bluuebunny/crossref_metadata_2025_split huggingface dataset:
mRNA expression pattern study of esophageal basaloid squamous cell carcinoma.
Authors: Li Yan , Liu Linxiu , Xie Tongji , Pan Yi , Cheng Na , Guo Changyuan , Xue Xuemin , Zeng Hua , Xue Liyan 
Published: June 2022

e16062 Background: Esophageal squamous cell carcinoma (SCC) is one of the most common cancers and the leading cause of cancer-related death in China, and esophageal basaloid squamous cell carcinoma (BSC) is a rare variant (2.2%-11.3%) of SCC with highly aggressive behavior due to its propensity for vessel invasion and distant metastasis. Most reports stated that BSCs had poorer prognosis than conventional esophageal SCC. However, because of the histological morphologic similarity and lacking of diagnostic approaches, esophageal BSC can easily result in misdiagnosis as SCC. Methods: To deepen our understanding of esophageal BSC and seek for diagnostic biomarkers, we analyze the difference of mRNA expression between esophageal BSC and conventional SCC. Nanostring nCounter PanCancer Progression gene expression panel was used on different tumor components from 36 patients diagnosed with esophageal BSC component (Ba) coexisting with conventional SCC component (Co), who underwent esophagectomy at our Hospital (Cancer Hospital, Chinese Academy of Medical Sciences, China). Immunohistochemistry (IHC) was used for verification of candidate biomarkers sFRP1 concluded from mRNA expression analysis. The expression of sFRP1 was evaluated by H-score = % cells staining (0-100%) * intensity (1 to 3). Results: Among 770 RNAs analyzed in the study, 22.9% (176/770) showed downregulation (FDR-adjusted p < 0.05) in Ba than Co, while 5.3% (41/770) showed upregulation. A set of significantly upregulated RNAs (FDR-adjusted p < 0.01, log2(fold change) > 2) were observed in Ba, including sFRP1, FGFR1, ITGA9, VIT, VWA2 and PROM1, which were associated with angiogenesis response, basement membrane, and epithelial-mesenchymal transition (EMT). Besides, significant downregulation (FDR-adjusted p < 0.01, log2(fold change) < -2) of KRT14 was observed in Ba, which was well known as a biomarker for squamous differentiation. Clustering analysis with different pathway scores according to mRNA expression results of Ba yielded two major clusters: Cluster1 with higher pathway scores with resembled to Co, and Cluster2 with lower pathway scores. Survival analysis revealed that patients in Cluster1 seemed to have a longer RFS and a longer OS than those in Cluster2 (Figure 4C&D), although with no statistically significance (RFS: p = 0.322, median RFS = 23.7 vs 10.8 months; OS: p = 0.217, median OS = 51.6 vs 26.5 months), which was probably due to the limited number of patients evolved (10 patients in Cluster1 and 26 in Cluster2). The most upregulated mRNA, sFRP1, was validated by IHC. Receiver operating characteristic (ROC) curve revealed that sFRP1 IHC could be a remarkable diagnosis biomarker to distinguish BSC from conventional SCC (area under ROC = 0.935, p < 0.001 95%CI = 0.871-1.000). Conclusions: Our results revealed BSC as a subtype with distinct RNA expression pattern compared with conventional SCC, and provided a remarkable biomarker, sFRP1, for diagnosis.
Differences in outcomes between premenopausal women and men with gastric cancer in the United States.
Authors: Lee Yi , Aziz Hassan , Li Pin , Zhao Wei , Jehangir Qasim , Goodman Judie R. , Saif Wasif M. 
