bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of HPSE in BRAF V600E-mutant colorectal cancer.
Authors: Liu Mengling , Xu Xiaojing , Peng Ke , Hou Pengcong , Liu Qing , Yu Yiyi , Liu Tianshu 
Published: June 2021

3530 Background: BRAF mutations occur in about 10% of colorectal cancer (CRC), more than 90% of which are BRAF V600E mutation. Patients (pts) with BRAF V600E mutation present poor prognosis. Complex molecular biological mechanisms in this population have not been well annotated. HPSE plays a multifunctional role in cell proliferation, invasion and angiogenesis in cancer. Here we identified differentially expressed genes (DEGs) between pts with and without BRAF V600E mutation, and then focused on the function of HPSE, one of top DEGs, in BRAF V600E-mutant CRC. Methods: Clinical and transcriptional data of pts with CRC from The Cancer Genome Atlas (TCGA, n = 525) database and GSE39582 dataset (n = 510) were analyzed to explore the top overlapped DEGs between BRAF V600E mutant and wild-type pts. Records and tumor samples of 172 pts with BRAF V600E-mutant CRC diagnosed at Zhongshan Hospital Fudan University between 6/2015-12/2018 were collected. The HPSE protein expression status of tumor samples was evaluated by immunohistochemistry staining. Moderate or strong staining in > 25% of tumor cells was interpreted as HPSE positive. Overall survival (OS) was analyzed using Kaplan-Meier Curves with Log-rank test and multivariable Cox regression. Next, lentiviral shRNA-based silencing of HPSE was performed in two BRAF V600E-mutant CRC cell lines (HT-29, RKO). The effect of HPSE on tumor growth was investigated through colony formation assays, cell cycle assays and subcutaneous xenograft models. Results: The top overlapped genes of the DEGs list included HPSE, TFF2, AXIN2, MLH1, RNF43, EPM2AIP1. Among them, HPSE had significantly high expression in BRAF V600E-mutant group. Of 172 pts with BRAF V600E mutation, 83 were identified as HPSE positive and 89 were negative. Two groups were generally well balanced on age (p = 0.096), gender (p = 1.000), location (p = 0.658), stage (p = 0.249) and MMR status (p = 0.129). HPSE positive pts had a significantly worse OS in comparison to HPSE negative pts (p = 0.037, median OS not reached). The multivariate analysis showed that HPSE positive was independently associated with inferior OS [HR 1.97 (95%CI: 1.02 – 3.80), p = 0.044). Silencing HPSE gene impaired colony formation activity significantly and arrested more cells in G0/G1 phase of BRAF V600E-mutant CRC cell lines. Tumor growth was inhibited apparently in HPSE-silencing xenograft models. Conclusions: Pts with BRAF V600E-mutant CRC had a high HPSE expression level, while HPSE protein expression was an independent prognostic factor for this population. The silencing of HPSE expression in BRAF V600E-mutant CRC cell lines inhibited cell proliferation and tumor growth in vitro and in vivo. HPSE may contribute to the poor prognosis of BRAF V600E-mutant CRC and might be a promising therapeutic target for this subtype of CRC.
Investigating intra-tumor microbes, blood microbes, and CEA for development of non-invasive biomarkers in colorectal cancer.
