The incidence and mortality rates of pancreatic cancer are rising globally. This study examines global and regional trends in pancreatic cancer incidence, Disability Adjusted Life Years (DALYs), and mortality from 1990 to 2021, utilizing data from the most recent Global Burden of Disease (GBD) 2021 database. Data were sourced from the GBD database over the period from 1990 to 2021. Age-standardized rates for incidence, DALYs, and mortality were calculated per 100,000 population. We also calculated the proportion of DALYs and mortality attributable to risk factors. The Bayesian age-period-cohort model was applied to project future trends until 2050. Between 1990 and 2021, the global incidence of pancreatic cancer increased significantly, with the number of cases rising from approximately 207,905 to 508,533 and the age-standardized incidence rate (ASIR) increasing from 5.47 to 5.96 per 100,000 population. The global burden of pancreatic cancer, measured in DALYs, rose from 5.21 million to 11.32 million. Mortality rates showed a similar upward trend, with the number of deaths increasing from around 211,613 to 505,752, and the age-standardized mortality rate (ASMR) rising from 5.655 to 5.948 per 100,000 population. Notable increases in ASIR and ASMR were observed in low-middle and low sociodemographic index regions with males experienced higher rates compared to females. Age-standardized DALYs rate (ASDR) and ASMR worldwide were attributable to tobacco smoking, high BMI, and high fasting plasma glucose. Furthermore, our projection model estimates that the ASIR and ASMR of pancreatic cancer will significantly decline, while the ASDR is anticipated to maintain a steady downward trend by 2050. This study offers a comprehensive analysis of pancreatic cancer trends, providing crucial insights for public health planning and policy-making. Addressing identified risk factors and targeting high-risk populations are essential for effective strategies to reduce the global burden of pancreatic cancer.

Pancreatic cancer remains one of the most lethal diseases worldwide. Cancer-derived exosomes, benefiting from the protective role of the lipid membrane, exhibit remarkable stability in the circulatory system. These exosomes, released by tumor microenvironment, contain various biomolecules such as proteins, RNAs, and lipids that plays a pivotal role in mediating distant communication between the local pancreatic tumor and other organs or tissues. They facilitate the transfer of oncogenic factors to distant sites, contributing to the compromised body immune system, distant metastasis, diabetes, cachexia, and promoting a microenvironment conducive to tumor growth and metastasis in pancreatic cancer patients. Beyond their intrinsic roles, circulating exosomes in peripheral blood can be detected to facilitate accurate liquid biopsy. This approach offers a novel and promising method for the diagnosis and management of pancreatic cancer. Consequently, circulating exosomes are not only crucial mediators of systemic cell-cell communication during pancreatic cancer progression but also hold great potential as precise tools for pancreatic cancer management and treatment. Exosome-based liquid biopsy and therapy represent promising advancements in the diagnosis and treatment of pancreatic cancer. Exosomes can serve as drug delivery vehicles, enhancing the targeting and efficacy of anticancer treatments, modulating the immune system, and facilitating gene editing to suppress tumor growth. Ongoing research focuses on biomarker identification, drug delivery systems, and clinical trials to validate the safety and efficacy of exosome-based therapies, offering new possibilities for early diagnosis and precision treatment in pancreatic cancer. Leveraging the therapeutic potential of exosomes, including their ability to deliver targeted drugs and modulate immune responses, opens new avenues for innovative treatment strategies.

