Laparoscopic pancreaticoduodenectomy with portal or superior mesenteric vein resection and reconstruction for pancreatic cancer:A single-center experience

Background: Open pancreaticoduodenectomy(OPD) with portal or superior mesenteric vein resection and reconstruction has been applied in pancreatic cancer patients with tumor infiltration or adherence. However, it is controversial whether laparoscopic pancreaticoduodenectomy(LPD) with major vascular resection and reconstruction is feasible. This study aimed to evaluate the safety and feasibility of LPD with major vascular resection compared with OPD with major vascular resection. Methods: We reviewed data for all pancreatic cancer patients undergoing LPD or OPD with vascular resection at Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, between February 2018 and May 2022. We compared the preoperative, intraoperative, and postoperative clinicopathological data of the two groups to conduct a comprehensive evaluation of LPD with major vascular resection. Results: A total of 63 patients underwent pancreaticoduodenectomy(PD) with portal or superior mesenteric vein resection and reconstruction, including 25 LPDs and 38 OPDs. The LPD group had less intraoperative blood loss(200 vs. 400 m L, P < 0.001), lower proportion of intraoperative blood transfusion(16.0% vs. 39.5%, P = 0.047), longer operation time(390 vs. 334 min, P = 0.004) and shorter postoperative hospital stay(11 vs. 14 days, P = 0.005). There was no perioperative death in all patients. There was no significant difference in the incidence of total postoperative complications, grade B/C postoperative pancreatic fistula, delayed gastric emptying and abdominal infection between the two groups. No postpancreatectomy hemorrhage nor bile leakage occurred during perioperative period. There was no significant difference in R0 resection rate and number of lymph nodes harvested between the two groups. Patency of reconstructed vessels in the two groups were 96.0% and 92.1%, respectively( P = 0.927). Conclusions: LPD with portal or superior mesenteric vein resection and reconstruction was safe, feasible and oncologically acceptable for selected patients with pancreatic cancer, and it can achieve similar or even better perioperative results compared to open approach.

The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer:A meta-analysis

Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.

Haemoglobin,albumin,lymphocyte and platelet predicts postoperative survival in pancreatic cancer

BACKGROUND Systemic inflammation and nutrition status play an important role in cancer metastasis.The combined index of hemoglobin,albumin,lymphocyte,and platelet(HALP),consisting of haemoglobin,albumin,lymphocytes,and platelets,is considered as a novel marker to reflect both systemic inflammation and nutrition status.However,no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection.AIM To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients.METHODS The preoperative serum levels of hemoglobin,albumin,lymphocyte counts,and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection.The relationship between postoperative survival and the preoperative level of HALP was investigated.RESULTS Low levels of HALP were significantly associated with lymph node metastasis(P=0.002),poor tumor differentiation(P=0.032),high TNM stage(P=0.008),female patients(P=0.005)and tumor location in the head of the pancreas(P<0.001).Low levels of HALP were associated with early recurrence[7.3 mo vs 16.3 mo,P<0.001 for recurrence-free survival(RFS)]and short survival[11.5 mo vs 23.6 mo,P<0.001 for overall survival(OS)]in patients with resected pancreatic adenocarcinoma.A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location.CONCLUSION Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.

Time to think: Selecting patients who may benefit from synchronous resection of primary pancreatic cancer and liver metastases

Pancreatic cancer remains a lethal disease and is associated with poor prognosis, particularly for patients with distant metastasis at diagnosis. Recently, Oweira reported a retrospective study that included 13233 metastatic pancreatic cancer patients from the Surveillance, Epidemiology and End Results database. They demonstrated that pancreatic cancer patients with isolated liver metastases had worse outcomes than patients with isolated lung metastases or distant nodal metastases. At present, the standard treatment for metastatic pancreatic cancer is chemotherapy. However, improvement in the safety of pancreatic surgery has led to the consideration of more aggressive surgical approaches. Schneitler reported two cases of hepatic metastatic pancreatic cancer in which negative margin(R0) resection and long survival were achieved after effective preoperative chemotherapy. In general, these two studies indicate that although pancreatic cancer patients with liver metastasis have a poor prognosis, surgical approaches may prolong survival for a few of these patients. A strategy to select hepatic metastatic pancreatic cancer patients who may benefit from surgical intervention is urgently needed.

