Poor clinical outcomes and immunoevasive contexture in CD161+CD8+ T cells barren human pancreatic cancer.

BACKGROUND: The role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC. METHODS: This study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status. RESULTS: We observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules. CONCLUSION: CD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

Cancer-associated fibroblasts in neoadjuvant setting for solid cancers.

Therapeutic approaches for cancer have become increasingly diverse in recent times. A comprehensive understanding of the tumor microenvironment (TME) holds great potential for enhancing the precision of tumor therapies. Neoadjuvant therapy offers the possibility of alleviating patient symptoms and improving overall quality of life. Additionally, it may facilitate the reduction of inoperable tumors and prevent potential preoperative micrometastases. Within the TME, cancer-associated fibroblasts (CAFs) play a prominent role as they generate various elements that contribute to tumor progression. Particularly, extracellular matrix (ECM) produced by CAFs prevents immune cell infiltration into the TME, hampers drug penetration, and diminishes therapeutic efficacy. Therefore, this review provides a summary of the heterogeneity and interactions of CAFs within the TME, with a specific focus on the influence of neoadjuvant therapy on the microenvironment, particularly CAFs. Finally, we propose several potential and promising therapeutic strategies targeting CAFs, which may efficiently eliminate CAFs to decrease stroma density and impair their functions.

Tumor Microenvironment Responsive CD8+ T Cells and Myeloid-Derived Suppressor Cells to Trigger CD73 Inhibitor AB680-Based Synergistic Therapy for Pancreatic Cancer.

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.

Biological and clinical implications of early-onset cancers: A unique subtype.

In recent years, the incidence of cancers is continuously increasing in young adults. Early-onset cancer (EOC) is usually defined as patients with cancers under the age of 50, and may represent a unique subgroup due to its special disease features. Overall, EOCs often initiate at a young age, present as a better physical performance but high degree of malignancy. EOCs also share common epidemiological and hereditary risk factors. In this review, we discuss several representative EOCs which were well studied previously. By revealing their clinical and molecular similarities and differences, we consider the group of EOCs as a unique subtype compared to ordinary cancers. In consideration of EOC as a rising threat to human health, more researches on molecular mechanisms, and large-scale, prospective clinical trials should be carried out to further translate into improved outcomes.

The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications.

Neutrophils, the most prevalent innate immune cells in humans, have garnered significant attention in recent years due to their involvement in cancer progression. This comprehensive review aimed to elucidate the important roles and underlying mechanisms of neutrophils in cancer from the perspective of their whole life cycle, tracking them from development in the bone marrow to circulation and finally to the tumor microenvironment (TME). Based on an understanding of their heterogeneity, we described the relationship between abnormal neutrophils and clinical manifestations in cancer. Specifically, we explored the function, origin, and polarization of neutrophils within the TME. Furthermore, we also undertook an extensive analysis of the intricate relationship between neutrophils and clinical management, including neutrophil-based clinical treatment strategies. In conclusion, we firmly assert that directing future research endeavors towards comprehending the remarkable heterogeneity exhibited by neutrophils is of paramount importance.

Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) are increasingly receiving systemic neoadjuvant chemotherapy (NAC), particularly those with borderline resectable and locally advanced disease. However, the specific role of additional adjuvant chemotherapy (AC) in these patients is unknown. The objective of this study is to further assess the clinical benefit and impact of systemic AC in patients with resected PDAC after NAC. METHODS: Data on PDAC patients with or without AC following systemic NAC and surgical resection were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database between 2006 and 2019. A matched cohort was created using propensity score matching (PSM), and baseline characteristics were balanced to reduce bias. Overall survival (OS) and cancer-specific survival (CSS) were calculated using matching cohorts. RESULTS: The study enrolled a total of 1589 patients, with 623 (39.2%) in the AC group and 966 (51.8%) in the non-AC group [mean age, 64.0 (9.9) years; 766 (48.2%) were females and 823 (51.8%) were males]. All patients received NAC, and among the crude population, 582 (36.6%) received neoadjuvant radiotherapy, while 168 (10.6%) received adjuvant radiotherapy. Following the 1:1 PSM, 597 patients from each group were evaluated further. The AC and non-AC groups had significantly different median OS (30.0 vs. 25.0 months, P =0.002) and CSS (33.0 vs. 27.0 months, P =0.004). After multivariate Cox regression analysis, systemic AC was independently associated with improved survival ( P =0.003, HR=0.782; 95% CI, 0.667-0.917 for OS; P =0.004, HR=0.784; 95% CI, 0.663-0.926 for CSS), and age, tumor grade, and AJCC N staging were also independent predictors of survival. Only patients younger than 65 years old and those with a pathological N1 category showed a significant association between systemic AC and improved survival in the subgroup analysis adjusted for these covariates. CONCLUSION: Systemic AC provides a significant survival benefit in patients with resected PDAC following NAC compared to non-AC patients. Our study discovered that younger patients, patients with aggressive tumors and potentially well response to NAC might benefit from AC to achieve prolonged survival after curative tumor resection.