Authors: Malalur Pannaga G. , Mo Xiaokui , Hoyd Rebecca , Hays John L. , Carbone David Paul , Spakowicz Daniel 
Published: June 2021

3551 Background: The development of non-invasive biomarkers has the potential to revolutionize clinical care for colorectal cancer (CRC) patients. The presence of bacteria in CRC tumor biopsies has been shown to contribute to CRC development. In a previous study, our group showed some intra-tumor microbes in CRC tumor biopsies correlated with overall survival in CRC patients. However, the correlations between microbes in tumor vs blood, and between non-invasive serum marker carcinoembryonic antigen (CEA) and microbes are unknown. We hypothesize that tumor microbes will also be found in blood, and that CEA will correlate with certain microbes. Methods: We obtained RNA-seq data from CRC tumor biopsies from patients treated at The Ohio State University Comprehensive Cancer Center as part of the Oncology Research Information Exchange Network (ORIEN). Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. RNA-seq from CRC tumor biopsies as well as peripheral blood at the Cancer Genome Atlas (TCGA) consortium were processed by the same method. Results: The analyzed ORIEN cohort included 93 CRC patients with an age range from 30-83 years, 60.2% male, 87.1% adenocarcinoma, and 47.3% with metastatic CRC. The TGCA cohort included 495 CRC patients with an age range from 31-90 years, 53.3% male, 85.1% adenocarcinoma, and 15.5% with metastatic CRC. Over fifteen exogenous phyla (including bacteria, viruses, fungi) were observed in both ORIEN and TCGA cohorts. Several of the samples were dominated by viral sequences while others by bacteria, suggesting considerable tumor microbiome heterogeneity. Evaluation of the fraction of microbes in tumor and blood showed that nearly all the microbes found in blood (97.6%) were also observable in tumor in the TCGA cohort. Microbial abundances of various taxa, including Fusobacterium, significantly correlated between blood and tumor. Several bacteria including members of the genera Bacillus and Staphylococcus were positively associated with tumor stage (metastatic vs non-metastatic), but microbial relative abundances were not correlated with the location of tumor in colon (right, left, transverse colon). Certain microbial species from the ORIEN cohort were found to positively correlate with CEA, (including from the genera Fusobacterium, Lactobacillus, Pseudomonas, Vibrio, Clostridium) and these associations remained when adjusted for alcohol and smoking by multivariate analysis. Conclusions: Nearly all the microbes found in blood were found in tumor and abundances of various taxa were significantly correlated, suggesting that blood-based cancer microbiome analysis has great potential. Serum CEA has a low diagnostic ability when used alone, but combining this with blood microbiome could improve diagnostic/prognostic utility as a non-invasive biomarker.
Patient-specific meta-analysis of 3 validation studies of the 12-gene colon cancer recurrence score assay for recurrence risk assessment after surgery with or without 5FU and oxaliplatin.
Authors: Yothers Greg , Venook Alan P. , Yamanaka Takeharu , Lin Yan , Crager Michael , Chao Calvin Y. , Baehner Frederick L , Yoshino Takayuki 
Published: June 2021

3599 Background: The 12-gene Oncotype DX Colon Recurrence Score assay is a clinically validated genomic assay that evaluates recurrence risks in stage II and stage III colon cancer patients independent of clinical-pathologic features. Improved colon cancer care has reduced recurrence rates since the late 1990’s. Methods: Pre-specified patient-specific meta-analysis methods were used to estimate 1-, 3- and 5-year recurrence risk combining the 12-gene colon recurrence score (RS) validation studies CALGB 9581, NSABP C-07 and SUNRISE. Cox models had effects for RS result, number of nodes examined (<12 or ≥ 12), T-stage, MMR status, and stage (II, IIIAB or IIIC). Baseline cumulative hazard estimates used the latest two studies to reflect current medical practice. Estimates for surgery, surgery+5FU and surgery+5FU+oxaliplatin treatment were provided by integrating stage-specific 5FU hazard ratios from a meta-analysis of the QUASAR study (2007) and a pooled analysis of NSABP studies (Wilkinson 2010), and oxaliplatin treatment effect estimates from NSABP C-07. Recurrence risk with 5FU alone was not estimated for MMR-deficient patients due to expected lack of 5FU efficacy in these patients (Sargent 2010). Results: In the overall population of 2,179 patients, 55%, 32% and 13% were Stage II, IIIA/B and IIIC, 63% had ≥12 nodes examined, 90% were T3, and 88% were MMR proficient. Median RS result was 31 (IQR 23–39). RS result and each clinical-pathologic factor contributed independent prognostic information (meta-analysis Wald tests, all p<.001). Risk estimates are generally lower than previous RS report risk estimates. For patients with pathological stage II, T3, MMR-proficient tumors with ≥12 nodes examined, approximately 40% are expected to have 5-year recurrence risk ≤10% with surgery alone based on the distribution of RS results. The table shows example 5-year recurrence risk estimates for specific RS results and clinical-pathologic characteristics. Conclusions: The new recurrence risk estimates provide more patient-specific information reflecting more current medical practice than previous reports using RS result, allowing better, more individualized treatment decisions.[Table: see text]
Final survival results from a multicenter, randomized phase II trial of intravenous paclitaxel plus FOLFOX (ivPOF) and/or intraperitoneal paclitaxel plus FOLFOX (ipPOF) versus mFOLFOX6 as first-line treatment of advanced gastric cancer (AGC): SYLT/FNF 004.
