Metformin and pancreatic neuroendocrine tumors:A systematic review and meta-analysis

BACKGROUND Most patients with advanced pancreatic neuroendocrine tumors(pNETs)die due to tumor progression.Therefore,identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant.In this perspective,metformin is emerging as a molecule of interest.Retrospective studies have described metformin,a widely used agent for the treatment of patients with type 2 diabetes mellitus(T2DM),to be effective in modulating different tumor-related events,including cancer incidence,recurrence and survival by inhibiting mTOR phosphorylation.This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.AIM To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and posttreatment outcomes of pNET.METHODS A systematic review of the published literature was undertaken,focusing on the role of T2DM and metformin in insurgence and prognosis of pNET,measured through outcomes of tumor-free survival(TFS),overall survival and progression free survival.RESULTS A total of 13 studies(5674 patients)were included in this review.Analysis of 809 pNET cases from five retrospective studies(low study heterogeneity with I^(2)=0%)confirms the correlation between T2DM and insurgence of pNET(OR=2.13,95%CI=1.56-4.55;P<0.001).The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients(hazard ratio=1.84,95%CI=0.78-2.90;P<0.001).The study heterogeneity was intermediate,with I^(2)=51%.A few studies limited the possibility of performing pooled analysis in the setting of metformin;therefore,results were heterogeneous,with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.CONCLUSION T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients.Unfortunately,a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Pancreatic neuroendocrine tumors:Are tumors smaller than 2 cm truly indolent?

BACKGROUND Pancreatic neuroendocrine tumors(PNETs)are relatively rare but rank as the second most common pancreatic neoplasm.They can be functional,causing early metabolic disturbances due to hormone secretion,or non-functional and diagnosed later based on tumor size-related symptoms.Recent diagnoses of PNETs under 2 cm in size have sparked debates about their management;some practitioners advocate for surgical removal and others suggest observation due to the tumors’lower potential for malignancy.However,it is unclear whether managing these small tumors expectantly is truly safe.AIM To evaluate poor prognostic factors in PNETs based on tumor size(>2 cm or<2 cm)in surgically treated patients.METHODS This cohort study included 64 patients with PNETs who underwent surgical resection between 2006 and 2019 at a high-complexity reference hospital in Medellín,Colombia.To assess patient survival,quarterly follow-ups were conducted during the first year after surgery,followed by semi-annual con-sultations at the hospital's hepatobiliary surgery department.Qualitative variables were described using absolute and relative frequencies,and quantitative variables were expressed using measures of central tendency and their corresponding measures of dispersion.RESULTS The presence of lymph node involvement,neural involvement,and lymphovascular invasion were all associated with an increased risk of mortality,with hazard ratios of 5.68(95%CI:1.26–25.61,P=0.024),6.44(95%CI:1.43–28.93,P=0.015),and 24.87(95%CI:2.98–207.19,P=0.003),respectively.Neural involvement and lymphovascular invasion were present in tumors smaller than 2 cm in diameter and those larger than 2 cm in diameter.The recurrence rates between the two tumor groups were furthermore similar:18.2%for tumors smaller than 2 cm and 21.4%for tumors larger than 2 cm.Patient survival was additionally comparable between the two tumor groups.CONCLUSION Tumor size does not dictate prognosis;lymph node and lymphovascular involvement affect mortality,which high-lights that histopathological factors-rather than tumor size-may play a role in management.

Advancements in medical treatment for pancreatic neuroendocrine tumors:A beacon of hope

This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors(pan-NETs),emphasizing tailored approaches for specific subtypes.Cytoreductive surgery and somatostatin analogs(SSAs)play pivotal roles in managing tumors,while palliative options such as molecular targeted therapy,peptide receptor radionuclide therapy,and chemotherapy are reserved for SSA-refractory patients.Gastrinomas,insul-inomas,glucagonomas,carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies.Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research.This review underscores the evolving landscape of pan-NET treatment,offering renewed hope and improved outcomes for patients facing this complex disease.