Zinc finger E-box-binding homeobox 1 mediates aerobic glycolysis via suppression of sirtuin 3 in pancreatic cancer

AIM To uncover the roles of tumor-promoting gene ZEB1 in aerobic glycolysis regulation and shed light on the underlying molecular mechanism.METHODS Endogenous zinc finger E-box binding homeobox-1(ZEB1) was silenced using a lentivirus-mediated method, and the impact of ZEB1 and methyl-CpG binding domain protein 1(MBD1) on aerobic glycolysis was measured using seahorse cellular flux analyzers, reactive oxygen species quantification, and mitochondrial membrane potential measurement. The interaction between ZEB1 and MBD1 was assessed by co-immunoprecipitation and immunofluorescence assays. The impact of ZEB1 and MBD1 interaction on sirtuin 3(SIRT3) expression was confirmed by quantitative polymerase chain reaction, western blotting, and dual-luciferase and chromatinimmunoprecipitation assays.RESULTS ZEB1 was a positive regulator of aerobic glycolysis in pancreatic cancer. ZEB1 transcriptionally silenced expression of SIRT3, a mitochondrial-localized tumor suppressor, through interaction with MBD1. CONCLUSION ZEB1 silenced SIRT3 expression via interaction with MBD1 to promote aerobic glycolysis in pancreatic cancer.

Development and multicenter validation of a nomogram for preoperative prediction of lymph node positivity in pancreatic cancer(NeoPangram)

Background:Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node(LN)-positive pancreatic cancer.This study aimed to develop and validate a nomogram to preoperatively predict LN-positive disease.Methods:A total of 558 patients with resected pancreatic cancer were randomly and equally divided into development and internal validation cohorts.Multivariate logistic regression analysis was used to construct the nomogram.Model performance was evaluated by discrimination,calibration,and clinical usefulness.An independent multicenter cohort consisting of 250 patients was used for external validation.Results:A four-marker signature was built consisting of carbohydrate antigen 19–9(CA19–9),CA125,CA50,and CA242.A nomogram was constructed to predict LN metastasis using three predictors identified by multivariate analysis:risk score of the four-marker signature,computed tomography-reported LN status,and clinical tumor stage.The prediction model exhibited good discrimination ability,with C-indexes of 0.806,0.742 and 0.763 for the development,internal validation,and external validation cohorts,respectively.The model also showed good calibration and clinical usefulness.A cut-off value(0.72)for the probability of LN metastasis was determined to separate low-risk and high-risk patients.Kaplan-Meier survival analysis revealed a good agreement of the survival curves between the nomogram-predicted status and the true LN status.Conclusions:This nomogram enables the identification of pancreatic cancer patients at high risk for LN positivity who may have more advanced disease and thus could potentially benefit from neoadjuvant therapy.

Anatomical features and technical difficulties in laparoscopic pancreaticoduodenectomy with various superior mesenteric artery-first approaches

Laparoscopic pancreaticoduodenectomy(LPD) at its early stage failed to demonstrate the superiority compared with open pancreaticoduodenectomy(OPD) [1]. The well-known randomized trial, LEOPARD-2, was even terminated due to the safety issue [2], but recent researches [3,4] revealed that LPD is technically safe and feasible with acceptable rates of morbidity and mortality and therefore, gains popularity recently.

Recent research hotspots in sequencing and the pancreatic neuroendocrine tumor microenvironment

Multiple endocrine neoplasia 1(MEN1)syndrome,a disease arising from a genetic predisposition to tumor development caused by MEN1 loss-of-function mutations,is characterized by the combined occurrence of neuroendocrine tumors in multiple human organs.With advances in diagnostic technologies and improvements in living standards.