Circulating cytokines allow for identification of malignant intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are the precursor lesions of pancreatic cancers, requiring active surgical intervention during cancer development. However, the current criteria for predicting malignant IPMNs remain challenging and limited. Hence, this study aimed to assess the discriminatory performance of circulating cytokines, including TNF-α, IL-2R, IL-6, and IL-8, then build a novel predictive model to improve the diagnostic accuracy. METHOD: A total of 131 retrospective (from March 2016 to December 2019) and 53 prospective (from March 2020 to January 2021) patients who were histologically confirmed as IPMNs were consecutively collected and analyzed. RESULT: The circulating levels of TNF-α, IL-2R, IL-6, and IL-8 were significantly elevated in malignant IPMNs, and were verified as independent factors for malignant IPMNs (p < 0.05). Then, a novel score, the circulating cytokine score (CCS), was calculated and demonstrated as an independent predictive indicator with a higher area under the curve (AUC) than each cytokine alone (p < 0.001). Besides the CCS, two high-risk stigmata features, the presence of solid component (PSC), and main pancreatic duct (MPD) dilation ≥10 mm were also demonstrated as independent indicators for predicting malignant IPMNs. Finally, a novel nomogram incorporating the CCS and these two high-risk stigmata features presented a remarkable diagnostic performance, both in the training and validation cohorts with AUCs of 0.928 and 0.873, respectively. CONCLUSION: The CCS can be considered a novel independent predictive indicator for malignant IPMNs. Additionally, the formulated nomogram model integrating the CCS, PSC, and MPD ≥10 mm can be a valuable and promising tool for predicting the malignant transformation of IPMNs during long-term follow-ups to assist in timely and accurate surgical decisions.

Identification of an Immune-Related BAT Signature for Predicting Adjuvant Chemotherapy Response and Overall Survival in Patients with Resected Ductal Adenocarcinoma of the Pancreas.

BACKGROUND: Adjuvant chemotherapy (ACT) is widely accepted in patients with pancreatic ductal adenocarcinoma (PDAC) after surgery; however, effective models for predicting ACT response are scarce. Thus, the objective of this study was to develop a novel signature for predicting its response and overall survival (OS) in resected PDAC patients. METHODS: A total of 50 PDAC patients with the transcriptome expression profiles, information about chemotherapy, and relevant clinical data were retrieved from the Cancer Genome Atlas (TCGA), and twenty-nine patients with tissue specimens and clinical data from our hospital were included as a validation. A novel gene signature was developed using bioinformatic differentially expressed genes (DEGs) analysis, Lasso-penalized Cox regression, and multivariate Cox regression studies. RESULTS: Between chemotherapy-resistant and chemotherapy-sensitive cohorts, 569 DEGs were identified, with 490 upregulated and 79 downregulated genes mainly specialized in the regulation of peptide/protein/hormone secretion, calcium ion homeostasis, and T cell activation regulation in biological processes. After Lasso-penalized Cox and multivariate Cox regression analysis, BAT (BCHE, ADH1A, and TNS4) signature was established to predict ACT response and OS. Moreover, BAT signature was verified as an independent risk factor for ACT response (p = 0.042) and OS (median OS: 17.5 months vs. 34.8 months, p = 0.040) and significantly associated with immune infiltrations (p < 0.05). Then, this signature was further validated as the independent risk factor for recurrence-free survival (RFS) in PDAC patients receiving postoperative ACT (median RFS: 9.0 months vs. not reached, p = 0.014), and tumor-infiltrating CD4+ and CD8+ T cells were further validated to be significantly decreased in tissues with higher BAT signature scores (p = 0.015 and 0.021, respectively). CONCLUSION: The BAT signature is a novel formulated and independent risk factor for predicting ACT response and long-term survival in patients with resected PDAC. This signature could comprehensively reflect local immune-related response, tumor purity, potential biological behavior, and chemo drug susceptibility.

