bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of peritoneal cancer index and prognosis in peritoneal metastasis of gastric cancer using NLR-PLR-DDI score.
Authors: Jiang Zhihui , Pengfei Yu , Yu Pingyuan , Cao Yang , Ye Zeyao , Chai Tengjiao , Du Yian
Published: June 2022

e16022

Background: Peritoneal metastasis is the most common metastatic mode of advanced gastric cancer, which is prone to poor prognosis and is also one of the common causes of death in patients with distant gastric cancer metastasis.The purpose of this paper was to establish a new hematologic scoring (an NPD scoring) by the neutrophil-lymphocyte ratio (NLR) and platelet- lymphocyte ratio (PLR) A and D-dimer (DDI), and its association with the peritoneal cancer index (PCI) was evaluated, and the ability of NPD scoring system to judge the prognosis of peritoneal metastasis of gastric cancer. Methods: This was a single-center, nonrandomized, retrospective, cohort study.102 patients with peritoneal metastasis of gastric cancer who underwent diagnostic staging laparoscopy (DSL) were enrolled and assessed with PCI scores.. According to the first PCI (PCI < 15), the patients were divided into low PCI group (n = 67) and high PCI group (n = 35). Through univariate analysis and multivariate analysis, it was found that NLR, PLR and DDI were related to high PCI (≥ 15), and NPD scoring system was established. Chi-square test was used to evaluate the relationship between NPD score, PCI and prognosis. Results: The cohort study found that the differences of NLR, PLR and DDI between low PCI group (n = 67) and high PCI group (n = 35) were statistically significant (P < 0.05). Univariate and multivariate analysis showed that NLR, PLR and DDI were independent risk factors for high PCI (P < 0.05). The NPD score of patients in the high PCI group was significantly higher than those in the low PCI group (P = 0.001). The survival rate of patients in high-risk group (NPD ≥ 2 points) was significantly lower than that in low-risk group (NPD < 2 points) (P = 0.003). Multivariate analysis showed that PCI and NPD score ≥ - 2 were independent predictors of OS. Conclusions: NPD score can be used as a blood marker to predict PCI and prognosis in patients with peritoneal metastasis of gastric cancer, and to guide clinical treatment. This new scoring system is an economic and convenient tool for predicting PCI and judge the prognosis of peritoneal metastasis.
Comparison of surgical resection combined with chemotherapy and palliative chemotherapy for synchronous hepatic metastases from gastric cancer.
Authors: Yu Pingyuan , Pengfei Yu , Jiang Zhihui , Cao Yang , Ye Zeyao , Chai Tengjiao , Du Yian
Published: June 2022

e16041

Background: Hepatic metastases of gastric cancer(HMGC) are an important factor affecting the prognosis of gastric cancer patients, and 3-14% of gastric cancer cases were diagnosed with synchronous hepatic metastases of gastric cancer (SHMGC). However, there remains much unidentified about the therapy effect of surgical resection on SHMGC. Here, we investigated the associations of surgical resection with the overall survival of SHMGC, which might develop more effective therapy strategies for patients of HMGC. Methods: Patients diagnosed with SHMGC from January 2010 to December 2015 were selected in the study. Kaplan-Meier analysis and multivariable analysis based on the Cox proportional hazards model were performed to compare the effects of surgical resection (including gastrectomy and metastasectomy) combined with chemotherapy (surgical resection group, SR group) and palliative chemotherapy (palliative chemotherapy group, PC group) on survival. Results: A total of 132 patients were enrolled in this study. Overall, 57 (43.2%) were treated with surgical resection/chemotherapy and 75 (56.8%) palliative chemotherapy. Overall survival (OS) was significantly prolonged in the SR group compared with the PC group (33.6 vs. 12.4 months, P < 0.001). In the SR group, the R0 resection (68.4%, 39/57) contributed to markedly prolonged OS compared with the non-R0 resection subgroup (45.1 vs. 13.5 months, P < 0.001). Surgical resection and single hepatic metastasis were independent predictors of OS in multivariate analysis with hazard ratio (HR) of 0.453 (95% confidence interval [CI] 0.276-0.813, p = 0.009) and 0.540 (95%CI 0.315-0.796, p = 0.043), respectively. Conclusions: For patients with synchronous hepatic metastases of gastric cancer, radical surgical resection combined with appropriate chemotherapy may be more beneficial than palliative chemotherapy. Moreover, single hepatic metastasis might achieve better survival after aggressive surgical resection.
Addition of anti-PD1 antibodies to chemotherapy (CT) in first-line treatment of advanced esophageal cancer (EC): A systematic review and meta-analysis.
Authors: Rice Anastasia , Fedyanin Mikhail , Ignatova Ekaterina , Polyanskaya Elizaveta , Dinaeva Elmira , Besova Natalia , Tryakin Alexey
Published: June 2022