Multifunctional RGD coated a single-atom iron nanozyme:A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer

Nanozyme is a new promising approach to cancer therapy for its ability to induce ferroptosis by activating H_(2)O_(2)via a traditional radical pathway and enhance cancer immunotherapy.However,short half-life period of hydroxyl radical(·OH)results in unsatisfied effectiveness.Herein,we synthesized a single-atom iron nanozyme(Fe-SAzyme),which can activate H_(2)O_(2)via a non-radical pathway to generate Fe-based reactive oxygen species(ROS)(O=FeO_(3)=O)for promoting the ferroptosis of pancreatic cancer cells.This Fe-SAzyme could be specifically phagocytosed by pancreatic cancer cells,increasing ROS levels and inhibiting glutathione(GSH)synthesis,which activates ferroptosis.Tumor magnetic resonance imaging(MRI)showed decreased T2 signal after intravenous injection of RGD@Fe-AC(AC=activated carbon).Moreover,RGD@Fe-AC promoted dendritic cell(DC)maturation,overcame Treg-mediated immunosuppression,activated T cells to trigger adaptive immune responses,and enhanced the efficacy ofα-PD-L1 immunotherapy.Our research demonstrated that RGD@Fe-AC provided a straightforward,easily implemented,and selective approach for pancreatic cancer treatment and immunotherapy.

Effect of the number of positive lymph nodes and lymph node ratio on prognosis of patients after resection of pancreatic adenocarcinoma

BACKGROUND: The prognostic factors related to lymph node involvement [lymph node status, the number of positive lymph nodes, lymph node ratio (LNR)] and the number of nodes evaluated in patients with pancreatic adenocarcinoma after pancreatectomy are poorly defined.METHODS: A total of 167 patients who had undergone resection of pancreatic adenocarcinoma from February 2010 to August2011 were included in this study. Histological examination was performed to evaluate the tumor differentiation and lymph node involvement. Univariate and multivariate analyses were made to determine the relationship between the variables related to nodal involvement and the number of nodes and survival.RESULTS: The median number of total nodes examined was10 (range 0-44) for the entire cohort. The median number of total nodes examined in node-negative (pN 0) patients was similar to that in node-positive (pN 1) patients. Patients with pN 1 diseases had significantly worse survival than those with pN 0 ones (P=0.000). Patients with three or more positive nodes had a poorer prognosis compared with those with the negative nodes (P=0.000). The prognosis of the patients with negative nodes was similar to that of those with one to two positive nodes (P=0.114). The median survival of patients with an LNR≥0.4 was shorter than that of patients with an LNR <0.4 in thepN 1 cohort (P=0.014). No significance was found between the number of total nodes examined and the prognosis, regardless of the cutoff of 10 or 12 and in the entire cohort or the pN 0 and pN 1 groups. Based on the multivariate analysis of the entire cohort and the pN 1 group, the nodal status, the number of positive nodes and the LNR were all associated with survival.CONCLUSIONS: In addition to the nodal status, the number of positive nodes and the LNR can serve as comprehensive factors for the evaluation of nodal involvement. This approach may be more effective for predicting the survival of patients with pancreatic adenocarcinoma after pancreatectomy.

Stathmin destabilizing microtubule dynamics promotes malignant potential in cancer cells by epithelial-mesenchymal transition

BACKGROUND: Stathmin is a ubiquitous cytosolic regulatory phosphoprotein and is overexpressed in different human malignancies. The main physiological function of stathmin is to interfere with microtubule dynamics by promoting depolymerization of microtubules or by preventing polymerization of tubulin heterodimers. Stathmin plays important roles in regulating many cellular functions as a result of its microtubuledestabilizing activity. Currently, the critical roles of stathmin in cancer cells, as well as in lymphocytes have been valued. This review discusses stathmin and microtubule dynamics in cancer development, and hypothesizes their possible relationship with epithelial-mesenchymal transition(EMT).DATA SOURCES: A PubMed search using such terms as "stathmin", "microtubule dynamics", "epithelial-mesenchymal transition", "EMT", "malignant potential" and "cancer" was performed to identify relevant studies published in English.More than 100 related articles were reviewed.RESULTS: The literature clearly documented the relationship between stathmin and its microtubule-destabilizing activity of cancer development. However, the particular mechanism is poorly understood. Microtubule disruption is essential for EMT, which is a crucial process during cancer development. As a microtubule-destabilizing protein, stathmin may promote malignant potential in cancer cells by initiating EMT.CONCLUSIONS: We propose that there is a stathminmicrotubule dynamics-EMT(S-M-E) axis during cancer development. By this axis, stathmin together with itsmicrotubule-destabilizing activity contributes to EMT, which stimulates the malignant potential in cancer cells.

