KRASG12D exhibited significantly decreased overall survival compared to KRASWT (m (95% CI); 32.4 months (27.6-37.6 months) [ KRASWT], 20.1 months (17.0-22.7 months) [ KRASG12D], 21.7 months (20.0-25.0 months) [ KRASnon-G12D]; Cox model p-value < 0.001) as well as significantly shortened time to chemotherapy failure compared to both KRASnon-G12D and KRASWT (m (95% CI); 10.8 months (9.6-11.6 months) [ KRASWT], 7.8 months (7.3-8.7 months) [ KRASG12D], 9.8 months (8.8-11.1 months) [ KRASnon-G12D]; Cox model p-value < 0.01). Within the KRASG12D cohort, no co-mutations were significantly associated with overall survival. Conclusions: This study demonstrates the acute need for KRAS G12D-targeted agents in the clinic, as patients with KRAS G12D-driven PDAC experience particularly poor patient outcomes and lack alternative molecular targets.
Depth of response in patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory subgroup analysis of JCOG1407.
Authors: Shibuki Taro , Ikeda Masafumi , Ozaka Masato , Kobayashi Satoshi , Ohba Akihiro , Todaka Akiko , Uemura Kohei , Sano Yusuke , Horie Yoshiki , Kumamoto Yusuke , Shioji Kazuhiko , Kanai Masashi , Nishina Tomohiro , Okabayashi Takehiro , Fujimori Nao , Katanuma Akio , Takayama Yukiko , Tsumura Hidetaka , Furuse Junji , Ueno Makoto 
Published: January 2023

746 Background: Depth of response (DpR; max% reduction from baseline in sum of target lesion diameters), has been reported to be associated with improved prognosis in several malignancies. However, there have been few reports regarding DpR in patients with locally advanced pancreatic cancer (LAPC). Thus, we investigated the association between DpR and overall survival (OS), and whether there were any differences in treatment efficacy on DpR between modified FOLFIRINOX (mFFX) versus gemcitabine plus nab-paclitaxel (GnP) as 1st-line chemotherapy for LAPC, using the results from JCOG1407 which was a randomized phase II trial comparing these regimens. Methods: Of the 126 patients enrolled in JCOG1407, patients were eligible except for the followings; patients who never had an imaging study or had only non-target lesions. The association between DpR and OS was investigated by dividing DpR into 3 groups at the tertile point (T1, T2 and T3 from largest to smallest), and whether DpR contributes to OS was examined by multivariable analysis. The differences in treatment efficacy between both regimens were investigated byevaluating DpR, time to DpR, and duration of response (DoR). Results: A total of 109 patients were eligible for this study (n = 53/56 in mFFX/GnP). The number of patients in T1, T2, and T3 were 37, 36, and 36, respectively. The median OS of T1, T2, and T3 were 29.3 (95% CI, 21.0-NE), 20.6 (95% CI, 15.8-24.5), and 19.0 months (95% CI, 12.7-22.4), respectively ( P= 0.0237). Multivariable analysis identified DpR as an independent prognostic factor for OS (HR 1.883, 95% CI 1.030-3.442, P= 0.040 for T2 vs. T1, and HR 2.523, 95% CI 1.342-4.744, P= 0.004 for T3 vs. T1). The median DpR in GnP was better than that in mFFX (28.9 vs. 22.7%; P= 0.041). The median DoR in mFFX tended to be longer compared to that in GnP (8.2 vs. 5.3 months; P= 0.132). No differences in mean time to DpR were observed between the two regimens. Conclusions: In LAPC patients receiving 1st-line chemotherapy, larger DpR contributed to OS. Although OS and PFS between mFFX and GnP were similar, the treatment efficacy on DpR and DoR might be different between the two regimens. Clinical trial information: UMIN000023143 .
The role of Smad4/TGFB signaling in tumorigenesis of pancreatic ductal adenocarcinoma (PDAC).
