bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA and RNA sequencing analysis revealed alterations of ANK3, PKHD1 and olfactory transduction as potential biomarker of three-year survival in gastric cancer.
Authors: Wang Jian , Li Si , Xi Wenjing , Chen Dongsheng , Xiao Mingzhe 
Published: June 2021

4034 Background: Gastric cancer is the third leading cause of cancer related death worldwide. Although targeted and immune therapy have brought new benefit for patients, it still faces challenges of limited effective group and survival. Here we investigate the association of overall survival with DNA and RNA alterations to explore potential biomarkers of prognosis in gastric cancer. Methods: Whole-exome sequencing, RNA sequencing and clinical data of 442 patients with stomach cancer were downloaded from TCGA. Clinical factors and mutational landscape (insertion/ deletion/ single nucleotide variant) were compared between group of OS3+ (overall survival > 3 years) and OS3- (OS < 3 years). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed based on differentially expressed RNAs between the two groups. Results: 415 of 442 patients with stage information were included. The corresponding rates of OS3+ for patients in stage of I/II/III/IV was 15.5% (9/58), 10.8% (9/58), 10.9% (9/58), 13.6% (9/58), respectively. When comparing the 49 patients with OS3+ to others with OS3-, no difference of stage or sex distribution was discovered, except that OS3+ group had lower median age at diagnosis than OS3- group (63 vs. 71 years, P = 0.029). Tumor mutation burden was comparable between groups. Mutational landscape showed that the two groups shared 70% of top 20 mutations. Among the 20 hot genes, mutations of ANK3(P = 0.006), PKHD1(P = 0.008) were more frequent in OS3+ group, Studies in breast and prostate cancer inferred that, ANK3 was involved in activity of androgen receptor signaling and cyclins, increased expression of ANK3 in cancer was probably associated with better survival. PKHD1 was involved in calcium ion binding and actin binding and was identified as a protective factor for colorectal cancer. OS3- group tend to have higher mutation frequency of HMCN1(P = 0.062). Previous reports showed that mutation of HMCN1 was enriched in peritoneal metastasis of gastric cancer, it might contribute to progression in gastric cancer. Enrichment analysis revealed difference between the two groups in olfactory transduction ( P < 0.01, KEGG analysis), neuroactive ligand-receptor interaction ( P < 0.05, KEGG analysis) and detection of chemical stimulus in sensory perception of smell ( P < 0.01, GO analysis). Numbers of discussions have inferred that genes involved in olfactory transduction may also participate in tumor cell proliferation, migration, and invasion. Conclusions: Patients with OS3+ was enriched with mutations of ANK3 and PKHD1 and present significant functional difference in olfactory transduction. These are potential biomarkers of better survival in gastric cancer. Further studies are needed to figure out their roles in tumor activity and provide insight for novel antitumor treatment development.
The prognosis of gastric adenocarcinoma depends on the crosstalk between immune profiles and tumor genomic alterations.