Strategies for pancreatic anastomosis after pancreaticoduodenectomy:What really matters?

Background: The postoperative pancreatic fistula rate remains approximately 10–20% even in institutions treating a high-volume of pancreatic cases. The best strategy to restore the continuity between the pancreatic remnant and the digestive tract is still in debate.Data sources: Studies were identified by searching Pub Med for studies published between January 1934 (when pancreaticogastrostomy was technically feasible) and December 2016. The following search terms were used: "duct-to-mucosa", "invagination", "pancreaticojejunostomy", "pancreaticogastrostomy," and"pancreaticoduodenectomy". The search was limited to English publications.Results: Many technical methods have been developed and optimized to restore pancreaticoenteric continuity, including pancreaticojejunostomy, pancreaticogastrostomy, and stented drainage of the pancreatic duct, among other modifications. Researchers have also attempted to decrease the postoperative pancreatic fistula after pancreaticoduodenectomy by using fibrin glue and somatostatin analogues. However, no significant decrease in postoperative pancreatic fistula has been observed in most of these studies, and only an external pancreatic duct stent has been found to decrease the leakage rate of pancreatic anastomosis after pancreaticojejunostomy.Conclusion: Pancreatic surgeons should choose a suitable technique according to the characteristics of individual cases.

Tumor-infiltrating platelets predict postoperative recurrence and survival in resectable pancreatic neuroendocrine tumor

BACKGROUND Platelets have been reported to participate in tumor cell growth,extravasation,epithelial–mesenchymal transition,metastasis,and drug resistance.However,the importance of platelets in pancreatic neuroendocrine tumor(pNET)lacks adequate literature support.The predictive value of tumor-infiltrating platelets(TIPs)in pNET remains unclear.AIM To investigate the relationship between TIPs and the prognosis of patients with pNET following radical resection.METHODS In total,113 patients who had undergone radical surgical resection with a pathologic diagnosis of pNET were enrolled in this study.Immunohistochemical analysis of cluster of differentiation 42b(CD42b)expression in the tumor specimens was performed to determine the presence of TIPs.Univariate and multivariate analyses were used to analyze the prognostic value of TIPs.RESULTS TIPs were observed in intratumoral areas in 54 patients.Neither basic characteristics nor preoperative platelet-associated indicators showed a significant relationship with the presence of TIPs(all P>0.05).Patients with positive intratumoral CD42b expression had worse overall survival(P=0.005)and recurrence-free survival(P<0.001)than those with negative intratumoral CD42b expression.Multivariate analysis demonstrated that TIPs were independent prognostic factors for overall survival(P=0.049)and recurrencefree survival(P=0.003).Nevertheless,platelet count,mean platelet volume,and platelet-to-lymphocyte ratio were not associated with postoperative survival or recurrence in pNET patients(all P>0.05).CONCLUSION TIPs are a useful prognostic biomarker for patients with resectable pNET,and their detection represents a promising tool for pNET treatment strategy decisions.

Guidelines for the diagnosis and treatment of pancreatic adenocarcinoma(2018 edition): A standardized procedure recommended in China

Pancreatic adenocarcinoma is the fifth leading cause of cancerrelated deaths worldwide,and this incidence is projected to increase further in future decades[1].Furthermore,despite years of attempting to improve treatment for patients with pancreatic adenocarcinoma,the 5-year overall survival rate remains low at<7%[2].Thus,this cancer is devastating,and effective treatment strategies are desperately needed.Although the available diagnosis and treatment measures do not significantly improve patient outcomes,several years of hard work have revolutionized the field using new concepts from medical oncology and produced several scientific advances in the diagnosis and treatment of pancreatic adenocarcinoma.