Published: June 2022

e16066 Background: Over the past decades, the incidence rate of gastric cancer has only dropped by 1.5% despite the identification of modifiable risk factors. Gastric cancer has a male predominance; the lower incidence in females may be associated with a protective hormonal effect. Studies reported the expression of estrogen receptor alpha (ERα) and beta (ERβ) in gastric cancer, yet their roles in incidence and prognosis remain inconclusive. We analyzed the hormonal association with the in-hospital outcomes using a cohort of premenopausal women and men with gastric cancer. Methods: Using Nationwide Inpatient Sample Database from 2016 to 2019, we selected adult women under age 51 as premenopausal as defined by the American College of Obstetricians and Gynecologists and compared to men of the same age group. The primary outcome was in-hospital mortality. Secondary outcomes included hospital length of stay (LOS), thromboembolism, and gastrointestinal hemorrhage. Types of surgical interventions were also studied. Data were extracted using ICD-10 codes. Results: A total of 25,595 patients (based on a weighted sample) were included in the analysis; 44.6% were men, 7.5% were obese, and 13.7% were smokers. White race was most common (32.9% men vs 41.9% women), followed by Hispanic (34% vs 27.1%), African American (16.3% vs 16.1%), Asian (8.8% vs 7.7%), and Native American (1.3% vs 0.8%); p < 0.05. The prevalence of common comorbidities was consistent among men and women; 29.5% had hypertension, 10.4% had diabetes mellitus, 2% had coronary artery disease, and 2.8% had congestive heart failure (CHF). Men had higher in-hospital mortality (7.9% vs 6%; p < 0.05) and incidence of gastrointestinal hemorrhage compared to women (16.2% vs 9.7%; p < 0.05). The median LOS was 5 days (IQR: 3-9) in men and 5 days (IQR: 2-9) in women; p = 0.59. The incidence of venous thromboembolism was 8.2% (no difference among sex) and myocardial infarction was 0.6% (0.8% men vs 0.2% women; p < 0.05). Notably, in this younger population (age: 18-51), 63% patients had metastatic disease (62.8% men vs 63.4% women; p = 0.92). Among all patients, 27.8% underwent gastrectomy: partial gastrectomy (21.2%), total gastrectomy (4.9%), and robotic gastrectomy (1.7%). The multivariate logistic regression model adjusted for baseline demographics, comorbidities, metastatic disease, and socioeconomic status indicated that male sex (OR: 1.37; 95% CI: 1.07-1.73; p < 0.05), Asian race (OR: 1.64; 95% CI: 1.09-2.46; p < 0.05), CHF (OR: 4.05; 95% CI: 2.44-6.74; p < 0.05), and metastasis (OR: 3.84; 95% CI: 2.73-5.37; p < 0.05) were independent risk factors of in-hospital mortality. Conclusions: Our study shows that women have a lower incidence of gastric cancer and associated in-hospital mortality, which may support the protective role of estrogen. This highlights the need for translational and clinical studies on potential actionable mechanisms in gastric cancer management.
Molecular profiles of gastric adenocarcinoma among Hispanic patients at a safety-net healthcare system.
Authors: Zhu Huili , Sada Yvonne , Jin Ramon 
Published: June 2022

e16067 Background: Hispanic patients with gastric cancer are more likely to have advanced stage at diagnosis, signet ring histology, and worse survival outcomes than non-Hispanic patients. Although socioeconomic factors may contribute to these disparities, the molecular biology of gastric cancer in Hispanic patients has not been well characterized. Hispanic patients comprise < 0.05% of gastric adenocarcinoma cases in The Cancer Genome Atlas (TCGA). Methods: We conducted a retrospective study of patients with gastric adenocarcinoma diagnosed between January 2019 to January 2022 at a safety net hospital in Houston, Texas. The hospital serves a patient population of which 91% are racial/ethnic minorities and 57% are Hispanic. Next generation sequencing data was obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations. We compared mutation findings in Hispanic vs non-Hispanic patients. Results: Among 56 patients with gastric adenocarcinoma, 45 (80%) were Hispanic, 11 (20%) were non-Hispanic White, Black, or other, 30 (54%) were male, median age was 54±13, and 14 (25%) were younger than 50 years old. The majority were metastatic (65%), and 6 (11%) were signet ring cell subtype. The most common pathogenic somatic variants across the entire cohort included: TP53 (55%) , CDH1 (34%) , ARID1A (25%) , LRP1B (20%) , RHOA (16%) , SMAD4 (16%) , ERBB2 (14%) , KRAS (14%) , CDKN2A (12%), and PIK3CA (12%). Microsatellite instability was found in 1 (0.02%) patient. Somatic CDH1 mutations were present in 15 (33%) Hispanic patients, of whom 7 were younger than 50 years old, and 2 (18%) non-Hispanic patients. Germline CDH1 mutations was identified in 1 Hispanic patient. TP53 mutations occurred in 14 (31%) Hispanic patients and 6 (55%) non-Hispanic patients. Conclusions: CDH1 mutations, which are associated with familial gastric cancers and more aggressive disease, were present in 33% of Hispanic patients with gastric adenocarcinoma in our study. Nearly half of these identified patients were younger than 50 years old. The high frequency of CDH1 mutations may contribute to the unique pathogenesis of gastric cancers in Hispanic patients.