Authors: Wang Deqiang , Chen Xiaofeng , Xu Yaping , He Yuange , Li Lifeng , Shu Yongqian 
Published: June 2021

4035 Background: Gastric adenocarcinoma (GAC) is with a complex microenvironment of tumor cells. A better understanding of the immune landscape of GACs may lead to the improved treatment strategies with ICIs. Methods: To determine whether the molecular characteristics can serve in prognostic stratification of GACs, tumor tissue and blood samples were collected from 231 GAC patients. The median follow-up time was 34 months. The TCR profile was determined by TCR-β CDR3 sequencing while mutation and gene expression profiles were determined by whole exon and whole transcriptome sequencing, respectively. Tumour-infiltrating immune cells were characterized using immunofluorescence (IF) staining. Results: The results showed the OS of patients with high levels of TCR clonality (TCR clonal expansion) was significantly improved compared with patients with low levels (HR = 1.80 and 2.22, p = 0.022 and 0.008, respectively) in the whole group and in the subgroup of patients with stages IB to III disease. Furthermore, low local clonality was an independent risk factor for OS (adjusted-HR = 1.68 and 1.95, p = 0.049 and 0.029, respectively). Thus, TCR clonal expansion in tumour tissue had a strong prognostic value for GAC patients, independent of clinicopathological factors. Based on whole exon and whole transcriptome sequencing, RNF43/FBXW7/ARID2 mutations and local TCR clonality jointly impacted prognosis (p < 0.001), and functional changes in corresponding Wnt pathway/Notch pathway/SWI/SNF complex characterized a GAC subset with enhanced tumour immunogenicity and TCR clonal expansion. TCR CDR3 sequence similarity comparisons yielded clusters of TCR clones of likely similar functions. The most expansive TCR clusters negatively correlated with the percentage of subclonal mutations (Pearson r = -0.8183, p < 0.001), indicating that tumors with less genomic heterogeneity might induce a greater immune response. By IF staining and mutual correlation analysis, only M1 macrophages showed a significant positive correlation with local TCR clonality for epithelia, stroma, and total cell counts. Tumors were categorized according to the density of M1 macrophages, M1 macrophage infiltrated subtype was associated with favorable OS (p = 0.040 and 0.043) and its combination with the local TCR clonality improved prognosis stratification (p < 0.001). Finally, the scoring by local TCR clonality, RNF43/FBXW7/ARID2 mutations and M1 infiltration determined the best prognosis (p < 0.001). Conclusions: TCR profiles were associated with genomic alterations and may serve as a prognostic biomarker for GACs. A multi-omic model including TCR profiles might produce an improved stratification for treatments and outcomes.
Subgroup analysis by Ki-67 and baseline CgA of the randomized, placebo-controlled phase 3 study of surufatinib in advanced well-differentiated pancreatic neuroendocrine tumors (SANET-p).
Authors: Yu Xianjun , Xu Jianming , Shen Lin , Bai Chunmei , Li Jie , Zhou Zhiwei , Li Zhiping , LI Enxiao , Yuan Xianglin , Chi Yihebali , Yin Yongmei , Lou Wenhui , Xu Nong , Bai Yuxian , Zhang Tao , Xiu Dianrong , Wang Xiuwen , Guan Sha , Xu Qian , Su Weiguo 
Published: June 2021

4111 Background: In the phase 3 SANET-p trial (NCT02589821), surufatinib significantly increased progression-free survival (PFS) compared with placebo in patients with progressive, well-differentiated (grade 1 or 2), advanced pancreatic neuroendocrine tumors (NETs). Here we report the relationship of Ki-67 and baseline Chromogranin A (CgA) on efficacy outcomes. Methods: A total of 172 patients with advanced pancreatic NETs were randomized to surufatinib or placebo in a 2:1 ratio. Investigator-assessed PFS and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were used for the analysis. The post-hoc subgroup analyses were performed on Ki-67 subcategory: < 5% (n = 40 vs 21), 5-10% (n = 57 vs 31), > 10% (n = 16 vs 7), and baseline CgA subcategory: ≤ 2 times of upper limit of normal (ULN) (n = 59 vs 31), > 2 × ULN (n = 44 vs 24). Results: In the intent-to-treat population, surufatinib was superior to placebo, median PFS (mPFS) of 10.9 vs 3.7 months (mo) ( p = 0.0011), with a stratified hazard ratio (HR) of 0.491 (95% confidence interval [CI]: 0.319, 0.755). mPFS was statistically significantly longer in the surufatinib arm versus that in the placebo arm in subgroups of Ki-67 5-10% (11.0 vs 3.7 mo, HR = 0.33, p= 0.0002), Ki-67 > 10% (11.1 vs 2.8 mo, HR = 0.04, p = 0.0003) and CgA > 2 × ULN (11.0 vs 3.7 mo, HR = 0.36, p = 0.0036). There was numerical PFS improvement with surufatinib compared to placebo in subgroup of Ki-67 < 5% (9.3 vs 5.6 mo, HR = 0.91, p = 0.8015) and CgA ≤ 2 × ULN (9.4 vs 3.7 mo, HR = 0.61, p = 0.0809). ORRs in the subgroups of Ki-67 < 5%, 5-10%, and > 10% with surufatinib were 15.8%, 24.0% and 12.5% respectively. There was only one partial response in the placebo arm (with Ki-67 < 5%). ORRs in the subgroups of CgA ≤ 2 × ULN and > 2 × ULN with surufatinib were 18.9% and 21.4%, while also only one partial response in the placebo arm with CgA ≤ 2 × ULN. Conclusions: Surufatinib showed statistically significant and clinically meaningful improvement in PFS compared to placebo in patients with advanced, progressive, well-differentiated pancreatic NETs. From this exploratory analysis, surufatinib demonstrated benefit irrespective of Ki-67 expression levels or baseline CgA. Clinical trial information: NCT02589821.