e16055

Background: The addition of anti-PD-1 antibodies to first-line CT is the new standard of care for pts with advanced EC. However, available data on the efficacy of such therapy in different clinical subgroups is still lacking. Therefore, we performed a meta-analysis to determine the efficacy of combination anti-PD1 and systemic CT in terms of overall survival (OS) in pts with advanced EC. Methods: We searched PubMed, proceedings of ASCO, and ESMO conferences up to February 2022. We included prospective randomized phase III trials comparing the combination of anti-PD1 and CT with CT alone as the first-line treatment option for pts with advanced EC. The primary outcome was OS. Meta-analysis was conducted by Review Manager (Ver. 5.3) software. Results: Five trials with a total of 3163 pts were included, of which 1576 received anti-PD1+CT and 1587 received CT alone. There was a significant improvement in PFS (HR, 0.62; 95% CI, 0.56-0.67; p < 0.00001; I2 = 45%, p for heterogeneity 0.12), OS (HR, 0.69; 95% CI, 0.63-0.76; p < 0.00001; I2 = 0%) and ORR (OR, 2.07; 95% CI, 1.76-2.43; p < 0.00001; I2 = 21%) in pts received anti-PD1+CT. OS was improved in pts regardless of age, race, CT regimen, presence of liver metastases, ECOG PS, or histology. Subgroup analysis suggested that the addition of anti-PD1 have a better effect in pts with PDL expression on tumor cells > 1, ≥ 10, and < 10 and in pts with CPS ≥ 10, but not in pts with PDL < 1. We found a tendency towards survival advantage in pts with CPS < 10. No survival benefit was observed in women (tab). Conclusions: Improved OS was found to be associated with addition of anti-PD1 antibodies to systemic CT in different patient subgroups with advanced EC, except for female and in pts with low PDL expression. Despite of meta-analysis results we need prospective randomized trial for pts with CPS < 10.[Table: see text]
Development of combination strategies for focal adhesion kinase inhibition in diffuse gastric cancer.
Authors: Peng Ke , Bass Adam Joel
Published: June 2022