A phase Ib, open-label, multi-cohort study of metronomic capecitabine plus camrelizumab for treatment of refractory solid tumor: McCrest trial.
Authors: Zhou Chenfei , Shangguan Chengfang , Xi Wenqi , Yang Hui , Guo Liting , Shi Min , Cai Qu , Ji Jun , Shi Yan , Liu Jing , Zhu Zhenggang , Zhang Jun 
Published: June 2022

e16079 Background: The efficacy of immune checkpoint inhibitors (ICIs) monotherapy for refractory solid tumor is relatively poor. Combination therapy is an effective strategy to improve its efficacy. Metronomic chemotherapy that can modulate tumor immunomicroenvironment is a potential partner for ICIs, which is also well-tolerated and low-cost. Methods: This was a phase Ib, open-label, single-center, multi-cohort study designed to evaluate the safety and efficacy of camrelizumab combined with metronomic capecitabine for refractory solid tumors. Patients who were disease progression after standard treatment could be enrolled. PD-L1 status was not compulsory. Capecitabine was administrated orally at 500mg bid every day, with camrelizumab at 200mg IV on Day 1 of a 14-day cycle. Primary endpoint was adverse events (AEs). Secondary endpoints including progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR). The exploratory endpoint was also set to identify the potential molecular alterations during treatment by liquid biopsy analysis. Results: As of December 12, 2021, 19 patients were enrolled including gastric cancer (8), esophageal cancer (6), pancreatic cancer (2), cholangiocarcinoma (2) and duodenal cancer (1). Ten patients had 2 or more prior lines of therapy. The common treatment-related AEs including reactive cutaneous capillary endothelial proliferation (10/19), fatigue (9/19), leukemia (5/19), anemia (5/19), hyponatremia (4/10) and blood bilirubin increased (4/19). Grade 3 AEs including fatigue (2/19) and bronchitis (1/19), and no grade 4 AEs was observed. Three patients suffered severe AEs, including bowel perforation (1), bowel obstruction (1) and bleeding (1), which were all treatment unrelated. There were 4 patients still under treatment, and median number of treatment cycle was 4 (1-16 cycles). The median PFS and OS was 2.1 months (95%CI 1.9-2.3 months) and 5.1 months (95%CI 1.6-8.5 months) respectively. Partial response was observed in 1 esophageal cancer patient with PD-L1 TPS < 1. For 12 patients with assessable lesions, the DCR was 41.6% (5/12). Peripheral blood samples were collected during treatment, and molecular alterations after administration of metronomic capecitabine and camrelizumab were under analysis. Conclusions: The combination of metronomic capecitabine plus camrelizumab was well tolerated in patients with refractory solid tumors. Its efficacy should be assessed in further study. Clinical trial information: NCT04508686, NCT04510818, NCT04932187.
Genomic characterization of Chinese locally advanced or metastatic gastric cancer.