Authors: Zhao Shen , Lin Rongbo , Fan Nan-Feng , Chen Yigui , Li Xiaofeng , Lin Peicheng , Chen Wujin , Fang Wenzheng , Zhu Jinfeng , Li Hui , Liu Jie 
Published: June 2021

4041 Background: Progression-free (PFS) and overall (OS) survival for SYLT/FNF 004 were previously reported in ASCO and ASCO-GI 2019. At that time, PFS was statistically significantly improved with ivPOF or ipPOF compared to mFOLFOX6 as first-line treatment of AGC; however, there were no significant between-treatment differences in OS. Herein, we report final survival results for this trial. Methods: Subjects were randomly assigned to one of three treatments: intravenous paclitaxel 135 mg/m2 + mFOLFOX6 omitting the 5-FU bolus (ivPOF); intraperitoneal paclitaxel 80 mg/m2 + mFOLFOX6 omitting the 5-FU bolus (ipPOF); or mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 as a 46-hour continuous infusion). Treatment cycles were repeated every 14 days for up to 9 cycles. Thereafter, maintenance treatment with S-1 80 mg/m2/day for 14 days every 3 weeks until disease progression, unacceptable toxicity, patient refusal, or physician decision. The original study objective was to compare ivPOF or ipPOF vs. mFOLFOX6 for PFS. Due to slow accrual, the protocol was later amended to compare POF (ivPOF and ipPOF) with mFOLFOX6 for PFS. Results: Between Nov 2015 and May 2018, 89 subjects (30 ivPOF, 29 ipPOF, 30 mFOLFOX6) were enrolled. As of the data cutoff on Dec 31, 2020, median follow-up was 41 (IQR: 37-43) months. The median number of cycles administered was 7 (IQR: 4-9) for POF; 6 (IQR: 4-9) for ivPOF; 9 (IQR: 4-9) for ipPOF; and 4 (IQR: 3-9) for mFOLFOX6. Median PFS and OS, respectively, were 6.23 (95% CI: 4.90 to 9.07) and 10.17 (95% CI: 8.97 to 16.4) months for POF and 4.55 (95% CI: 2.73 to 6.87) and 6.87 (95% CI: 5.83 to 13.6) months for mFOLFOX6. Both PFS and OS were statistically significantly better with POF, ivPOF or ipPOF versus mFOLFOX6 (Table). Safety was consistent with previous reports. Conclusions: POF, ivPOF or ipPOF improved both PFS and OS compared with mFOLFOX6, with similarly manageable adverse effects. Clinical trial information: NCT02845908. [Table: see text]
Real-world outcomes of second-line ramucirumab plus paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma: A nationwide retrospective study in Korea (KCSG-ST19-16).