Ligamentum teres hepatis patch enhances the healing of pancreatic fistula after distal pancreatectomy

Pancreatic fistula is one of the most common complications after the distal pancreatectomy.Many methods have been tried to solve the problem,but no one is optimal,especially for the soft pancreatic stump cases.This study used ligamentum teres hepatis as a patch to cover the pancreatic stump.Between October 2010 and December 2012,seventyseven patients who had undergone distal pancreatectomy with a soft pancreatic stump were divided into two groups:group A(n=39,patients received conventional ligated main pancreatic duct method)and group B(n=38,patients underwent a coverage procedure).Patients in group A had a longer recovery from postoperative pancreatic fistula than those in group B(16.4±3.5 vs 10.8±1.6 days,P<0.05).The coverage procedure with ligamentum teres hepatis is a safe,effective and convenient method for patients with a soft pancreas remnant during distal pancreatectomy.

Active surveillance in metastatic pancreatic neuroendocrine tumors:A 20-year single-institutional experience

BACKGROUND Pancreatic neuroendocrine tumors(PanNETs)are heterogeneous and indolent;systemic therapy is not essential for every patient with metastatic PanNET.The National Comprehensive Cancer Network guidelines state that delaying treatment is an option for PanNET with distant metastasis,if the patient has stable disease.However,specific factors that influence surveillance were not mentioned.In addition,data regarding the period of active surveillance in patients with metastatic PanNET are lacking.AIM To specifically determine factors influencing active surveillance in patients with liver metastatic nonfunctioning PanNETs(NF-PanNETs).METHODS Seventy-six patients with liver metastatic NF-PanNETs who received active surveillance from a high-volume institution were enrolled.Time to disease progression(TTP)and time to initiation of systemic therapy were determined.RESULTS Thirty-one(40.8%)patients had recurrent liver disease after R0 resection;45(59.2%)were diagnosed with liver metastasis.The median follow-up period was 42 mo and 90.7%patients were observed to have disease progression.The median TTP(mTTP)was 10 mo.Multivariate analysis showed that the largest axis of the liver metastasis>5 mm(P=0.04),non-resection of the primary tumor(P=0.024),and T3-4 stage(P=0.028)were associated with a shorter TTP.The mTTP in patients with no risk factors was 24 mo,which was significantly longer than that in patients with one(10 mo)or more(6 mo)risk factors(P<0.001).A nomogram with three risk factors showed reasonable calibration,with a C-index of 0.603(95%confidence interval:0.47-0.74).CONCLUSION Active surveillance may only be safe for metastatic NF-PanNET patients with favorable risk factors,and other patients progressed rapidly without treatment.Further studies with a larger sample size and a control group are needed.

Clinicopathological characteristics and prognosis of 232 patients with poorly differentiated gastric neuroendocrine neoplasms

BACKGROUND Poorly differentiated gastric neuroendocrine neoplasms(PDGNENs)include gastric neuroendocrine carcinoma(NEC)and mixed adenoneuroendocrine carcinoma,which are highly malignant and rare tumors,and their incidence has increased over the past few decades.However,the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated.AIM To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs.METHODS The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively.RESULTS Among the 232 patients with PDGNENs,191(82.3%)were male,with an average age of 62.83±9.11 years.One hundred and thirteen(49.34%)of 229 patients had a stage III disease and 86(37.55%)had stage IV disease.Three(1.58%)of 190 patients had no clinical symptoms,while 187(98.42%)patients presented clinical symptoms.The tumors were mainly(89.17%)solitary and located in the upper third of the stomach(cardia and fundus of stomach:115/215,53.49%).Most lesions were ulcers(157/232,67.67%),with an average diameter of 4.66±2.77 cm.In terms of tumor invasion,the majority of tumors invaded the serosa(116/198,58.58%).The median survival time of the 232 patients was 13.50 mo(7,31 mo),and the overall 1-year,3-year,and 5-year survival rates were 49%,19%,and 5%,respectively.According to univariate analysis,tumor number,tumor diameter,gastric invasion status,American Joint Committee on Cancer(AJCC)stage,and distant metastasis status were prognostic factors for patients with PDGNENs.Multivariate analysis showed that tumor number,tumor diameter,AJCC stage,and distant metastasis status were independent prognostic factors for patients with PDGNENs.CONCLUSION The overall prognosis of patients with PDGNENs is poor.The outcomes of patients with a tumor diameter>5 cm,multiple tumors,and stage IV tumors are worse than those of other patients.