Authors: Yoo Hannah , Means Anna 
Published: January 2023

748 Background: Pancreatic cancer ranks 4th among cancers as a cause of death in the United States and 85- 90% of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated 2 major types of precursors to PDAC including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN); the mechanisms by which IPMNs give rise to PDAC are incompletely defined. We hypothesize that SMAD4 signaling is specifically involved in IPMN pathway with PanINs and IPMN having partially overlapping signaling pathways and molecular markers. Methods: We performed immunohistochemistry staining on different precursor lesions of mouse pancreatic tissue (PanIN precursor: Ptf1aCre LSL-KrasG12D; IPMN precursor: Ptf1aCreERT LSL- KrasG12D Smad4fl/fl treated with tamoxifen) using markers of different IPMN subtypes and signaling pathways known to be involved in PDAC including, MUC1, MUC2, MUC5AC, SMAD4, ERK1/2, SOX9, and YAP. We treated IPMN cells lines derived from Ptf1aCreERTM LSL-KrasG12D GnasR201C mice with TGF-β, BMP-2, or vehicle control and quantified RNA expression of Smad7, Serpine1, Id2, and normalized to Pmm1 expression. We performed a western blot to detect the protein expression of phospho-SMAD1, phospho-SMAD2, SMAD1, and SMAD2. Results: Both PanIN and IPMN mouse models exhibited strong expression of MUC5AC and MUC1, reflecting the pancreatobiliary subtype. The tumor cells in both models expressed phosphorylated substrates of protein kinase A, phosphorylated ERK1/2, and SOX9. Regional differences were noted for SOX9 signaling with IPMN demonstrating a greater expression around the outer edges of the lesion, compared to the center. PanIN model demonstrated a more prominent nuclear YAP staining. Treatment of BMP2 and TGF-β in pancreatic IPMN cells from Ptf1aCreERTM LSL-KrasG12D GnasR201C cell line significantly increased RNA levels of Serpine1 (2.4 and 199.6, respectively; n = 4; p < 0.05) and Smad7 (2.9 and 6.3, respectively; n = 4; p < 0.05). BMP2 treatment significantly increased RNA levels of Id2 (1.9; n = 4; p < 0.05) while TGF-β significantly decreased Id2 level (0.3; n = 4; p < 0.05). Phosphorylated-SMAD2 was detected only with TGF-β treatment while phosphorylated-SMAD1 was detected with vehicle, TGF-β, and BMP2 treatment with the highest level with BMP2 treatment. Conclusions: Knocking out Smad4, concurrent with activating KrasG12D mutation, induces a specific IPMN progression model that shares similar molecular markers as the PanIN progression model, shown in Kras mutation alone. SMAD4 signaling remains intact in IPMN lesions that arise from activating the KrasG12D GnasR201C mutation, possibly suggesting that Smad4 mutation induces the IPMN-PDAC progression model that differs from Gas-cAMP-PAK-YAP1 cascade found in GNAS signaling.
Clinical performance of a multimodal screening blood test for advanced adenomas and CRC in an average-risk cohort of 1,038 participants.
Authors: Friedland Shai , Watson Drew , Rex Douglas K. , Nimgaonkar Ashish , Zhang Zhen , Atkins Alex , Hsieh Ben , Lai Jr-Ming , Su Stephen , Wu Jen-chia , Shao Hung-Jen , Tesoriero Jessica , Hannah Lindsey , McGowan John , Gupta Samir , Sninsky John J. , Mei Rui 
Published: January 2023

75 Background: The National Polyp Study and 2021 USPSTF CRC-update highlight that the detection and removal of precancerous advanced adenomas (AA) prevents colorectal cancer (CRC), decreases mortality, and leads to higher cost savings than early cancer detection. Performance of a multimodal blood-based test for the detection of CRC and AA that integrates sensitive and accurate detection of circulating gastrointestinal epithelial cells and somatic oncologic variants as well as SEER data of the impact of sex and age is described. Methods: The prospective study included average-risk, asymptomatic screening subjects from 18 geographically dispersed US colonoscopy centers with blood drawn before colonoscopy. Monte Carlo cross-validation (MCCV) methods were used to evaluate the robustness of test performance through 2000 iterations of independent training and validation using bootstrap resampling with stratification to balance patient histopathology, age, and gender. Results include point estimates, confidence intervals, and distributions of sensitivity and