e16057

Background: Diffuse gastric cancer (DGC) is an aggressive and frequently lethal pathological subtype of gastric cancer (GC). Since DGC often lacks genomic aberrations that indicate clear candidate therapeutic targets, it has been challenging to develop target therapies for this GC subtype. Our previous study highlighted the contribution of focal adhesion kinase (FAK) in the tumorigenesis of DGC, and the potential for small molecule FAK inhibitors to have efficacy in DGC. Currently, FAK inhibitors are under active clinical evaluation in several tumor types. To date, FAK inhibitor monotherapy has been tolerated in the clinic, but has shown only modest clinical efficacy in cancer treatment, which inspired us to explore targets for the combination with FAK inhibitors in DGC. Methods: We constructed the engineered murine DGC model of Cdh1-/- RHOAY42C/+ organoids, with Cdh1 (E-Cadherin) loss and RHOA Y42C mutation, in our previous study. Using this DGC organoids model, we performed genome-scale libraries of open reading frames (ORF) screen to identify candidate mechanisms of resistance to FAK inhibitors (defactinib or PF-573228). For the top hits found in ORF screen, further validations were performed in Cdh1-/- RHOAY42C/+ organoids and human DGC cell lines of NUGC4 and SNU668 to check whether they could function as candidates for the combination with FAK inhibitors. Besides, we used Digiwest, a high-throughput protein analysis assay, to investigate pathway alterations of Cdh1-/- RHOAY42C/+ organoids treated with FAK inhibitors (defactinib or PF-573228). We then explored whether the activated pathways were the candidates for the drug combination. Zero Interaction Potency (ZIP) model was used to measure the synergistic effect between the drugs. The combination strategies were also tested in vivo. Results: We identified that cyclin-dependent kinase 6 (CDK6) promotes FAK inhibitors (defactinib and PF-573228) resistance according to ORF screen, and CDK4/6 inhibitor, Palbociclib, enhances the efficacy of defactinib for DGC models. Furthermore, we demonstrated that FAK inhibitors (defactinib and PF-573228) treatment in DGC models leads to compensatory activation of MAPK pathway in DGC, and the RAF/MEK dual inhibitor VS-6766 effectively enhances the antitumor efficacy of FAK inhibitors in vitro and in vivo. Conclusions: These data suggest that combinations of FAK inhibitors with MAPK inhibitors or CDK4/6 inhibitors are promising treatment strategies for DGC that warrant further testing in clinical trials.
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]
Regorafenib joins immune checkpoint inhibitors (ICIs) for previously ICIs plus TKIs failed advanced hepatocellular carcinoma (HCC) patients: A retrospective study.
Authors: Zhao Jie , Yang Chao , Han Guoyong , Zhang Long , Jiang Chuanwei , Ding Wenzhou , Hu Yuanchang , Ni Ming , Wu Chen , Xia Yongxiang
Published: June 2022

e16118

Background: The development of ICIs has promoted a major breakthrough in the field of cancer therapy. A number of patients experience primary or acquired resistance to ICIs based first line therapy. Because of the similar mechanisms, PD-(L)1 inhibitors replacement after PD-(L)1 inhibitors-based therapy resistance is difficult to sustain benefits. Therefore, whether suspending immunotherapy, or maintenance immunotherapy and switching the combination drugs in the follow-up strategy is worth to explore. Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis and metastasis. Besides, regorafenib could regulate the immune microenvironment. This retrospective trial aims to evaluate the efficacy of regorafenib in combinations with previous ICI in advanced HCC patients who failed to previous ICI-TKI treatment. Methods: In this study, eligible patients were advanced HCC, who failed to previous treatment with TKIs and PD-1 inhibitors. 17 patients were received PD-1 inhibitor the same as the first-line treatment (dosage and mode of administration according to instructions) and regorafenib (40, 80, 120mg/m2, po, qd, d1-21) every 4 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was objective response rate (ORR), the secondly endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS), duration of response (DOR) and safety. Results: From Nov 15, 2020 to Jan 31, 2022, 17 patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1 (16 male vs. 1 female, 13 second-line recipients vs. 4 third-line recipients, median age of 55 years) had been enrolled. 52.94% of the patients had BCLC stage B and others had BCLC stage C. The median follow-up was 8.8 months (range, 2.7-14.7). Confirmed ORR and DCR were 41.2% and 64.7%, respectively. The median PFS was 5.21 months (95% CI, 2.65-7.77). For 13 second line patients, confirmed ORR and DCR were 46.2% and 69.2%, respectively. Median OS and DOR had not yet been reached. 12 recipients had treatment-related adverse events (TRAEs). Most frequent TEAEs (≥5%) included fatigue (15.8%), diarrhea (15.8%), periodontal disease (10.5%), hypertension (10.5%), albuminuria (5.3%). Grade 3 TRAEs occurred in 3 (17.6%) patients included gastrointestinal bleeding, hand-foot syndrome and albuminuria. No Grade 4 TRAE and new safety signal were identified. Conclusions: Regorafenib plus PD-1 inhibitor showed a promising efficacy with favorable safety in HCC patients with PD-1 inhibitor resistance, especially in the standard second line patients. Moreover, the strategy showed a higher ORR than RESORCE study (46.2% vs. 10.6%).
Efficacy and safety of anlotinib with PD-1 blockades in the treatment of advanced biliary tract cancer: A real-world study.
Authors: Chen Kehe , Huang Xianshi , Yu Lei , Hou Encun , Ou Mei , Wang Junping , Huang Xiao , Pan Deng , Liu Yu , Huang Min , Zhong Wenhe , Pan Zhuang , Zhang Shijie , Li Bin , Nong Xiansheng , Chen Kefan
Published: June 2022