Validation and head-to-head comparison of four models for predicting malignancy of intraductal papillary mucinous neoplasm of the pancreas: A study based on endoscopic ultrasound findings

BACKGROUND Several models are currently available for predicting the malignancy of pancreatic intraductal papillary mucinous neoplasm(IPMN),namely,the Pancreatic Surgery Consortium(PSC),the Japan Pancreas Society(JPS),the Johns Hopkins Hospital(JHH),and the Japan-Korea(JPN-KOR)models.However,a head-to-head comparison that shows which model is more accurate for this individualized prediction is lacking.AIM To perform a head-to-head comparison of the four models for predicting the malignancy of pancreatic IPMN.METHODS A total of 181 patients with IPMN who had undergone surgical resection were identified from a prospectively maintained database.The characteristics of IPMN in patients were recorded from endoscopic ultrasound imaging data and report archives.The performance of all four models was examined using Harrell’s concordance index(C-index),calibration plots,decision curve analyses,and diagnostic tests.RESULTS Of the 181 included patients,94 were categorized as having benign disease,and the remaining 87 were categorized as having malignant disease.The C-indexes were 0.842[95%confidence interval(CI):0.782-0.901],0.704(95%CI:0.626-0.782),0.754(95%CI:0.684-0.824),and 0.650(95%CI:0.483-0.817)for the PSC,JPS,JHH,and JPN-KOR models,respectively.Calibration plots showed that the PSC model had the least pronounced departure from ideal predictions.Of the remaining three models,the JPS and JHH models underestimated the probability of malignancy,while the JPN-KOR model overestimated the malignant potential of branch duct-IPMN.Decision curve analysis revealed that the PSC model resulted in a better clinical net benefit than the three other models.Diagnostic tests also showed a higher accuracy(0.801)for the PSC model.CONCLUSION The PSC model exhibited the best performance characteristics.Therefore,the PSC model should be considered the best tool for the individualized prediction of malignancy in patients with pancreatic IPMN.

Signaling pathways in cancer-associated fibroblasts:recent advances and future perspectives

As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-known signaling pathways,including the transforming growth factor-β(TGF-β),Hedgehog(Hh),Notch,Wnt,Hippo,nuclear factor kappa-B(NF-κB),Janus kinase(JAK)/signal transducer and activator of transcription(STAT),mitogen-activated protein kinase(MAPK),and phosphoinositide 3-kinase(PI3K)/AKT pathways,as well as transcription factors,including hypoxia-inducible factor(HIF),heat shock transcription factor 1(HSF1),P53,Snail,and Twist,constitute complex regulatory networks in theTMEtomodulate the formation,activation,heterogeneity,metabolic characteristics and malignant phenotype of CAFs.Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics,and this modulation partially depends on the regulation of signaling cascades.The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures(e.g.,NCT01130142 and NCT01064622).Hence,a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies.Here,we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

Consensus of clinical diagnosis and treatment for non-functional pancreatic neuroendocrine neoplasms with diameter<2 cm

In clinical practice,pancreatic neuroendocrine neoplasms(pNENs)with a diameter smaller than 2 cm are commonly referred to as small pNENs.Due to their generally favorable biological characteristics,the diagnosis and treatment of small pNENs differ from other pNENs and are somewhat controversial.In response to this,the Chinese Pancreatic Surgery Association,Chinese Society of Surgery,Chinese Medical Association have developed a consensus on the diagnosis and treatment of small pNENs,which is based on evidence-based medicine and expert opinions.This consensus covers various topics,including concepts,disease assessment,treatment selection,follow-up,and other relevant aspects.