Authors: Zhang Xiaotian , Wang Yakun , Xinying Shi , QI Changsong , Peng Zhi , Xie Tong , Liu Dan , Cheng Siyuan , Zhang Panpan , Zhang Yiqun , Wan Qianhui , Hu Nana , Pei Zhihua , Wang Dongliang , Shen Lin 
Published: June 2022

e16085 Background: The comprehensive molecular characterization of gastric cancer has been uncovered by The Cancer Genome Atlas (TCGA) research work. However, the genomic feature of Chinese locally advanced or metastatic gastric cancer has been seldom reported. This study aims to explore the genomic landscape of Chinese locally advanced or metastatic gastric cancer. Methods: 556 locally advanced or metastatic gastric cancer patients were enrolled in this study and 245 eligible patients with adequate clinicopathological data were analyzed. The baseline tumor tissues and corresponding blood were collected and target-captured sequencing were applied. Both tumor fragments and fragmented genomic DNA were subjected to the NGS platform aiming a panel covering exon regions of 599 genes. Genetic alterations were analyzed to investigate the mutational profile of Chinese locally advanced or metastatic gastric cancer. Results: The top 10 common tumor driver gene alterations among all cases were TP53, ARID1A, CDH1, ARID1B, NOTCH1, ATRX, AR, RAD50, SMAD4 and ZFHX3. TP53 mutation was detected in 70% of all cases, which was significantly higher than that in the TCGA non-Asian (44%) and Asian (46%) advanced gastric cancer patients. 90% (20/22) MSI-H patients had high TMB values, and 32.7% (20/61) high TMB patients were MSI-H. Neither TMB values nor MSI scores was statistically different between patients with response (CR+PR) and without response (PD+SD) to chemotherapy (p = 0.366, 0.436). While the combination of SPTA1 and TP53 mutation was significantly more frequent in response (CR+PR) than non-response (PD+SD) patients. Conclusions: The mutated driver genes of Chinese locally advanced or metastatic gastric cancer were different from the TCGA advanced gastric cancer. The combination of TP53 and and SPTA1 could identify the patients’ response to chemotherapy.
Randomized, phase 3 study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma, RATIONALE 302: Asia subgroup.
Authors: Zhao Kuaile , Kim Sung-Bae , Kato Ken , Hsu Chih-Hung , Hu Sheng , Wang Feng , Kojima Takashi , Kim Young Saing , Van Cutsem Eric , Ajani Jaffer A. , Li Liyun , Ding Ningning , Tao Aiyang , Shen Lin 
Published: June 2022

e16107 Background: In the global Phase 3 study RATIONALE 302 (NCT03430843), tislelizumab (TIS) demonstrated statistically and clinically significant improvement in overall survival (OS) vs chemotherapy (chemo) (median OS 8.6 vs 6.3 months; HR 0.70; 95% CI 0.57, 0.85; p=0.0001) in patients with advanced or metastatic ESCC. Here, we report data from the Asia subgroup. Methods: Eligible patients who had disease progression after first-line systemic therapy were randomized 1:1 to receive TIS 200 mg intravenously once every three weeks or chemo (paclitaxel, docetaxel, or irinotecan) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS in all randomized patients (intent-to-treat population). The key secondary endpoint was OS in patients with PD-L1 Tumor Area Positivity Score* ≥ 10%; other secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), health-related quality of life, and safety. Results: Of the 512 randomized patients, 404 (79%) were enrolled from China, Taiwan, Japan, and Korea and constituted the Asia subgroup (n=201 TIS, n=203 chemo). At data cut-off (December 1, 2020), median follow-up was 6.9 months in the Asia subgroup. Median OS was 8.5 months with TIS vs 6.3 months with chemo (HR 0.73; 95% CI 0.59, 0.90). Median PFS was 1.5 months with TIS vs 1.7 months with chemo (HR 0.81; 95% CI 0.64, 1.02). TIS resulted in a higher ORR (20.4% [95% CI 15.1, 26.6] vs 9.4% [95% CI 5.7, 14.2]) and longer median DoR (7.4 vs 4.0 months; HR 0.42; 95% CI 0.21, 0.84) vs chemo. In the safety analysis set (n=201 TIS, n=191 chemo), patients treated with TIS had fewer treatment-related adverse events (TRAEs) (74.1% vs 95.3%), fewer ≥ Grade 3 TRAEs (19.4% vs 57.1%), fewer serious TRAEs (15.4% vs 20.9%), and a similar incidence of TRAEs leading to death (2.5% vs 2.6%) vs chemo. Conclusions: In the Asia subgroup, TIS improved OS and tumor response vs chemo as second-line treatment in patients with advanced or metastatic ESCC and showed a well-tolerated safety profile. These findings were consistent with published results in the overall population. *The TAP score methodology has been previously referred to as visually-estimated combined positive score (vCPS) and was previously presented at the American Society of Clinical Oncology 2021, June 4–8, 2021, ESMO World Gastrointestinal Congress 2021, June 30–July 3, 2021, and The Chinese Society of Clinical Oncology 2021, September 25–29, 2021. Clinical trial information: NCT03430843.