The fear of cancer progression and recurrence in patients with pancreatic cancer.
Authors: Pijnappel Esther N. , Dijksterhuis Willemieke P.M. , Sprangers Mirjam A.G. , Augustinus Simone , van de Poll-Franse Lonneke V , de Vos-Geelen Judith , van Santvoort Hjalmar , de Hingh Ignace H.J.T. , Molenaar I. Quintus , Busch Olivier R.C. , Besselink Marc G.H. , Wilmink Johanna , Van Laarhoven Hanneke W.M. 
Published: June 2021

4132 Background: Patients with pancreatic cancer run a considerable risk of disease progression or, after resection, disease recurrence, ultimately leading to death. Therefore, it is plausible that pancreatic cancer patients experience fear of cancer recurrence or progression (FOP). The aim of this study was to compare FOP in patients with pancreatic cancer treated with surgery, palliative systemic treatment or best supportive care (BSC), and examine the association between quality of life (QoL) and FOP and between FOP and overall survival (OS), respectively. Methods: This prospective multicenter cohort study included patients diagnosed with pancreatic cancer between 2015 and 2018, who participated in the Dutch Pancreatic Cancer Project (PACAP). Data on FOP (worry of cancer progression scale [WOPS]) and QoL (EORTC QLQ-C30 summary scale score), were obtained from the PACAP database. Data regarding patient and tumor characteristics were derived from the nationwide Netherlands Cancer Registry. The association between QoL and WOPS was assessed with logistic regression analysis. OS was evaluated using Kaplan Meier curves with log-rank test and multivariable Cox proportional hazard analyses. Results: In total, 315 patients were included, of whom 111 patients underwent surgery, 138 received palliative systemic treatment, and 66 BSC. WOPS scores tended to decrease and stabilize over time in all subgroups. Patients who underwent surgery had significantly lower WOPS scores (i.e. less FOP) at initial diagnosis compared to patients in the palliative systemic treatment and BSC group (p = 0.004). Higher QoL scores were independently associated with a lower probability of high WOPS scores in patients receiving BSC only (OR 0.95, P = 0.006). Baseline WOPS score was not independently associated with OS. Conclusions: Pancreatic cancer patients reported FOP at diagnosis, which decreased and stabilized over time. Given the distress that FOP evokes, FOP should be explicitly addressed by health care providers when guiding pancreatic cancer patients through their treatment trajectory, especially those receiving palliative treatment or BSC.