specificity to detect AA and CRC. Results: The study cohort (53.2% female; mean age 56.7 yrs.) consisted of 1,038 subjects (White 65.1%; Black 8.5%; Hispanic 24.8%; Asian 1.7%); of which 954 (92%) were asymptomatic, average-risk screening subjects without age enrichment (including 11 CRC and 93 AA) and 84 (8%) were enriched case-control (65 CRC and 19 AA) subjects. The algorithm derives a test score from 0 (low risk) to 100 (high risk) as a quantitative measure of AA and CRC risk. A pre-defined cut point of 47.2 yields a test specificity > 90%, and 92.1% and 54.5% sensitivity for the detection of CRC and AA, respectively. Estimated sensitivities and selected Clopper-Pearson (Exact) 95% confidence intervals based on validation results from MCCV are presented. A split analysis shows for the 954 intended-use, asymptomatic, average-risk screening subjects, the sensitivity for CRC and AA are 100% and 55.9%. Conclusions: A multi-site, prospective, average-risk CRC screening study using a multimodal assay had high sensitivity and specificity for AA and CRC. The quantitative correlation of test scores with disease pathology indicates that the modes of the assay interrogate the primary underlying pathophysiology of disease. The results demonstrate the potential of this novel test to meet the clinically unmet need for a noninvasive strategy for CRC screening and prevention that detects CRC and AA. Clinical trial information: NCT05127096 . [Table: see text]
The Endoscopic Ultrasound Molecular Analysis of Pancreatic Cancer (EUMEPC) study.
Authors: Lundy Joanne , Gao Hugh , Wilson Trevor , McKay Owen , Perry Andrew , Marshall Vikki M , Croagh Daniel 
Published: January 2023

751 Background: Pancreatic cancer carries a dismal prognosis and limited treatment options. Attempts to implement precision therapies have proved difficult to date, in part due to challenges obtaining high quality genetic material from pancreatic biopsies. Endoscopic ultrasound (EUS) is a common diagnostic procedure, but limited data is available on the clinical utility of these biopsies for comprehensive molecular profiling (CMP) to inform therapeutic choices. Methods: This study aimed to enrol up to 150 patients undergoing EUS biopsies for pancreatic cancer, in order to complete targeted DNA/RNA sequencing on 100. The primary outcome was to characterise the proportion of patients able to undergo CMP on their diagnostic EUS biopsies, with fresh-frozen biopsies preferred but FFPE specimens accepted if there was no alternative. Secondary endpoints included the proportion of patients with clinically relevant molecular findings as determined by Molecular Tumour Board (MTB) discussion, proportion of patients initiating targeted therapies, and quantitative/qualitative analysis on molecular material derived from fresh-frozen versus FFPE EUS biopsies. Results: 109 patients have been enrolled since May 2020, and molecular profiling has been completed for 102 patients. 2 patients (1.8%) were excluded due to having no available biopsies, and 5 biopsies (4.7%) were unable to be sequenced due to inadequate quality metrics. Common oncogenes were detected at roughly expected frequencies, with mutations in KRAS occurring in 91 (89.2%), TP53 in 67 (65.7%), SMAD4 in 11 (10.8%) and CDKN2A in 7 (6.8%). Median tumour mutation burden (TMB) in this cohort was low at 3.1Mut/Mb although 7 patients (6.9%) had a high TMB (defined as >10Mut/Mb), of which 3 (2.9%) had markedly hypermutated tumours (>200Mut/Mb). All processed samples were microsatellite stable. Therapeutically relevant mutations were detected in 21 (20.6%) including RNF43 in 7 patients (6.9%), KRAS G12C and BRCA in 3 patients each (2.9%), in addition to BRAF V600E in 2 (1.9%), and CHEK2 and BARD1 mutations in 1 each (0.9%). High TMB was observed in 7 patients (6.9%). To date, 5 patients (4.9%) have commenced on targeted therapies, with one patient notably experiencing a complete response to targeted therapy which has now been sustained for >12 months. Conclusions: This real-world study confirms the utility of endoscopic biopsies as a valuable and reliable source of genetic material for clinically relevant molecular tumour profiling. Secondary analyses are underway to further characterise treatment and survival implications in this cohort.