Authors: Zang Dae Young , Han Hye Sook , Kim Bum Jun , Jee Hee-Jung , Suh Young Ju , An Hyonggin , Byun Ji-Hye , Kim Dong Sook , Park Se Hoon , Rha Sun Young , Oh Do-Youn , Kim Jong Gwang , Bae Woo Kyun , Kim In-Ho , Sym Sun Jin , Oh So Yeon , Kim Hyeong Su , Lee Keun Wook , Ryu Min-Hee 
Published: June 2021

4056 Background: Ramucirumab as monotherapy or in combination with paclitaxel is a second-line treatment option recommended for patients with locally advanced unresectable or metastatic gastroesophageal junction (GEJ) or gastric adenocarcinoma. However, real-world data of large samples focused on ramucirumab plus paclitaxel in gastric cancer are limited. We conducted a nationwide retrospective study to evaluate the efficacy, safety, and factors potentially associated with survival in patients with gastric or GEJ adenocarcinoma who received second-line ramucirumab plus paclitaxel in a real-world setting. Methods: The study population comprised all patients with gastric or GEJ cancer who received ramucirumab plus paclitaxel in South Korea between May 1, 2018, and December 31, 2018. We included patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum and fluoropyrimidine-containing combination chemotherapy. Results: A total of 1,063 patients with advanced gastric or GEJ adenocarcinoma who received ramucirumab plus paclitaxel were included. The objective response rate and disease control rate were 15.1% and 57.7%, respectively; the median progression-free survival was 4.03 months (95% CI, 3.80–4.27), and the median overall survival was 10.3 months (95% CI, 9.33–10.73). The common treatment-related adverse events (TRAEs) at any grade were neutropenia (44.7%), anemia (41.8%), neuropathy (29.1%), fatigue (25.9%), and anorexia (25.0%). Grade 3 or higher TRAEs with incidences of ≥5% were neutropenia (35.1%) and anemia (10.5%). Adverse events of special interest were infrequent, including hypertension (2.1%) and proteinuria (3.0%). Based on multivariate analysis, overall survival was negatively associated with Eastern Cooperative Oncology Group performance status ≥2, weight loss in the previous 3 months ≥10%, GEJ of primary tumor, poor or unknown histology grade, number of metastatic sites ≥3, presence of peritoneal metastasis, no prior gastrectomy, and time to second-line since first-line treatment < 6 months. Conclusions: Our large-scale, nationwide, real-world data analysis of an unselected real-world population added evidence for the efficacy and safety of second-line ramucirumab plus paclitaxel in patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Clinical trial information: NCT04192734.
Alternating gemcitabine/nab-paclitaxel (GA) and 5-FU/leucovorin/irinotecan (FOLFIRI) as first-line treatment for de novo metastatic pancreatic cancer (MPC): Safety and effect.
Authors: Schroeder Brett A. , Mandelson Margaret T. , Picozzi Vincent J. 
Published: June 2021

4125 Background: Both gemcitabine and 5FU-based chemotherapy have demonstrated efficacy in MPC. Alternating regimens may 1) reduce toxicity 2) slow resistant cancer biology emergence and 3) provide a broader platform for addition of other therapeutic agents. Alternating GA and FOLFIRI in MPC has been previously reported as part of the SEENA -1 trial,our own institution, and elsewhere (Picozzi et.al. GI Cancer Symposium 2017, Picozzi et.al, ASCO 2018 Assenat et,al, ASCO 2018). An extension of our institutional observations are reported here. Methods: Pt eligibility required the following: 1) biopsy proven de novo MPC, 2) no prior evidence MPC on CT, 3) ECOG performance status ≤ 2, and 4) bi-dimensionally measurable disease. Treatment (Rx) entailed gemcitabine 1000mg/m2 and nab-paclitaxel 125mg/m2 1, (8), 15 alternating every 8 wks (2 cycles) with FOLFIRI using standard dosing. Patients were radiographically re-staged every 8 wks. Rx was continued up to 48 wks; Rx thereafter decided by pt/MD. Results: 108 pts met eligibility requirements from 10/2015 and 12/2020. Pt characteristics included median age 68 ( range 35-81), ECOG PS 0/≥1 54%/46%, # diseases sites 1/≥1 62%/38%, liver /non-liver 76%/24%, biliary obstruction yes/no 40%/60%, C 19.9 NL/ < 59XNL/ > 59X NL 12%/32%/56%; median Ca 19.9 4598 With median f/u of 19.7 mo, 17 pts remain on Rx < 48 wks, 35/91 (38%) completed 48 wks Rx, 56/91 (62%) pts progressed prior to 48 wks. Median # mos on Rx was 8.9. ≥ grade 3 heme toxicity included anemia 7%, neutropenia 9%, thrombocytopenia 5%. Neutrophil growth factors were not used in this pt cohort. ≥ 3 non-hem toxicity included neuropathy1%, nausea/vomiting 2%, mucositis 2%, diarrhea 1%. Disease control at 16 wks was 81% (35% PR/46% SD/16% PD, 95% CI 72-87%). Median OS was 13.7 mo (95% CI 10.9-18.7 mo). 