Lysyl hydroxylase PLOD1 enhances actin network to promote confined migration of hepatocellular carcinoma cells via binding with Septin2.
Authors: Yang Zihan , Zhou Zhi-hang , Yang Mengsu 
Published: June 2022

e16111 Background: Hepatocellular carcinoma (HCC) is one of the most lethal cancers due to metastasis. Liver cirrhosis increases tumor stiffness and forms confine space for HCC cells. How HCC cells overcome the confined space to evade is largely unknown. Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase (PLOD) family members, mainly responsible for lysyl hydroxylation, play important roles in tumor progression. The role of PLOD1 in confine migration remains unclear. Methods: LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissues. Microfluidic confine migration device with 6μm high channels was designed to mimic the in vivo confined space. Real-time microscope was used to monitor cell migration. The high throughput 3D invasion assays using Matrigel and Collagen I mixture added to adherent cells was applied to evaluate 3D invasion with high content screening instrument. 3D spheroid formation assays developed by different substitution percentage GelMA created various stiffness environment. IP was performed to pull down the PLOD1-binding proteins. IF staining, Western blot, FRAP, and others were used to evaluate the target expression and cellular phenotype. Results: LC-MS analysis showed that PLOD1 is highly expressed in HCC tissues. High PLOD1 expression level was associated with advanced tumor stage and unfavorable prognosis in 130 HCC patients. We found that confine migration was enhanced by PLOD1 overexpression. With the PLOD1 knockdown or inhibition, the migration speed significantly decreased. Transwell migration also showed PLOD1-overexpressed cell line can migrate faster. 3D invasion and spheroid formation assays also supports the previous findings on chip that PLOD1-overexpressed cells can invade further and generate more spheroids under high stiffness. IP-MS analysis showed that PLOD1 could bind to actin related proteins, including Septin2 (SEPT2). We found that PLOD1 can promote the formation of F-actin network, Septin network and actin polymerization. In addition, knockdown of SEPT2 was able to reverse the effect of PLOD1 on confine migration and inhibited the formation of F-actin network. Co-IP experiments showed that SEPT2 can bind to α-actin. We further found that PLOD1 could promote the binding between SEPT2 and other Septin members. Mechanically, we found that PLOD1 can increase the hydroxylation of SEPT2 protein stabilize it. Finally, orthotopic transplantation assay showed that PLOD1 promoted intrahepatic or extrahepatic metastasis. Conclusions: We demonstrated that PLOD1 increased SEPT2 stability by modifying its hydroxylation, thereby promoting the formation of Septin and F-actin networks, which in turn promotes the confined migration of HCC cells. The current work revealed novel molecular mechanism of PLOD1 on HCC confine migration and metastasis.
Capecitabine for advanced biliary tract cancers during COVID-19 pandemic.
Authors: Das Chandan Krushna , Yadav T D , Singh Harjeet 
Published: June 2022

e16116 Background: Despite chemotherapy, metastatic gall bladder cancers (mGBC) have the worst prognosis. Many patients are unfit for the standard of care Cisplatin-based injectable chemotherapy. The study evaluates single-agent Capecitabine as an effective therapy option for frontline advanced GBC patients in a COVID pandemic affected hospital access. Methods: This is a retrospective analysis of mGBC patients treated at the PGIMER Medical Oncology Clinic between December 2019 and August 2021. Patients with an Eastern Cooperative Oncology Group performance rating of 0-2 were given Capecitabine 1,000 mg/m2 twice daily for 14 days. The primary goal was to measure progression-free survival (PFS). The secondary objectives were overall survival (OS), safety, and the need for biliary diversion. Results: A total of 72 patients were analyzed. With a median follow up of 12 months, the median PFS was 5.4 months (4.0-9.1), and the interim overall survival OS was 11.9 months (5.2-16). During treatment, 12% of patients required biliary diversion. The safety profile was consistent with previous capecitabine use, and no new safety signals were detected. There were 9.7 percent (7/72) of grade 3/4 adverse events (AEs) reported. Due to poor tolerability, one-third of patients (30.5%) required dose reduction/interruption. Conclusions: In a COVID pandemic situation, Capecitabine is safe, effective, and comparable efficacy for patients with advanced mGBC. However, It needs to be evaluated in randomized clinical trials comparing the standard of care.[Table: see text]