Clinical benefit of granulocyte-colony stimulating factor (GCSF) use during chemoimmunotherapy treatment for metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Lyman Jaclyn P. , Cabanski Christopher R , Maddock Stephen , Wolff Robert A. , Wainberg Zev A. , Ko Andrew H. , Rahma Osama E. , Fisher George A. , Gabriel Peter Edward , Doucette Abigail , Zheng-Lin Binbin , Maloy Molly A. , Dugan Ute , Fairchild Justin P. , Spasic Marko , O'Donnell-Tormey Jill , Vonderheide Robert H. , O'Hara Mark H. , O'Reilly Eileen Mary 
Published: January 2023

757 Background: GCSF is used for primary/secondary prophylaxis of chemotherapy(chemo)-associated neutropenia in patients (pts) with mPDAC. GCSF may also increase the populations of healthy, naïve immune cells in an otherwise immunologically dysregulated and cold environment, potentially augmenting therapy outcome with immunomodulatory (IO) agents. Here, we describe the impact of GCSF administration on OS, PFS, and time on treatment (TOT) in the setting of mPDAC for (1) a trial in which pts were administered chemo-IO combinations and (2) a synthetic control arm using retrospective real-world data from pts who received standard-of-care (SOC) chemo (PASCAL). Methods: PRINCE is a ph1b/2 study evaluating gemcitabine (gem) and nab-paclitaxel (NP) ± sotigalimab (sotiga; CD40 agonist) ± nivolumab (nivo; anti-PD1) for pts with mPDAC (NCT0324250), where prophylactic GCSF use was prohibited. PASCAL pts received SOC gem/NP and primary/secondary GCSF use was allowed. In this retrospective analysis, GCSF use was defined as receiving at least 1 dose of GCSF anytime during treatment. OS, PFS, and TOT and associated HRs and CIs were calculated using Kaplan-Meier and Cox methods. PFS data not available for PASCAL. Results: 32/123 (26%) and 16/68 (24%) pts received GCSF in PRINCE and PASCAL, with 84% and 88% of pts receiving at least 1 dose within the first 3 cycles, respectively. In PRINCE, GCSF use was associated with significant improvements in OS (HR [95% CI]: 0.62 [0.40-0.97]), PFS (0.71 [0.47-1.08]), and TOT (0.67 [0.45-1.01]). These improvements were most notable in the sotiga-containing arms (table). In the absence of IO treatment, however, no statistical significance was observed in PASCAL (HR [95% CI]: OS = 0.81 [0.44-1.51]; TOT = 0.90 [0.51-1.58]). Additional work is ongoing to understand the association of GCSF usage with known prognostic factors. Conclusions: These analyses suggest that GCSF use may enhance the clinical benefits of chemo-IO in mPDAC. These potential benefits of GCSF usage warrant further evaluation in other chemo-IO trials as well as prospective evaluation in pre-clinical and clinical settings. Clinical trial information: NCT03214250 . [Table: see text]
Next-generation whole blood transcriptome-based assay for advanced adenoma detection.