e16129

Background: Several clinical trials have demonstrated that antiangiogenic drugs combined with PD-1 blockades are effective for patients with advanced biliary tract cancer (BTC). However, the efficacy of this combination in real-world patients needs to be explored. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been licensed for treatment of considerable malignancies in China. The aim of this study was to investigate the efficacy and safety of anlotinib combined with PD-1 blockades in the treatment of advanced BTC in real world. Methods: This is a multi-center prospective real-world study. Patients with advanced BTC receiving anlotinib combined with PD-1 blockades were recruited. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigator according to RECIST version 1.1. The primary endpoint was overall survival (OS), secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: From May 2020 to Sep 2021, a total of 14 eligible pts were recruited. 1 patient was in stage IIIa, 4 pts in stage IIIb, and 9 pts in stage IV. Among them, 10 pts received anlotinib as first-line treatment, 3 pts as second-line treatment and 1 pts as third-line treatment. DCR was 85.71% (57.19%, 98.22%). At the data cut-off date, 7 pts discontinued treatment due to disease progression, the preliminarily prognostic results indicated that the median OS was 8.21 months (95%CI: 5.88, NA) and the median PFS of the 14pts was 6.28 months (95%CI: 3.17-8.21). The safety profile suggested that the most common drug-related adverse events were hypertension (21.43%), decreased white blood cell count (21.43%), decreased platelet count (21.43%), hypoalbuminemia (14.29%), vomit (14.29%), gastrointestinal bleeding (14.29%). The common grade 3 adverse event were gastrointestinal bleeding (7.14%), anemia (7.14%), biliary infection (7.14%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 blockades exhibited potential efficacy and manageable adverse events in the treatment of advanced BTC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521.
Construction and validation of the prognostic model for patients with gallbladder neuroendocrine neoplasm-based a nationwide retrospective registry study.
Authors: Sun Xuheng , WANG Yijun , Liu Yingbin
Published: June 2022

e16140

Background: Gallbladder neuroendocrine neoplasm (GB-NEN) is an extremely rare type of gallbladder neoplasm and the prognosis of patients with GB-NENs varies widely. The focus of this study was to construct and validate a prognostic model of GB-NENs based on the data from a nationwide retrospective multicenter registry cohort. Methods: The Chinese Research Group of Gallbladder Cancer (CRGGC) study is a multicenter retrospective registry cohort study reviewing the electronic medical records from 76 tertiary and secondary hospitals across 28 provinces in China. We assembled patients with GB-NEN diagnosed between 2010 and 2017 in 24 tertiary hospitals from CRGGC study. Influential factors of recurrence free survival (RFS) and overall survival (OS) were identified using Least absolute shrinkage and selection operator (LASSO) regression and Cox predicting model was constructed for predicting RFS and OS. The prognostic model was validated both internally and externally. Performance of the model was assessed by concordance index (C-index) and calibration curves stratified by risk categories. Results: A total of 84 patients with GB-NEN was extracted from CRGGC study, among which 3 were diagnosed with GB-NEN Grade 1, 8 were diagnosed with GB-NEN Grade 2 and 35 with GB-NEN Grade 3. Of the 35 patients with GB-NEN Grade 3, 3 had poorly differentiated small-cell neuroendocrine carcinomas (SC-NECs) and 8 patients had Mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). 53 patients were included in the training group (median survival, 21.1 months; 95% confidence interval (CI), 13.8-37.6 months) and 31 patients in the validation cohort (median survival, 34.3 months; 95% CI, 9.63-58.97months). A Cox predicting model was built, including 5 variables (age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined). The C-index was 78.1 (95% CI, 63.9-92.3), with a good calibration, and these results were confirmed in the internal validation cohorts. Conclusions: We have built a clinical model for GB-NEN patients and clinical doctors for prognosis prediction based on age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined which can be easily obtained in one’s case history. It can be used to determine subgroups of patients who may have poorer prognosis and assist individualized and precise treatment for GB-NEN.
Immune checkpoint inhibitors (ICIs) plus CAPOX in the treatment of unresectable advanced or recurrent biliary tract carcinoma (BTC): A retrospective study.
Authors: Zhao Jie , Yang Chao , Ding Wenzhou , Han Guoyong , Zhang Long , Jiang Chuanwei , Wu Chen , Ni Ming , Xia Yongxiang
Published: June 2022