6 /12/18/24 mo OS were 87%/55%/41%/ 20% respectively. Prognostic significance was seen with Rx > vs < 48 wks (21.1 vs 8.0 mo, p <.0001), and ECOG PS 0 vs. ≥1 ( 17.8 vs. 10.9 mo, p = 0.03) Age, # metastatic sites, liver involvement, biliary obstruction and magnitude of CA 19.9 elevation all failed to achieve prognostic significance at the p <.05 level. Conclusions: 1) Alternating GA/ FOLFIRI in MPC has a more favorable toxicity profile than standard regimens 2) Med OS appears superior to GA and competitive with FOLFIRINOX ; longer term (18/24 mo ) OS seemed particularly encouraging 3) ≥ 48 wks Rx and ECOG PS 0 were prognostically significant 4) Further investigation using this regimen including a) randomized comparisons, b) incorporation of molecular data and c) addition of additional agents seems indicated Updated survival data will be presented at the meeting
Fecal microbiome composition in pancreatic cancer cachexia and response to nutrition support.
Authors: Moshayedi Natalie , Yang Julianne , Lagishetty Venu , Jacobs Jonathan , Placencio-Hickok Veronica , Osipov Arsen , Hendifar Andrew Eugene , Gong Jun 
Published: June 2021

4129 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis with a 5-year survival rate of 10.0%. Previous studies in stool microbiome indicate that microbiome composition has been associated with therapy response and pathogenesis across multiple cancers, and PDAC patients (pts) with higher bacterial diversity have demonstrated greater long-term survival. The fecal microbiome has not previously been characterized for PDAC pts with cancer cachexia or associated interventions. The study addressed the changes in microbiome over the course of treatment and the association between baseline bacterial composition and outcome in PDAC pts with cachexia. Methods: Stool specimens were collected from the PNCX1 trial (NCT02400398), where all pts were given a semi-elemental diet—enzymatically hydrolyzed protein—with enteral tube feeding. Stool samples (n = 29) were collected at time points aligned with enteral feeding and chemotherapy cycles separated by 6 weeks (C1D1, C2D1, and C3D1) and analyzed using 16S v4 sequencing of the microbiome. Microbiome changes from C1D1 to C3D1, weight stability, and overall survival (OS) were measured alongside microbiome characterization. Results: Pts with a complete set of stool samples were analyzed (n = 6) for differences in microbiome composition across treatment cycles. C3D1 samples were significantly associated with both an increased population of Veillonella and Actinomyces and decreased Bacteroides and Butyricicoccus compared to C1D1. Baseline stool microbiome composition was also evaluated to predict weight stability throughout treatment. In patient stool samples (n = 8) at C1D1, greater abundance of Veillonella (p = 0.0006) and reduced Bifidobacterium (p = 2.62E-5) were linked to greater weight stability. Microbiome alpha-diversity was also characterized using Shannon and Chao1 indices, where stable weight was related to reduced species richness (Chao1, p = 0.0194) but not evenness (Shannon, p = 0.1716). C1D1 patient stool samples were then analyzed and compared to OS (n = 16). Although no significant differences in global microbiome composition were noted between OS < 180 days and OS > 180 days, Parasutterella, Tyzzerella, Phascolarctobacterium, and Lachnoclostridium were identified as more prevalent in OS > 180 days despite their relatively low abundance. Conclusions: We are among the first evaluate stool bacteria changes over treatment course in PDAC pts. While Veillonella was associated with weight stability in a cohort of advanced PDAC pts all receiving enteral feeding, several genera were found in abundance in pts with prolonged OS, though this needs further validation. The potential impact of the gut microbiome and enteral feeding on weight stability is provocative given that cachexia is a hallmark of PDAC and an effective strategy to mitigate this process would be transformative.