Authors: Ehrensberger Sahar Hosseinian , Wosika Victoria , Hadadi Noushin , Fonseca Costa Sara , Durandau Eric , Monnier-Benoit Sylvain , Ciarloni Laura , Scherer Stefan J. , Tejpar Sabine 
Published: January 2023

77 Background: Colorectal Cancer (CRC) is the second leading cause of cancer mortality worldwide although highly curable if detected early. An accurate liquid biopsy test for early cancer and precancerous lesion, detection is key to promote prevention and reduce mortality. We previously developed a liquid biopsy test based on immune cells response to the tumor, commercialised under the name of Colox, with best-in-class clinical performances for AA detection (52% sensitivity and 92% specificity) (Ciarloni L et al, Clin Cancer Res, 2016). An improved second generation of the test, leveraging transcriptome profiling and advanced machine learning tools, is under development and first results are presented. Methods: Prospective peripheral whole-blood (PAXgene) samples from subjects diagnosed with CRC, advanced adenoma (AA), non-advanced adenoma, other types of cancer as well as controls without colorectal neoplasia (CON) were divided into discovery and validation sets. Transcriptome profiles were generated by RNA-seq and gene expression signatures identified leveraging Novigenix’s proprietary LITOseek platform, which integrates several advanced Machine Learning (ML) methods into a ranking systems. Biological functional analysis was performed by over-representation (ORA), gene set enrichment (GSEA) and gene network analyses (STRINGdb). Results: Significant changes in the whole blood transcriptome profile of AA compared to CON were identified. Functional analysis highlighted upregulation of fatty acid derivative biosynthesis, interferon signaling, tryptophan catabolism to kynurenine, and downregulation of DNA repair in AA blood samples compared to CON. A novel gene classifier was generated, showing for AA detection 71% sensitivity, 94% specificity and an AUC of 74% by cross-validation on the discovery set. Validation of the gene classifier in an independent set is currently ongoing and will be presented at the congress. Conclusions: Capturing immune-related information using whole blood trascriptome profiling and applying cutting-edge machine learning technologies demonstrated to be valuable for identifying gene signatures for advanced adenoma detection. This differentiated solution has demonstrated best-in-class potential to significantly improve patient outcomes by detecting precancerous lesions with a simple non-invasive blood test.
Social vulnerability and survival in GI cancers.
Authors: Murimwa Gilbert Zvikomborero , Meier Jennie , Nehrubabu Mithin , Yopp Adam C. , Zeh Herbert J. , Polanco Patricio M. 
Published: January 2023

787 Background: Social vulnerability is a federal metric used to assess a community’s resilience in facing external stressors from disease or disaster. The social vulnerability index (SVI) includes 15 social factors obtained at the census tract level within counties and ranks them along 4 themes – socioeconomic status, household composition and disability, minority status & language, and housing/transportation. Social vulnerability has never been explored at the census tract level in any malignancy and the Texas cancer registry provides granular detail at both the patient and census block group level not available in national datasets. We sought to characterize the relationship between social vulnerability and survival in gastrointestinal cancers, as well as its potential to identify themes for focused interventions to mitigate disparities. Methods: We retrospectively reviewed 196,651 patients with colorectal (CRC), gastric (GC), pancreatic (PDAC), and hepatocellular cancer (HCC) from the Texas Cancer Registry from 2004-2019. We analyzed patient demographics, social vulnerability (SVI), individual poverty index (PI), and clinicopathologic factors to understand their impact on survival at 2 years. Unadjusted and covariable-adjusted cox proportional hazards were used for survival analysis. Values were considered significant at p<0.05. Results: Of 196,651 patients, 119,667 (61%) were CRC, 31,636 (16%) PDAC, 18,249 (9%) GC, and 27,099 (14%) HCC. The majority of HCC were localized (51.4%) while most CRC was regional (38%) and PDAC (55%) and GC (40%) were metastatic at diagnosis (median 65 years). In our cohort, 60% of patients received surgery and 34% received chemotherapy while half of those with pancreatic/hepatic malignancies received no therapy. Percentiles for SVI themes were consistently near the national average except for GC which was in the 80th percentile for the minority/language theme. At 2 years, individual poverty at 5-9%, 10-19%, and >20% of the federal poverty line (HR 1.06, 95%CI 1.03 - 1.09; HR 1.09, 95%CI 1.06 - 1.12; HR 1.13, 95%CI 1.10 - 1.17) was associated with increased risk of death. Medicaid as primary insurance, (HR 1.41, 95%CI 1.36 - 1.47), SVI socioeconomic status (HR 1.18, 95%CI 1.13 - 1.24), and household composition themes (HR 1.06, 95%CI 1.02 - 1.10) also associated with increased likelihood of death at 2 years. Notably, the minority theme was associated with improved survival (HR 0.85, 95%CI 0.82 - 0.89). Conclusions: Across four GI cancers, social vulnerability and poverty independently predicted survival at 2 years. Among SVI themes, socioeconomic status was the strongest predictor of worse survival, and the minority theme was associated with improved survival, potentially reflecting the Hispanic paradox. These findings suggest that the SVI may be used as a tool for identifying where resources can be targeted at a local level to mediate the survival disparity for vulnerable populations with GI malignancies.