Background: Early-onset pancreatic cancer (EOPC) in younger populations (age ≤50 years) is likely to be a more aggressive phenotype characterized by poor differentiation. The emerging analysis of the global burden of EOPC is limited and outdated. Aim: To systematically investigate the burden and trend of EOPC based on global populations. Methods: In this systematic analysis based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, the authors present the number of cases, age-standardized rates (ASRs) per 100 000 population, and risk factors for 204 countries and territories. The average annual percentage changes (AAPCs) for the incidence, mortality, and disability-adjusted life-years (DALYs) of EOPC were calculated using joinpoint regression analysis. Results: According to the GBD 2019 estimates, there were 36 852 new cases of EOPC and 32 004 related deaths. East Asia had the highest number of cases, with 11 401 incidences and 10 149 deaths. The ASRs were 0.94 per 100 000 individuals for incidence and 0.81 per 100 000 for mortality. From 1990 to 2019, the age-standardized incidence increased by 46.9%, mortality increased by 44.6%, and DALYs increased by 41.9% globally. In trend analysis, the global incidence (AAPC, 1.26), mortality (AAPC, 1.24), and DALYs (AAPC, 1.25) of EOPC showed an increasing pattern. The ASRs of incidence, mortality, and DALYs of EOPC in Africa, America, and Asia exhibited a continuous upward trend, while the trend in Europe was fluctuating. Asian males exhibited the fastest growth in incidence (AAPC, 2.15) and mortality (AAPC, 2.13), whereas males in the Americas experienced the slowest increase in new cases (AAPC, 0.72) and deaths (AAPC, 0.67). A certain proportion of EOPC DALYs were attributable to known risk factors: tobacco smoking (13.3%), high BMI, 5.6%, and high fasting plasma glucose 3.2%. Integrating the socio-demographic index (SDI), ASRs of incidence and mortality initially increased with rising SDI, reaching a peak in central Europe (1.5 per 100 000 <ASRs <2.0 per 100 000), and decreased with further increase in SDI in 2019. Conclusions: The findings offer valuable insights into the global distribution and magnitude of the EOPC burden. The burden is increasing at a rapid pace worldwide, particularly in Asia, and is notably high in central and eastern Europe. This highlights the need for additional preventive control efforts targeting high-risk populations.

Background: Although the anti-programmed death-1 (PD-1) inhibitor plus chemotherapy combination has been approved as the standard first-line treatment for advanced gastric cancer, a proportion of patients do not significantly benefit from this therapy. Who would respond poorly to this treatment and the underlying mechanisms of treatment failure are far from clear. Methods: We retrospectively analyzed the associations between the peripheral basophils at baseline and clinical outcomes in 63 advanced gastric cancer patients treated with anti-PD-1 plus chemotherapy and 54 patients treated with chemotherapy alone. Immunohistochemistry and immunofluorescence staining in gastric cancer samples were utilized to investigate the basophil-related immunophenotype. Results: The optimal cutoff of basophil count to distinguish responders to anti-PD-1 plus chemotherapy from non-responders was 20.0/μL. Compared with the low basophil group (≤ 20.0/μL, n = 40), the high basophil group (> 20.0/μL, n = 23) had a significantly lower objective response rate (ORR 17.4% vs. 67.5%, p = 0.0001), worse progression-free survival (median PFS 4.0 vs. 15.0 months, p = 0.0003), and worse overall survival (median OS not reached, p = 0.027). Multivariate analyses identified a basophil count of > 20.0/μL as an independent risk factor for a worse ORR (OR 0.040, 95% CI 0.007–0.241, p = 0.0004), worse PFS (HR 3.720, 95% CI 1.823–7.594, p = 0.0003) and worse OS (HR 3.427, 95% CI 1.698–6.917, p = 0.001). In contrast, there was no significant association between peripheral basophil counts and tumor response or survival in the chemotherapy-alone group (p > 0.05). In primary gastric cancer samples, we observed a correlation between higher peripheral basophil counts and the accumulation of tumor-infiltrating basophils (r = 0.6833, p = 0.005). Tumor-infiltrating basophils were found to be spatially proximate to M2 macrophages within TME and positively correlated with tumor M2 macrophage infiltration (r = 0.7234, p = 0.0023). The peripheral basophil counts also had a significant positive correlation with tumor-infiltrating M2 macrophage counts (r = 0.6584, p = 0.003). Further validation in tumor samples treated with the neoadjuvant anti-PD-1 inhibitor plus chemotherapy combination suggests that the peripheral basophils, tumor infiltration of basophils, and M2 macrophages were significantly more abundant in non-responders than in responders (p = 0.0333, p = 0.0007, and p = 0.0066, respectively). Conclusions: The peripheral basophil count was observed to be a potential biomarker of anti-PD-1 efficacy for advanced gastric cancer. Moreover, basophils may induce an immune-evasive tumor microenvironment by increasing M2 macrophage infiltration, which could be a potential immunotherapeutic target for advanced gastric cancer.