Cancer stem cells (CSCs) and long non-coding RNAs (lncRNAs) are particularly important for tumor cell growth and migration, and recurrence and drug resistance, including head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to explore stemness-related lncRNAs (SRlncRNAs) that could be used for prognosis of patients with HNSCC. HNSCC RNA sequencing data and matched clinical data were obtained from TCGA database, and stem cell characteristic genes related to HNSCC mRNAsi were obtained from the online database by WGCNA analysis, respectively. Further, SRlncRNAs were obtained. Then, the prognostic model was constructed to forecast patient survival through univariate Cox regression and LASSO-Cox method based on SRlncRNAs. Kaplan–Meier, ROC and AUC were used to evaluate the predictive ability of the model. Moreover, we probed the underlying biological functions, signalling pathways and immune status hidden within differences in prognosis of patients. We explored whether the model could guide personalized treatments included immunotherapy and chemotherapy for HNSCC patients. At last, RT‐qPCR was performed to analyze the expressions levels of SRlncRNAs in HNSCC cell lines. A SRlncRNAs signature was identified based on 5 SRlncRNAs (AC004943.2, AL022328.1, MIR9-3HG, AC015878.1 and FOXD2-AS1) in HNSCC. Also, risk scores were correlated with the abundance of tumor-infiltrating immune cells, whereas HNSCC-nominated chemotherapy drugs were considerably different from one another. The final finding was that these SRlncRNAs were abnormally expressed in HNSCCCS according to the results of RT-qPCR. These 5 SRlncRNAs signature, as a potential prognostic biomarker, can be utilized for personalized medicine in HNSCC patients.

Although the pre-clinical study of chimeric antigen receptor (CAR)-natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve their effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), and CAR-T cells targeting GPC3 have been tested in clinical trials. Based on an affinity-enhanced antibody (hYP7) targeting GPC3, we constructed GPC3-CAR-NK cells to explore their potential function in the treatment of HCC. We found that patients with HCC secreted high levels of soluble programmed death-ligand 1 (sPD-L1), which inhibits the function of CAR-NK cells targeting GPC3. In addition, we combined high-affinity sPD-L1 variant (L3C7c-Fc) with GPC3-CAR-NK cells to solve the problem of GPC3-CAR-NK inhibition. Our studies demonstrated that L3C7c-Fc could enhance the therapeutic effect of CAR-NK cells by reversing the suppression of sPD-L1, which provides the experimental evidence for the subsequent development of HCC immunotherapy strategies.

Surgery combined with chemotherapy and precision medicine is the only potential treatment for patients with colorectal cancer liver metastases (CRLM). The use of modern molecular biotechnology to identify suitable biomarkers is of great significance for predicting prognosis and formulating individualized treatment plans for these patients. BRAF mutations, particularly V600E, are widely believed to be associated with poor prognosis in patients with metastatic CRC (mCRC). However, it is unclear which specific factors affect the prognosis of CRLM patients with BRAF mutations. It is also unknown whether patients with resectable CRLM and BRAF mutations should undergo surgical treatment since there is an increased recurrence rate after surgery in these patients. In this review, we combined the molecular mechanism and clinical characteristics of BRAF mutations to explore the prognostic significance and potential targeted therapy strategies for patients with BRAF-mutated CRLM.

2615 Background: Application of Immune Checkpoint Inhibitors (ICIs) has become the first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). WDR49 gene belongs to the WDR (WD40-repeat) protein family which participates in a wide range of biological processes, including DNA damage repair and immune regulation, etc. However, the correlation between WDR49 mutation and immune efficacy is unclear. Methods: A total of three independent cohorts of NSCLC patients treated with immunotherapy were analyzed in this study: the Miao cohort (n = 56), the Rizvi cohort (n = 34), the Hellmann cohort (n = 75). Survival was estimated by Kaplan-Meier curves, with the p value determined by a log-rank test. HR was determined through the univariable and multivariable Cox regression. The CIBERSORT analysis relied on RNA-seq data in The Cancer Genome Atlas (TCGA) database. Two-sided P value < 0.05 was considered statistically significant. All the statistical analyses were conducted with R version 4.0.3. Results: In this merged cohort, the frequency of WDR49 mutation ( WDR49-mut) was 10.30% (17 in 165), and most patients with WDR49 mutation were lung adenocarcinoma (LUAD) (11.85%, 16 in 135). Meanwhile, the frequency of WDR49-mut in TCGA database was 7.05 % and 3.84% in LUAD and lung squamous cell carcinoma (LUSC), respectively. The Kaplan-Meier curves survival analysis indicated that WDR49-mut was associated with longer progression free survival (PFS) (median PFS 23 months vs 5.2 months, hazard ratio [HR] = 0.17 [95% CI, 0.06–0.47], P < 0.001) and higher objective response rate (ORR) (76% vs 27%, P < 0.001). Furtherly, WDR49-mut was significantly related to higher tumor mutational burden (TMB) (median TMB 495 vs 149, P < 0.001), but it had nothing to do with the expression of PD-L1 (Proportion of PD-L1 positive 72.7% vs 68.5%, P = 1). The CIBERSORT analysis revealed that CD8+ T cell infiltration was significantly higher in WDR49-mut group than WDR49 wildtype group (p < 0.05). Conclusions: Better treatment response and survival benefit in the mutant group suggest that the WDR49 mutation may serve as a novel predictive biomarker in NSCLC patients with ICIs. The significantly higher TMB and CD8+ T cell infiltration in WDR49-mut group may be the potential mechanism.