A metabolism-relevant signature as a predictor for prognosis and therapeutic response in pancreatic cancer.

Although several altered metabolic genes have been identified to be involved in the tumorigenesis and advance of pancreatic cancer (PC), their prognostic values remained unclear. The purpose of this study was to explore new targets and establish a metabolic signature to predict prognosis and chemotherapy response for optimal individualized treatment. The expression data of PC patients from two independent cohorts and metabolism-related genes from KEGG were utilized and analyzed for the establishment of the signature via lasso regression. Then, the differentially expressed candidate genes were further confirmed via online data mining platform and qRT-PCR of clinical specimens. Then, the analyses of gene set enrichment, mutation, and chemotherapeutic response were performed via R package. As results showed, 109 differentially expressed metabolic genes were screened out in PC. Then a metabolism-related five-gene signature comprising B3GNT3, BCAT1, KYNU, LDHA, and TYMS was constructed and showed excellent ability for predicting survival. A novel nomogram coordinating the metabolic signature and other independent prognostic parameters was developed and showed better predictive power in predicting survival. In addition, this metabolic signature was significantly involved in the activation of multiple oncological pathways and regulation of the tumor immune microenvironment. The patients with high risk scores had higher tumor mutation burdens and were prone to be more sensitive to chemotherapy. In summary, our work identified a new metabolic signature and established a superior prognostic nomogram which may supply more indications to explore novel strategies for diagnosis and treatment.

Current status and future perspectives of clinical research in pancreatic cancer: Establishment of evidence by science.

Pancreatic cancer is one of the most aggressive diseases in the world due to a lack of early detection, leading to an overall 5-year survival of only 10%. In recent years, clinical trials targeted pancreatic cancer in efforts to improve survival. These studies introduce new technologies, concepts, and evidence which have instilled new optimism for improving prognosis. This review summarizes the current status of the recent (5-year) clinical trials and describes contemporary research on pancreatic cancer, including surgical technology, diagnostic skills, traditional chemoradiotherapy, neoadjuvant chemotherapy, immunotherapy, targeted therapy, and precision medicine. Then, the future trend and direction of clinical trials on pancreatic cancer are discussed.

Prognostic value of tumor-associated N1/N2 neutrophil plasticity in patients following radical resection of pancreas ductal adenocarcinoma.

BACKGROUND: As an integral part of the tumor microenvironment (TME), tumor-associated neutrophils play a crucial role in tumor development. The objective of this study was to investigate the plasticity of tumor-associated N1 and N2 neutrophils in the TME of pancreatic ductal adenocarcinoma (PDAC), along with its impact on survival and association with immune infiltrations. METHODS: The primary and validation cohorts including 90 radical resection patients from September 2012 to May 2016 and 29 radical resection patients from September 2018 to October 2019, respectively, with complete survival data, were enrolled. Immunofluorescence staining was used to identify tumor-associated N1 and N2 neutrophils, and the N1/N2 ratio was used to evaluate N1 and N2 plasticity. Thereafter, the association between tumor-associated N1/N2 neutrophil plasticity, clinical features, and immune infiltrations was investigated. RESULTS: There was a significant increase in tumor-associated N2 neutrophils compared with tumor-associated N1 neutrophils. Low N1/N2 ratios were associated with the poorer differentiation of tumors, easier lymph node metastases, and a higher TNM stage. The median overall survival (OS) and recurrence-free survival (RFS) of the high tumor-associated N1 neutrophil group were significantly longer than those of the low group, while the tumor-associated N2 neutrophils played an opposite role. The multivariable analysis revealed that a high N1/N2 ratio was a significant prognostic indicator for OS and RFS. In addition, tumor-associated N1/N2 neutrophils showed an opposite correlation with tumor-infiltrating CD8+ T cells and Tregs. CONCLUSION: The plasticity of tumor-associated N1/N2 neutrophils was identified as a crucial prognostic indicator that might reflect the TME and immune escape in patients with PDAC. On further investigation and validation, our findings may be used to further stratify patients with varying prognoses to optimize treatment.

Basophils as a potential therapeutic target in cancer.

Basophils, which are considered as redundant relatives of mast cells and the rarest granulocytes in peripheral circulation, have been neglected by researchers in the past decades. Previous studies have revealed their vital roles in allergic diseases and parasitic infections. Intriguingly, recent studies even reported that basophils might be associated with cancer development, as activated basophils synthesize and release a variety of cytokines and chemokines in response to cancers. However, it is still subject to debate whether basophils function as tumor-protecting or tumor-promoting components; the answer may depend on the tumor biology and the microenvironment. Herein, we reviewed the role of basophils in cancers, and highlighted some potential and promising therapeutic strategies.

Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer.

Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC.

Chemokine C-C motif ligand 21 synergized with programmed death-ligand 1 blockade restrains tumor growth.

Programmed death-ligand 1 (PD-L1) blockade has revolutionized the prognosis of several cancers, but shows a weak effect on pancreatic cancer (PC) due to poor effective immune infiltration. Chemokine C-C motif ligand 21 (CCL21), a chemokine promoting T cell immunity by recruiting and colocalizing dendritic cells (DCs) and T cells, serves as a potential antitumor agent in many cancers. However, its antitumor response and mechanism combined with PD-L1 blockade in PC remain unclear. In our study, we found CCL21 played an important role in leukocyte chemotaxis, inflammatory response, and positive regulation of PI3K-AKT signaling in PC using Metascape and gene set enrichment analysis. The CCL21 level was verified to be positively correlated with infiltration of CD8+ T cells by the CIBERSORT algorithm, but no significant difference in survival was observed in either The Cancer Genome Atlas or the International Cancer Genome Consortium cohort when stratified by CCL21 expression. Additionally, we found the growth rate of allograft tumors was reduced and T cell infiltration was increased, but tumor PD-L1 abundance elevated simultaneously in the CCL21-overexpressed tumors. Then, CCL21 was further verified to increase tumor PD-L1 level through the AKT-glycogen synthase kinase-3ß axis in human PC cells, which partly impaired the antitumor T cell immunity. Finally, the combination of CCL21 and PD-L1 blockade showed superior synergistic tumor suppression in vitro and in vivo. Together, our findings suggested that CCL21 in combination with PD-L1 blockade might be an efficient and promising option for the treatment of PC.

Comprehensive Diagnostic Nomogram for Predicting Clinically Relevant Postoperative Pancreatic Fistula After Pancreatoduodenectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) remains a severe and challenging complication of pancreaticoduodenectomy (PD). This study aimed to establish a novel postoperative nomogram-based diagnostic model for the early detection of CR-POPF in patients subjected to PD. METHODS: Consecutive patients who underwent PD in Zhongshan Hospital, Fudan University from December 2018 to October 2020 were retrospectively enrolled. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for CR-POPF. Then, a novel predictive nomogram was established accordingly. RESULTS: Among the consecutive 176 patients who underwent PD, 37 (21.1%) patients developed CR-POPF. Through univariate and multivariate analyses, the drain amylase (P = 0.002), serum creatinine (P = 0.009), and serum C reactive protein (P = 0.045) at postoperative day 1 (POD1) as well as the neutrophil count (P = 0.025) and temperature (P = 0.025) at POD3 were identified as independent risk factors for CR-POPF. Based on this, a novel predictive nomogram containing these factors was constructed to predict the probability of CR-POPF after PD. The formulated nomogram showed better performance to detect CR-POPF after PD with a sensitivity of 0.784, specificity of 0.770, positive predictive value of 0.475, and negative predictive value of 0.930 when compared to other predictors. In addition, the predictive value of the nomogram was assessed by a concordance index of 0.814 (95% CI, 0.736-0.892), which was significantly higher than indicators alone. This was further validated and depicted by decision curve analysis and clinical impact curve. CONCLUSION: This study established a diagnostic nomogram of postoperative objective parameters that can predict the development of CR-POPF after PD with a good discriminative ability and predictive accuracy.