Background: Little is known on the tumor microenvironment (TME) response after neoadjuvant chemotherapy (NACT) in gastric cancer on the molecular level. Methods: Here, we profiled 33,589 cell transcriptomes in 14 samples from 11 gastric cancer patients (4 pre-treatment samples, 4 post-treatment samples and 3 pre-post pairs) using single-cell RNA sequencing (scRNA-seq) to generate the cell atlas. The ligand-receptor-based intercellular communication networks of the single cells were also characterized before and after NACT. Results: Compered to pre-treatment samples, CD4+ T cells (P = 0.018) and CD8+ T cells (P = 0.010) of post-treatment samples were significantly decreased, while endothelial cells and fibroblasts were increased (P = 0.034 and P = 0.005, respectively). No significant difference observed with respect to CD4+ Tregs cells, cycling T cells, B cells, plasma cells, macrophages, monocytes, dendritic cells, and mast cells (P > 0.05). In the unsupervised nonnegative matrix factorization (NMF) analysis, we revealed that there were three transcriptional programs (NMF1, NMF2 and NMF3) shared among these samples. Compared to pre-treatment samples, signature score of NMF1 was significantly downregulated after treatment (P = 0.009), while the NMF2 signature was significantly upregulated after treatment (P = 0.013). The downregulated NMF1 and upregulated NMF2 signatures were both associated with improved overall survival outcomes based on The Cancer Genome Atlas (TCGA) database. Additionally, proangiogenic pathways were activated in tumor and endothelial cells after treatment, indicating that NACT triggers vascular remodeling by cancer cells together with stromal cells. Conclusions: In conclusion, our study provided transcriptional profiles of TME between pre-treatment and post-treatment for in-depth understanding on the mechanisms of NACT in gastric cancer and empowering the development of potential optimized therapy procedures and novel drugs.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a type of lethal gastrointestinal malignancy. It is mainly discovered at, and diagnosed with, an advanced stage of metastasis. As the only potentially curative treatment for PDAC, surgical resection has an uncertain impact on the survival of these patients. As such, we aimed to investigate if patients with metastatic PDAC (mPDAC) benefit from surgery. Methods: Patients with pancreatic cancer in 18 registries of the Surveillance, Epidemiology, and End Results database between 2000 and 2018 were reviewed retrospectively. According to the American Joint Committee on Cancer (AJCC), the eighth edition staging system was utilized. Propensity score matching was applied to strengthen the comparability of the study. The impact of surgery on survival was evaluated by restricted mean survival time (RMST) and Kaplan–Meier analysis. Results: A total of 210 well-matched mPDAC patients were included in the study. The 1 year, 3 year, and 5 year overall survival (OS) of patients undergoing surgery was 34.3%, 15.2%, and 11.0%, respectively. The 1 year, 3 year, and 5 year cancer-specific survival (CSS) of these patients was 36.1%, 19.7%, and 14.2%, respectively. RMST analysis revealed that mPDAC patients with surgery had better OS and CSS than those without (OS: 9.49 months vs. 6.45 months, p < 0.01; CSS: 9.76 months vs. 6.54 months, p < 0.01). Nevertheless, subgroup analysis demonstrated that such statistical significance especially existed in oligometastatic PDAC patients, which refers to those metastases that were limited in number and concentrated to a single organ in this study. Additionally, surgery was identified as a significant predictor for the long-term prognosis of patients (OS: [HR, hazard ratio] = 0.48, 95% CI: 0.36–0.65, p < 0.001; CSS: HR = 0.45, 95% CI: 0.33–0.63, p < 0.001). Lastly, a nomogram was established to predict whether an individual was suitable for surgical treatment in this study. Conclusions: Surgical resection significantly prolonged the long-term prognosis of oligometastatic PDAC patients. Such insights might broaden the management of patients with mPDAC to a large extent. However, a prospective clinical trial should be conducted before a recommendation of surgery in these patients.

Anaplastic lymphoma kinase (ALK) rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients. Tissue microarray (TMA) was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC) cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC) assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (qRT-PCR), target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner. Among the tested cases, 2 (0.44%) CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4–ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1). One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing. The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.

Background: To date, the long-term outcomes of patients with locally advanced gastric cancer (LAGC) who achieved a pathological complete response (pCR) after neoadjuvant therapy are elusive. To evaluate the impact of pCR on the long-term survival of LAGC patients who underwent neoadjuvant therapy and evaluate the necessity of postoperative adjuvant chemotherapy. Methods: We conducted a retrospective study of clinicopathological and survival data of patients who achieved a pCR after neoadjuvant therapy and resection at the China National Cancer Center between January 2007 and December 2018. Results: Ultimately, 39 patients enrolled in the current study, with a median follow-up time was 30.4 (range 2.5–101.6) months. The 3- and 5-year overall survival (OS) rates were 88.9% and 88.9%, respectively. And the 3- and 5-year disease-free survival (DFS) rates were 88.9% and 88.9%, respectively. During the follow-up, recurrence was observed in 3 patients. Of all 39 patients, 51.3% (n=20) received postoperative adjuvant chemotherapy and 48.7% (n=19) did not. There was no significant difference in OS (P=0.48) and DFS (P=0.47) between patients who underwent postoperative adjuvant chemotherapy and patients who did not. Conclusions: Patients with LAGC who achieved a pCR after neoadjuvant therapy and resection might have a favorable OS and DFS. Our study failed to demonstrate the benefit of adjuvant chemotherapy for those patients.