Esophageal squamous cell carcinoma (ESCC) is common cancer in China. At the same time, microRNA-196b (miR-196b) has different promotion/inhibition effects in different cancers. The study aims to reveal the role of miR-196b in ESCC and explore its prognostic value. The expression of miR-196b in ESCC samples and cell lines was detected to explore the expression pattern of miR-196b in ESCC. Kaplan-Meier method was conducted for survival rate and Multivariate Cox analysis was used to explore the clinical significance of miR-196b in ESCC. The Cell Counting Kit-8 (CCK-8) assay, transwell migration and invasion tests were used to determine the biological function of miR-196b in ESCC. The relationship of miR-196b and SOCS2 in ESCC was detected by luciferase activity assay and RIP assay. Both in ESCC tissues and cell lines, miR-196b expression was up-regulated. miR-196b expression is related to TNM stage and lymph node metastasis. Combining with the results of Multivariate Cox regression analysis, miR-196b may be a potential independent prognostic marker for ESCC patients. The results of the functional analysis showed that miR-196b inhibitor can reduce cell proliferation, migration and invasion in ESCC cells. Besides, the suppressor of cytokine signaling 2 (SOCS2) is the target of miR-196b in ESCC. miR-196b may exist as a tumor-promoting factor in ESCC and enhance the proliferation abilities, migration capacities, and invasion potential of ESCC cells by targeting SOCS2. miR-196b and SOCS2 have a close negative correlation in ESCC, which may be used as a clinically poor prognostic biomarker and therapeutic target for ESCC.

Globally, esophageal cancer (ECA) is the seventh most common cancer and sixth most common cause of cancer-associated mortality. However, there are no reliable prognostic and predictive molecular markers for ECA; in addition, the pathogenesis of ECA is not fully elucidated. The expressions of circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) of ECA and control groups were obtained from the RNA-sequencing (RNA-seq) data of our hospital, the Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) datasets. Analyses of differentially expressed genes, the circRNA–miRNA–mRNA–competing endogenous RNA (ceRNA) network, and functional/pathway enrichment were conducted. The key targets in the ceRNA network that showed significant results in survival Cox regression analyses were selected. Furthermore, analyses of immune infiltration and autophagy genes related to the key targets were performed. Seven circRNAs, 22 miRNAs, and 34 mRNAs were identified as vital genes in ECA; the nuclear factor-κ-gene binding (NF-κB) and phosphatidylinositol-3 kinase/protein kinase B (PI3K-Akt) signaling were identified as the most enriched pathways. In addition, the LIM domain containing 2 (LIMD2) was an independent predictor of prognosis in ECA patients and closely associated with immunity and autophagy. Moreover, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed significant upregulation of LIMD2 expression in ECA tissues. ECA may be closely correlated with NF-κB and PI3K/Akt signaling. In addition, LIMD2 could be a potential prognostic and predictive marker of ECA.