Lymph Node Metastatic Patterns and Survival Predictors Based on Tumor Size in Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Larger tumor size is widely acknowledged to be associated with increased lymph node (LN) metastatic potential. However, the quantitative relationships between tumor size and LN metastasis or survival remain unclear. This study aims to quantify the objective relationship between tumor size and the prevalence of LN metastases across a spectrum primary tumor size. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 9958 patients with resected PDAC without distant metastasis. The prevalence of LN metastases, LN ratio (LNR), and N2/N1 ratio were assessed amongst different tumor sizes, and the relationships were displayed by matched curves. RESULTS: In the enrolled cohort, age, tumor site, grade, American Joint Committee on Cancer (AJCC) 8th node staging, tumor size, chemotherapy, and radiotherapy were identified as significant independent predictors for overall survival (OS) and cancer-specific survival (CSS). For tumors within 1-40 mm in size, the prevalence of node-positive disease is closely modelled using a logarithmic formula [0.249 × ln (size) + 0.452] × 100%. The prevalence plateaued between 70% and 80% beyond 40 mm. The mean LNR increased in a stepwise manner as tumor size increased from 1-5 mm (LNR = 0.024) to 41-45 mm (LNR = 0.177); then, beyond 45 mm, it plateaued near 0.170. N2/N1 ratio gradually increased along with tumor size from 1-5 mm (N2/N1 = 0.286) to 41-45 mm (N2/N1 = 1.016), and when tumor size reached to 41-45 mm or more, the ratio stabilized around 1.000. In addition, significant survival prediction by AJCC N staging was observed when tumors ranging between 16 and 45 mm in size. CONCLUSION: Regional LN involvement demonstrated a logarithmic growth with increasing tumor sizes in patients with resected PDAC . The probability of metastasis in each regional LN for resected PDAC with tumors greater than 40 mm in size was near 17.0% and their overall prevalence of LN metastasis was 70-80%. Among which, 50% of patients had an N2 stage. Such prediction may be a potential and promising tool for guiding lymphadenectomy in PDAC surgery.

The effect of primary site, functional status and treatment modality on survival in gastroenteropancreatic neuroendocrine neoplasms with synchronous liver metastasis: a US population-based study.

BACKGROUND: The incidence of indolent gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has increased dramatically. GEP-NENs often present late with concomitant liver metastasis, which is associated with poorer outcomes. METHODS: This is a retrospective cohort study of 3,188 patients with liver metastatic GEP-NENs from the national scale Surveillance, Epidemiology, and End Results (SEER) database in the USA between 2010 and 2016. The population-based sample of GEP-NENs with liver metastasis was stratified by primary site (intestinal, pancreatic or gastric), surgical intervention and functional status. RESULTS: Of the 3,188 patients with liver metastatic GEP-NENs in this study, intestinal NENs (iNENs) were the most common and displayed the best 5-year survival of 42.6% compared to 25.8% in pancreatic NENs (pNENs) and 12.0% in gastric NENs (gNENs). Surgical intervention [hazard ratio (HR): 0.46, 95% CI: (0.40-0.53), P<0.001] and carcinoid subtype showed robust survival advantages across all groups. pNENs with liver metastasis were associated with the greatest benefit of surgery [HR: 0.55, 95% CI: (0.41-0.75), P<0.001] while iNENs were the most commonly treated by surgery. After risk adjustment, primary site was not associated with outcome in the non-surgical group. CONCLUSIONS: Taken collectively, when diagnosed with liver metastasis, iNENs conferred a better overall prognosis than both pNENs and gNENs. Primary surgical resection, especially of carcinoid type tumors, emerged as a robust prognostic indicator of better outcomes irrespective of primary site. This finding was most pronounced in liver metastatic pNENs. When possible, we recommend surgical intervention in GEP-NENs with liver metastasis.

Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70.

BACKGROUND: Radiofrequency ablation (RFA) is widely used in palliative therapy of malignant cancers. Several studies have shown its applicability and safety for locally advanced pancreatic cancer (LAPC). The objective of this study was to modify the current regimen to improve its therapeutic effect. METHODS: Immune cell subtypes and related cytokines were quantified to uncover the immune pattern changes post-RFA treatment. Then, high-throughput proteome analysis was performed to identify differentially expressed proteins associated with RFA, which were further validated in in vitro and in vivo experiments. Finally, a combined therapy was tested in a murine model to observe its therapeutic effect. RESULTS: In preclinical murine models of RFA treatment, no significant therapeutic benefit was observed following RFA treatment. However, the proportion of tumor-infiltrating CD8+ T cells was significantly increased, whereas that of regulatory T cells (Tregs) was decreased post-RFA treatment, which indicated a beneficial anti-tumor environment. To identify the mechanism, high-throughput mass spectrum was obtained that identified heat shock protein 70 (HSP70) as the top differentially expressed protein. HSP70 expression in residual cancer cells was significantly increased post-RFA treatment, which notably promoted pancreatic cancer growth. Elevated HSP70 promoted cell proliferation by activating AKT-mTOR signaling. Finally, RFA treatment combined with an mTOR inhibitor exerted a synergetic repressive effect on tumor growth in the preclinical murine cancer model. CONCLUSIONS: RFA treatment in combination with mTOR signaling blockade can not only promote tumor immune response, but also restrain residual cancer cell proliferation. Such a combination may be a promising and effective therapeutic strategy for LAPC patients.