e16144

Background: Patients with advanced or unresectable BTC have limited treatment options and poor prognosis. The combination of ICIs with chemotherapy has demonstrated promising antitumor activity with manageable safety in the first- or second-line in treatment of patients with advanced or unresectable BTC, but only a subset of patients with BTC derive benefit. The standard systemic treatment for BTC has been gemcitabine (800-1250 mg/m2, i.v., d1 and d8, q3w) in combination with oxaliplatin/cisplatin. The regimen is associated with high frequency of intravenous injection or more hospital days. All above highlights the need for new combinations. Therefore, we conducted a retrospective trial to evaluate ICIs combined with CAPOX (more convenient dosing regimen) in patients with advanced or recurrent BTC who were treatment-naive or failed to previous treatment. Methods: In this study, eligible patients were diagnosed as unresectable advanced or recurrent BTC, therapy-naive or failed to previous treatment with chemotherapy, inhibitors of VEGFR or PD-1/PD-L1. In therapy phase, 28 patients were given with ICIs (dosage and mode of administration according to instructions, d1), oxaliplatin (130 mg/m2, i.v., d1), and capecitabine (1000mg/m2, po, bid, d1-14) every 3 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was progression-free survival (PFS), the secondly endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and adverse events (AEs). Results: From Dec 24, 2019 to Aug 6, 2021, 28 patients had been enrolled to receive therapy. The patients were characterized with a median age of 58 years (range 53-79), 75% intrahepatic cholangiocarcinoma (ICC) and 25% gallbladder cancer (GBC), 25% lymph node metastasis, 25% liver metastases, 54% with history of surgery, and 57% with therapy-native. As of Jan 23, 2022, with a median follow-up of 9.0 months (range, 2.1-23.4), safety and efficacy were assessed in 26 evaluable patients, with response of 12 PR and 6 SD. Confirmed ORR and disease control rate (DCR) were 46.2% (95% CI, 27.1%-66.2%) and 69.2% (95% CI, 48.1%-84.9%), respectively. The median PFS, median OS and median DOR were 6.1 months (95% CI, 4.9-7.3), 16.5 months (95% CI, 5.0-28.0) and 5.0 months (95% CI, 2.0-8.0), respectively. Grade 3-4 treatment-related adverse events occurred in 32.1% of patients, with thrombocytopenia and bone marrow depression ranking the most frequent. No new safety signal was identified. Conclusions: In this study, ICIs combined with CAPOX not only showed high level of safety and efficacy, but also provided convenience in the treatment of unresectable advanced or recurrent BTC.
Regorafenib combined with PD-1 monoclonal antibody in the second-line setting for hepatocellular carcinoma (HCC): A retrospective, real-world study in China.
Authors: Li Zhongchao , Li Lei , Zhong Jingtao , Cui Kai , Zhang Chengsheng , Shi Xuetao , Sun Pengfei
Published: June 2022