Presently 4T-1 luc cells were irradiated with proton under ultra-high dose rate FLASH or with gamma-ray with conventional dose rate, and then subcutaneous vaccination with or without Mn immuno-enhancing adjuvant into the mice for three times. One week later, we injected untreated 4T-1 luc cells on the other side of the vaccinated mice, and found that the untreated 4T-1 luc cells injected later nearly totally did not grow tumor (1/17) while controls without previous vaccination all grow tumors (18/18). The result is very interesting and the findings may help to explore in situ tumor vaccination as well as new combined radiotherapy strategies to effectively ablate primary and disseminated tumors. To our limited knowledge, this is the first paper reporting the high efficiency induction of systemic vaccination suppressing the metastasized/disseminated tumor progression.

Introduction: The cervix is a rare site of metastasis from advanced lung adenocarcinoma. Driven gene detection is particularly important for the treatment of advanced lung adenocarcinoma. Patient concerns: A 49-year-old Chinese female was sent to our hospital because of lumbago and sacroiliac joint pain; she was unable to walk and had vaginal bleeding. The following examinations were performed: imaging, colposcopy, bronchoscopy, immunohistochemistry and next-generation sequencing. Diagnosis: According to the clinical manifestations and the examination results, the diagnosis was lung adenocarcinoma with cervical, brain, adrenal gland and bone metastases. More importantly, EGFR gene mutations (del19) were detected in both the primary lung lesion and uterine cervical biopsy specimen. Interventions: Osimertinib was chosen as the first-line treatment. Outcomes: Lumbago and sacroiliac joint pain were significantly relieved. The levels of tumor markers decreased. Primary injuries and metastatic sites were significantly reduced. Conclusion: Physicians should be alert to the signals of vaginal bleeding and consider that primary lung adenocarcinoma may metastasize to the uterine cervix.

The authors regret that there are errors in Fig. 3B and Fig. 6. The correct versions of these figures can be found below.Fig. 6The expression of PUMA and p53 after anticancer drugs treatment jeg-3/ vp16 and jeg-3 cells treated with 1 μg/ml 5-FU or 1.25 μg/ml vp16 for 24 h were harvested, the expression of PUMA was assessed by Western blotting with whole-cell lysates. (1) Control, (2) 5-FU, (3) vp16.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The authors would like to apologise for any inconvenience caused. Ad-PUMA sensitizes drug-resistant choriocarcinoma cells to chemotherapeutic agentsGynecologic OncologyVol. 107Issue 3PreviewTo investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents. Full-Text PDF

Objectives: Accumulating evidence has illustrated greater benefit of immunotherapy in tumors with high tumor mutation burden (TMB), whereas its impact on targeted therapy or chemotherapy is undefined. Herein, we evaluated TMB outside of immuno-oncology in epidermal growth factor receptor (EGFR)-mutant patients and EGFR/ALK wild-type cohorts. Methods: In this retrospective study, we correlated TMB with response rate and progression-free survival (PFS) of patients who received EGFR-tyrosine kinase inhibitors (TKIs) or pemetrexed/platinum as first-line therapy. Tumor mutation burden was evaluated by targeted next-generation sequencing. Patients were divided into low (L)/intermediate (I)/high (H) TMB groups by tertiles. Results: In EGFR-mutant cohort, TMB-L patients had a massively improved PFS compared to TMB-I and TMB-H patients (16.4 vs. 9.0 vs. 7.4 months; log-rank p = 0.006) when treated with first-generation EGFR-TKIs. In EGFR/ALK wild-type cohorts who received pemetrexed/platinum regimen, the objective response rate (ORR) of TMB-L group was statistically superior than that of TMB-I and TMB-H groups (53.8% vs. 23% vs. 8.3%; log-rank p = 0.037), and patients with low TMB had a numerically but not significantly prolonged PFS (6.9 vs. 4.3 vs. 4.6 m; log-rank p = 0.22). Conclusion: Our data provide insights into the relevance between TMB and targeted/chemo therapy. Higher non-synonymous TMB correlates with inferior PFS for first-generation EGFR-TKIs in EGFR-driven patients and worse response to pemetrexed/platinum regimen in EGFR/ALK wild-type patients, which has potential clinical implications for cancer treatment but needs corroboration in larger studies.