Impact of the COVID-19 pandemic on care delivery and outcomes for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Paluri Ravi Kumar , Cockrum Paul , Laursen Ashley Ann , Gaeta Joseph Louis , Wang Shu , Surinach Andy 
Published: June 2021

4137 Background: The coronavirus disease 2019 (COVID-19) pandemic has caused abrupt changes to the US health system and disruption in cancer care delivery. Little has been reported on the impact of COVID-19 on patients with mPDAC and the care delivery. Our study aimed to characterize the impact of COVID-19 on healthcare utilization and outcomes for patients with mPDAC in the US in the community oncology setting. Methods: We performed a retrospective cohort study of adult patients diagnosed with mPDAC between March – September 2019 and March – September 2020 using the nationwide Flatiron Health EHR database, comprising data from over 280 (largely community based) cancer clinics. Patients were stratified into two cohorts based on the year of diagnosis (2019 vs. 2020). Clinical characteristics were summarized including age at metastatic diagnosis, stage at initial diagnosis, and ECOG performance score (PS). Overall survival (OS) from metastatic diagnosis was estimated using Kaplan-Meier methods. A sensitivity analysis limiting the follow-up time to November of each year was conducted. Results: Overall, 1,719 patients were included in the study (2019: n = 923, 2020: n = 796); both cohorts had similar demographic compositions in terms of age and sex (2019: median age = 70 (IQR: 62 – 76), 52.2% male; 2020: median age = 70 [IQR: 62 – 76], 53.5% male). In 2020, the number of newly diagnosed mPDAC patients decreased by 13.8% compared to 2019. A slightly higher proportion of patients were initially diagnosed with stage IV disease in 2020 (69.7%) vs 2019 (62.3%). A similar proportion of patients with ECOG PS 0-1 was observed between the two cohorts (2019: 48.5%; 2020: 47.9%). The number of visits recorded within the first 90 days after metastatic diagnosis was similar between the two cohorts (2019: median 8 [IQR: 3 – 14]; 2020: median 9 [IQR: 4 – 14]). For both cohorts, the proportion of patients who received 1L treatment was similar (2019: 75.8%; 2020: 76.5%), and the most common 1L treatment regimen was gemcitabine plus nab-paclitaxel (2019: 37.6%; 2020: 40.9%). Of the 1L treated populations, 37.6% of patients diagnosed in 2019 received second line (2L) compared to 17.9% of the 2020 cohort; 16.9% of 1L treated patients in 2019 received 2L in the sensitivity analysis. Patients diagnosed in 2020 had a significantly lower median OS of 6.1 months (95% CI: 5.4 – 6.9) compared to patients diagnosed in 2019: 8.4 months (7.5 – 9.0) (p < 0.001). Conclusions: During the COVID-19 pandemic era, the diagnoses of de novo mPDAC appears to have been impacted, with a higher number of patients diagnosed with advanced stage at presentation. Our analysis suggests that while patients diagnosed in 2020 received a similar level of care as those in 2019, their survival outcomes were adversely affected. Further research is necessary to characterize the impact of the COVID-19 pandemic on cancer care and outcomes.