e16145

Background: In China, the first-line TKI therapy for advanced HCC is a common standard treatment modality. Meanwhile regorafenib combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). Still，more clinical evidence is needed to optimize second-line treatment for uHCC. In this single-center, retrospective real-world study, we look forward to further clinical benefits of regorafenib combined with PD-1 monoclonal antibody as second-line treatment of uHCC in China. Methods: We reviewed the medical data of 55 patients with HCC and received regorafenib combined with PD-1 monoclonal antibody for second-line treatment from April 2019 to April 2021. Patients were treated with regorafenib combined with PD-1 monoclonal antibody for at least 1 cycle (21days). The progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were observed. Results: The median age was 52 years (range 29-72), 89.1% were male, 78.2% patients had hepatitis B. At study entry, the proportions of patients with Child–Pugh A/B class were 61.8%/36.4% (unknown: 1.8%); the proportions of patients with ECOG performance status 0/1/2 were 70.9%/21.8%/7.3%; the proportions of patients with BCLC stage A/B/C class were 5.5%/9.1%/83.6% (unknown: 1.8%); For prior targeted therapy, the proportion of patients with sorafenib/ lenvatinib / apatinib were 85.5%/9.1%/1.8% (unknown:1.8%), 1patient did not receive targeted therapy. Regorafenib combined with PD-1 monoclonal antibody was used for second-line systemic therapy, the PD-1s used mainly were sintilimab (n = 23), camrelizumab (n = 21), tislelizumab (n = 10); The median initial daily dose was 120 mg (rang,40-160),and the proportions of patients with the initial daily regorafenib dose 160mg/120mg/80mg/40mg were30.9%/16.4%/43.6%/1.8% (unknown :7.3%). The median PFS was 7.9 month (95%CI:5.1, NA), ORR was 27.3%, DCR was 56.4%. Conclusions: The preliminary results of this retrospective real-world study, indicate that regorafenib combined with pd-1 therapy as second-line treatment provide clinical benefits in uHCC patients with a manageable toxicity in Chinese patients. Data will be further collected to reduce bias caused by small sample size and baseline differences.
A multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis of the immune microenvironment of bile duct cancers (BDC) pre and post neoadjuvantchemotherapy (NACT).
Authors: Dharmapuri Sirish , Cabal Rafael , Ioannou Giorgio , Ozbey Sinem , Paulsen John , Ang Celina , Sarpel Umut , Sung Max W. , Kozuch Peter , Schwartz Myron E. , Cohen Deirdre Jill , Gnjatic Sacha , Pintova Sofya
Published: June 2022

e16151

Background: NACT is increasingly being used in the management of locally advanced BTC. Emerging evidence suggests a potential key contributing role of tumor infiltrating immune cells in the prognosis & response to therapy. We set out to characterize immune modulation of tumor immune microenvironment composition in BTC following NACT. Methods: Patients (pts) with locally advanced BTC who underwent a diagnostic biopsy, then NACT followed by resection between 2014 & 2018 were identified & consented after IRB approval. MICSSS, a sample-sparing chromogenic consecutive multiplex tissue staining method, was performed with a series of immune markers (Table), to characterize T cell subsets, B cells, macrophages, mature dendritic cells (DCs), and immune checkpoints on pre & post NACT formalin-fixed paraffin-embedded tumor tissue sections. Density was calculated for each marker (+ve cells/mm2) following annotation of tissues by tumor, fibrosis, necrosis, stromal & tumor infiltrating lymphocyte-enriched areas. Results: Nine pts were enrolled. Final analysis included 5 pts with adequate tissue. Median age = 48 (41-56), with 4 female, 4 intrahepatic cholangiocarcinomas & 1 gallbladder. All pts received Gemcitabine/Cisplatin as NACT with a median of 5 (4-7) cycles. Median time from diagnosis to surgery was 4.3 (1.4-7.8) months & last cycle to surgery was 0.9 (0.6-1.5) month. All pts were MMR proficient, 1 Her2+ & 2 with FGFR2 amplification. NACT on average produced a depletion of all immune markers (Table). Given the small N, each pt was considered their own control & changes in mean cell densities post NACT were calculated. Pt2 with a 40-fold increase in PDL1 expression & 5-fold decrease in CD8:FOXP3 ratio notably had the shortest disease-free interval (DFI). Pt3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold combined with a decrease in PDL1. Conclusions: Preliminary results suggest NACT may modulate immune microenvironment despite overall immune cell depletion. Future studies should focus on strategies to expand immune modulation of the tumor microenvironment in BTC by NACT, including immune oncology agent priming prior to or after NACT.[Table: see text]