Transl Lung Cancer Res 2020;9(3):807-810 | http://dx.doi.org/10.21037/tlcr-20-442 EGFR-TKI treatments are recommended to be used in non-small cell lung carcinomas with sensitizing mutations, and acquired resistance still is a vital issue for the treatment. More than 50% of resistance develops EGFR T790M (1-3). Besides, MET amplification has been described as a resistance mechanism in 5% to 20% of patients treated with first/second generation and up to 30% with thirdgeneration (osimertinib) TKIs (4). Here We report a rare case of later T790M mutation that occurred with a secondary MET amplification after first line icotinib treatment in EGFR-mutated lung adenocarcinoma. The emergence of two resistance mechanisms after EGFR-TKI may be challenging for successful treatment. The patient was a 65-year-old female never-smoker who presented with intermittent chest pain and was found to have bilateral lung infiltrates with a maximum of a 6×5 cm left lower lobe mass and mediastinal adenopathy. CTguided lung biopsy showed lung adenocarcinoma positive for an EGFR exon 19del mutation by direct sequencing. Then she was started on induction icotinib (150 mg tid PO). Image scans after four weeks showed partial response (PR) of the lung mass. After a progression-free survival (PFS) of ~12 months, she experienced progressive disease (PD) with new lung metastasis. Liquid biopsy and CT-guided lung rebiopsy revealed newly acquired MET amplification (2-fold in Tissue) conjunction with EGFR 19del (level: plasma 20.2%; tissue 87%), while no T790M mutation by next generation sequencing (NGS) assay. NGS also detected TP53 mutation (level: plasma 1.7%; tissue 32.8%), and amplification of EGFR (6.3-fold in tissue) and KRAS (2.1-fold in tissue). She was switched to palliative chemotherapy with single pemetrexed due to a patient’s score of ECOG performance status is two and fear of chemotherapy. Unfortunately, she developed progression as she was completing four cycles of chemotherapy, and then switched to third-line chemotherapy with single docetaxel. Also, she was undergoing disease progression with a left lung and mediastinal adenopathy, accompany with new malignant pleural effusions (PE). Molecular analysis by NGS was again performed and revealed persistent EGFR 19del (level: Plasma 27.9%; PE 84.8%), TP53 mutation (level: Plasma 1.9%; PE 74.3%), MET and EGFR amplification (2.9and 3.9-fold in PE). The patient’s clinical condition rapidly switched to a performance status of 4 when coming back in 2018-8. The patient developed respiratory failure with assisted oxygen requirement, and fourth-line joint therapy with crizotinib (200 mg bid PO) and icotinib (150 mg tid PO) was urgently initiated. The patient’s symptoms significantly improved within three days. Restaging scans obtained after one month of crizotinib and icotinib joint therapy showed marked pulmonary improvement and resolution of PE. Seven months after treatment, Letter to the Editor

The original version of this Article omitted the following from the Acknowledgements: Professor Stebbing sits on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare. This has now been corrected in both the PDF and HTML versions of the Article.

reverses EMT in breast cancer cells and to explore the underlying molecular mechanisms. Materials and methods: MTT assay was performed to evaluate cell viability. Wound-healing assay and transwell chamber assay were used to assess cell migration and invasion, respectively. Immuno fl uorescence and Western blot were used to study the expression of EMT-related molecules and α Ⅴ β 3 integrin/focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling transduction. Fibronectin, a physiologic ligand of α Ⅴ β 3 integrin, was used to stimulate α Ⅴ β 3 integrin signaling. Results: Our results demonstrated that oxymatrine effectively suppressed the viability of MDA-MB-231 and 4T1 breast cancer cells, and oxymatrine showed less cytotoxicity on normal breast mammary epithelial MCF-10A cells. In addition, oxymatrine reversed EMT in the MDA-MB-231 and 4T1 cells at nontoxic concentrations. Oxymatrine signi fi cantly inhibited cell migration and invasion, downregulated the expression of N-cadherin, vimentin, and Snail in MDA-MB-231 and 4T1 cells, but upregulated the expression of E-cadherin in 4T1 cells. The mechanism revealed that oxymatrine decreased the expression of α Ⅴ and β 3 integrin and their co-localization. It also inhibited α Ⅴ β 3 integrin downstream activation by suppressing the phosphorylation of FAK, PI3K, and Akt. Furthermore, oxymatrine prevented fi bronectin-induced EMT and α Ⅴ β 3 integrin/FAK/PI3K/Akt signaling activation. Conclusion: Our results revealed that oxymatrine effectively reversed EMT in breast cancer cells by depressing α Ⅴ β 3 integrin/FAK/PI3K/Akt signaling. Thus, oxymatrine could be a potential therapeutic candidate with anti-metastatic potential for the treatment of breast cancer.