TCOG T5217 trial: A phase II randomized study of SLOG versus modified FOLFIRINOX as the first-line treatment in locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Chiang Nai-Jung , Shan Yan-Shen , Bai Li-Yuan , Li Chung-Pin , Chen Jen-Shi , Yang Shih-Hung , Kuo Yung-Chia , Chao Yee , Hsieh Yao-yu , Kao Hsiang-fong , Hsiao Chin-Fu , Chen Li-Tzong 
Published: June 2021

4143 Background: The triplet regimen of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG) has shown promising efficacy for metastatic pancreatic ductal adenocarcinoma (PDAC) in our previous study. Current multicenter randomized, phase II study compared the efficacy and safety of SLOG versus modified FOLFIRINOX (mFOLFIRINOX) in patients with advanced/metastatic PDAC. Methods: Patients with chemo-naïve, histologically confirmed advanced/metastatic PDAC, were randomly assigned to either SLOG (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2 on day 1, plus daily 40/50/60 mg of S-1 based on BSA and 30 mg of oral leucovorin, twice daily, on days 1-7, every 2 weeks) or mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 and leucovorin 400 mg/m2 on day 1 plus 5-FU 2400 mg/m2 for 46 hrs, every 2 weeks). Patients were stratified according to disease extent, ECOG PS and primary tumor location. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS) and safety profile. Tumor response was assessed by CT/MRI every 8 weeks according to RECIST v1.1. As an exploratory trial, 130 (65 per arm) patients were estimated to detect a two-sided 15% difference in 6-month PFS (60% in SLOG and 45% in mFOLFIRINOX) with a significant level of α = 0.1 and β = 0.25. Results: Between March 2018 and October 2019, 130 patients were accrued. One patient who was assigned to mFOLFIRINOX arm didn’t receive assigned treatment. Of them, 62.3% were male, 45.4% were ECOG PS0, 81.5% had metastatic diseases, and 16.9% had prior surgery. The 6-month PFS rate was 55.4% in SLOG arm (n = 65) and 50% in mFOLFIRINOX arm (n = 64) (p = 0.850). The ORR and DCR in the SLOG and the mFOLFIRINOX arms were 40% versus 26.6% (p = 0.135) and 76.2% versus 71.9% (p = 0.550), respectively. The median PFS was 7.5 months in SLOG arm and 6.5 months in mFOLFIRINOX arm (p = 0.395); while the median OS was 12.9 months in SLOG arm and 12.1 months in mFOLFIRINOX arm (p = 0.88). Ten patients underwent conversion surgery, of whom 7 had SLOG and 3 had mFOLFIRINOX. The incidence of grade 3/4 neutropenia was significantly higher in mFOLFIRINOX arm (53.2% vs. 16.9% in SLOG arm, p < 0.0001). Conclusions: SLOG could achieve comparable but numerically better ORR, and median PFS and OS as compared to mFOLFIRINOX in patients of advanced PDAC. SLOG can be an alternative first-line regimen for advanced PDAC patients. Clinical trial information: NCT03443492.
Prognostic and predictive factors in patients treated with ramucirumab (RAM) with advanced hepatocellular carcinoma (aHCC) and elevated alpha-fetoprotein (AFP): Results from two phase III trials.
Authors: Llovet Josep M. , Singal Amit G. , Villanueva Augusto , Finn Richard S. , Kudo Masatoshi , Galle Peter R. , Wang Chunxiao , Widau Ryan C , Gonzalez Gugel Elena , Zhu Andrew X. 
Published: June 2021

4146 Background: Elevated AFP in patients with aHCC is a poor prognostic factor with distinct molecular features, including high vascular endothelial growth factor (VEGF) signalling and increased angiogenesis. RAM, a human IgG1 monoclonal antibody, VEGF receptor 2 (VEGFR2) inhibitor, demonstrated improved survival vs placebo among patients with elevated AFP in the REACH-2 trial and is accepted as a standard of care for management of aHCC. We analyzed prognostic factors in patients with AFP ≥400 ng/mL and predictors of clinical benefit to RAM in an individual participant data (IPD) meta-analysis of the REACH and REACH-2 Phase III trials. Methods: Patients with aHCC, Child-Pugh A, ECOG performance status (PS) ≤1, and prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or Placebo Q2W. Meta-analysis was conducted in patients with AFP ≥400 ng/mL (n = 542). Univariate (UV) and multivariate (MV) analyses were performed using a Cox proportional hazard regression model. MV used the cut-off p-value < 0.1 from UV, irrespective of treatment arm. Overall survival (OS) was evaluated by Kaplan-Meier estimator and Cox models. To define predictors of RAM benefit, treatment-by-covariate interactions terms were evaluated. Results: In terms of prognosis assessed by MV analysis in patients with AFP ≥400 ng/mL, 6 variables among demographic and baseline disease characteristics were associated with poor OS in the RAM cohort (ECOG PS 1, AFP > 1000 ng/mL, Child-Pugh > A5, Extrahepatic site > 1, neutrophil-to-lymphocyte ratio > 3.2 and aspartate aminotransferase > 57 U/L) with an additional 3 factors identified within the whole cohort (macrovascular invasion presence, etiology HCV vs. Other and alkaline phosphatase ≥146). RAM benefit was present across all subgroups, including patients with very aggressive HCCs (AFP > 4000 ng/mL; HR: 0.64; 95% CI: 0.49-0.84) and those with nonalcoholic steatohepatitis /alcohol related aHCC (HR: 0.56; 95% CI: 0.40-0.79). Of note, two treatment-emergent (TE) events were the only factors that were significantly associated with improved RAM-related survival: TE-hypertension (p interaction = 0.0392) and TE-ascites (p interaction = 0.0001). However, these results should be interpreted with caution given that TE events are factors only observed after randomization. Conclusions: Several poor prognostic factors for OS were identified in patients with aHCC and elevated AFP. RAM provided an OS benefit irrespective of baseline prognostic covariates, with greater benefit observed in patients with aggressive HCC and those who experienced TE-hypertension or TE-ascites. Clinical trial information: NCT01140347; NCT02435433.
Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Motzer Robert J. , Porta Camillo , Alekseev Boris , Rha Sun Young , Choueiri Toni K. , Mendez-Vidal Maria Jose , Hong Sung-Hoo , Kapoor Anil , Goh Jeffrey C. , Eto Masatoshi , Wang Jinyi , Pan Janice , Ayele Asfaw Alemseged , He Cixin Steven , Mody Kalgi , Cella David 
Published: June 2021

4502 Background: LEN + PEMBRO improved PFS, OS and ORR vs SUN in the first-line treatment of pts with aRCC; LEN + EVE improved PFS and ORR vs SUN (Motzer R et al. NEJM. 2021). We report results of a secondary objective of the CLEAR trial comparing the impact of LEN + PEMBRO or EVE vs SUN, on HRQoL. Methods: Pts (N=1069) were randomized (1:1:1) to receive LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + EVE 5 mg PO QD; or SUN 50 mg PO QD (4 wks on/2 wks off). HRQoL was assessed per FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-3L, at baseline, on day 1 of subsequent 3 wk cycles starting with cycle 2, and at the off-treatment visit. HRQoL analyses (unless otherwise noted) were based on data from randomized pts with any HRQoL data who received ≥1 dose of study treatment. No adjustments for multiple testing or estimation were used; P-values and CIs are nominal and descriptive. Results: For comparisons of LEN + PEMBRO vs SUN, overall changes from baseline at mean follow-up (wk 46) favored LEN + PEMBRO with significant differences between treatments for physical functioning (least squares mean difference [LS MD] [95% CI]: 3.0 [0.5, 5.5]) and fatigue (−2.8 [−5.5, −0.1]), dyspnea (−2.8 [−5.3, −0.3]), and constipation (−2.2 [−4.2, −0.2]). LS MD of the FKSI-DRS total score was 0.2 (−0.4, 0.7). For comparisons of LEN + EVE vs SUN, overall changes from baseline at wk 46 favored SUN with significant differences in overall HRQoL (−2.8 [−5.1, −0.5] assessed by the EORTC QLQ-C30 GHS/QoL scale) and pain (2.8 [0.1, 5.5]), appetite loss (4.2 [1.3, 7.1]), and diarrhea (5.3 [2.6, 7.9]). LS MD of the FKSI-DRS total score was −0.4 (−1.0, 0.2). 14 of 18 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in LS MD comparisons. The LEN + PEMBRO arm is favored over SUN for the median time to first deterioration (TTD) for physical functioning, dyspnea, appetite loss and EQ-5D VAS (Table). 15 of 19 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in TTD comparisons. Conclusions: Compared with SUN, pts in LEN + PEMBRO group had similar or better symptoms and HRQoL. Clinical trial information: NCT02811861. [Table: see text]