Treatment outcomes in renal cell carcinoma patients with metastases to the pancreas and other sites.
Authors: Duarte Cassandra , Beuselinck Benoit , Weise Nicole , Dizman Nazli , Collier Katharine , Li Haoran , Martinez Chanza Nieves , Elias Roy , Rose Tracy L , Brugarolas James , Agarwal Neeraj , Mortazavi Amir , Pal Sumanta K. , McKay Rana R. , Hu Junxiao , Lam Elaine Tat 
Published: June 2021

4557 Background: Metastatic RCC (mRCC) involving the pancreas is distinct from RCC involving other metastatic sites and is characterized by an indolent clinical course, heightened angiogenesis, and an inflamed stroma (PMID: 32271170). We previously reported on outcomes of RCC patients (pts) with pancreatic oligometastasis (ASCO GU 2020). We now report on outcomes in pts with mRCC involving the pancreas in conjunction with other metastases (mets). Methods: We conducted a retrospective, multi-institutional study of mRCC pts with mets to the pancreas and other sites. Data on pt demographics, tumor characteristics, systemic therapy, and outcomes were collected. Pts were classified based on treatment category: immunotherapy (IO) or vascular endothelial growth factor/receptor inhibitors (VEGFI). Outcomes measured included objective response rates (ORR), time-on-treatment (TOT), and overall survival (OS). Results: The analysis included 229 pts from 9 institutions, diagnosed between 1985-2020. Of these, 211 (92%) had clear-cell histology; 131 (57%) had nephrectomy; 41 (18%) had local pancreas-directed therapy; 111 (48%) had synchronous presentation of disease in the pancreas and other sites at time of mets. IMDC risk was favorable in 33%, intermediate in 41%, poor in 11%, and unknown in 15% pts. Median lines of therapy was 2 (range 0-9). Of 219 pts who received first-line (1L) therapy, 151 (69%) had VEGFI therapy, 41 (19%) had IO, and 18 (8%) had VEGFI/IO combination (Table). The IO group included 21 pts on checkpoint inhibitor (CPI), 16 pts on HD-IL2, 4 pts on other IO. 1L ORR was 39.7% for VEGFI (95% CI 31.8-48.0) and 31.7% for IO (95% CI 18.1-48.1) and was not statistically significant (NS, OR 1.4, 95% CI 0.65-3.23, p = 0.371). Median TOT for 1L therapy was 11.6m for VEGFI and 6.5m for IO (p = 0.0106). With a median follow-up of 51.5m, the median OS (mOS) for all pts from time of metastatic disease was 7.7 years (y) (95% CI 6.3-10.3). The mOS for pts who received 1L VEGFI was 7.6y (95% CI 5.5-9.5) and was not reached (NR) for those who got 1L IO (95%CI 6.5-NR); this difference was significant with an unadjusted p-value of 0.029. The pair-wise comparison between mOS of the 1L CPI subgroup compared to that of the 1L VEGFI group was significant (p = 0.0148). Conclusions: Consistent with the literature, mRCC pts with involvement of the pancreas in this study have prolonged OS compared to historical OS for the standard mRCC population. Additionally, our findings suggest that the choice of first-line therapy may impact outcomes. Additional analyses will be presented.[Table: see text]