The original version of this Article omitted the following from the Acknowledgements: Professor Stebbing sits on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare. This has now been corrected in both the PDF and HTML versions of the Article.

Background: Accumulating evidence illustrates greater benefit of immunotherapy in tumors with high-TMB, whereas its impact on response to targeted therapy or chemotherapy is undefined.Methods: In this retrospective study, we investigated the correlation of tumor mutation burden (TMB) and progression-free survival (PFS) of NSCLC patients who received EGFR-TKIs or Pemetrexed/Platinum as first line therapy. TMB was evaluated by targeted next generation sequencing (tNGS). Patients were divided into low(L) / intermediate(I) / high(H) TMB groups by tertiles.Results: In EGFR-mutant cohort, TMB-L patients had an massively improved PFS compared to TMB-I/H patients(P=0.006) when treated with first generation of EGFR-TKIs. In EGFR/ALK wild-type cohort who received Pemetrexed/Platinum regimen, the ORR in TMB-L group was statistically superior than that of TMB-I/H groups (P=0.037), and patients with low TMB had a numerically, but not significantly prolonged PFS (P=0.22). No difference in PFS was observed between TMB-I and TMB-H groups in two treatment arms.Conclusions: Low nonsynonymous TMB indicated a favorable PFS for EGFR-TKIs and positive response to Pemetrexed/Platinum in certain cohorts with advanced NSCLC, which could potentially identify patients more suitable for targeted therapy or chemotherapy, rather than immunotherapy.Funding Statement: This work was supported by National Natural Science Foundation of China (Grant No.81702248) and Zhejiang medical and health science and technology project (Grant No.2018KY309).Declaration of Interests: The authors have declared no conflicts of interest.Ethics Approval Statement: Study protocols were approved by the Ethical Review Community of Zhejiang Cancer Hospital. The requirement of informed consent was waived by the committee as it was a retrospective research.

Tumor cells can escape immune surveillance through the programmed cell death protein 1 (PD-1) axis suppressing T cells. However, we recently demonstrated that high-affinity variants of soluble human programmed death-ligand 1 (shPD-L1) could diminish the suppression. We propose that in comparison to the wild-type shPD-L1, the further affinity enhancement will confer the molecule with opposite characteristics that augment T-cell activation and immunotherapeutic drug potential. In this study, a new shPD-L1 variant, L3C7c, has been generated to demonstrate ∼167 fold greater affinity than wild-type hPD-L1. The L3C7c-Fc fusion protein demonstrated completely opposite effects of conventional PD-1 axis by promoting redirected T-cell proliferation, activation and cytotoxicity in vitro, as being slightly better than that of anti-PD1-Ab (Pembrolizumab). Moreover, L3C7c-Fc was more effective than Pembrolizumab in enhancing redirected T cells' ability to suppress Mel624 melanoma growth in vivo. As a downsized L3C7c-Fc variant, L3C7v-Fc improved the anti-tumor efficacy in vivo when combined with dendritic cell vaccines. In conclusion, our studies demonstrate that high-affinity hPD-L1 variants could be developed as the next generation reagents for tumor immunotherapy based on the blockade of the PD-1 axis.