Prediction of the lymphatic,microvascular,and perineural invasion of pancreatic neuroendocrine tumors using preoperative magnetic resonance imaging

BACKGROUND Significant correlation between lymphatic,microvascular,and perineural invasion(LMPI)and the prognosis of pancreatic neuroendocrine tumors(PENTs)was confirmed by previous studies.There was no previous study reported the relationship between magnetic resonance imaging(MRI)parameters and LMPI.AIM To determine the feasibility of using preoperative MRI of the pancreas to predict LMPI in patients with non-functioning PENTs(NFPNETs).METHODS A total of 61 patients with NFPNETs who underwent MRI scans and lymphadenectomy from May 2011 to June 2018 were included in this retrospective study.The patients were divided into group 1(n=34,LMPI negative)and group 2(n=27,LMPI positive).The clinical characteristics and qualitative MRI features were collected.In order to predict LMPI status in NF-PNETs,a multivariate logistic regression model was constructed.Diagnostic performance was evaluated by calculating the receiver operator characteristic(ROC)curve with area under ROC,sensitivity,specificity,positive predictive value(PPV),negative predictive value(NPV)and accuracy.RESULTS There were significant differences in the lymph node metastasis stage,tumor grade,neuron-specific enolase levels,tumor margin,main pancreatic ductal dilatation,common bile duct dilatation,enhancement pattern,vascular and adjacent tissue involvement,synchronous liver metastases,the long axis of the largest lymph node,the short axis of the largest lymph node,number of the lymph nodes with short axis>5 or 10 mm,and tumor volume between two groups(P<0.05).Multivariate analysis showed that tumor margin(odds ratio=11.523,P<0.001)was a predictive factor for LMPI of NF-PNETs.The area under the receiver value for the predictive performance of combined predictive factors was 0.855.The sensitivity,specificity,PPV,NPV and accuracy of the model were 48.1%(14/27),97.1%(33/34),97.1%(13/14),70.2%(33/47)and 0.754,respectively.CONCLUSION Using preoperative MRI,ill-defined tumor margins can effectively predict LMPI in patients with NF-PNETs.

Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations

Pancreatic neuroendocrine tumors(PNETs)are known to be the second most common epithelial malignancy of the pancreas.PNETs can be listed among the slowest growing as well as the fastest growing human cancers.The prevalence of PNETs is deceptively low;however,its incidence has significantly increased over the past decades.According to the American Cancer Society’s estimate,about 4032(>7%of all pancreatic malignancies)individuals will be diagnosed with PNETs in 2020.PNETs often cause severe morbidity due to excessive secretion of hormones(such as serotonin)and/or overall tumor mass.Patients can live for many years(except for those patients with poorly differentiated G3 neuroendocrine tumors);thus,the prevalence of the tumors that is the number of patients actually dealing with the disease at any given time is fairly high because the survival is much longer than pancreatic ductal adenocarcinoma.Due to significant heterogeneity,the management of PNETs is very complex and remains an unmet clinical challenge.In terms of research studies,modest improvements have been made over the past decades in the identification of potential oncogenic drivers in order to enhance the quality of life and increase survival for this growing population of patients.Unfortunately,the majority of systematic therapies approved for the management of advanced stage PNETs lack objective response or at most result in modest benefits in survival.In this review,we aim to discuss the broad challenges associated with the management and the study of PNETs.

Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment

In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms(p NENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3(p NETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas(p NECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the p NENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated p NECs and compare them to those of well-differentiated p NETs G3. For p NETs G3 and p NECs(due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between p NETs G3 and p NECs in order to deepen understanding of these diseases and discuss future research directions.

Pancreatic neuroendocrine tumors:A review of serum biomarkers,staging,and management

Pancreatic neuroendocrine tumors(pNETs)are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading,clinical staging,and presence of symptoms related to hormonal secretion.With regard to diagnosis,remarkable advances have been made:Chromogranin A is recommended as a general marker for pNETs.But other new biomarker modalities,like circulating tumor cells,multiple transcript analysis,microRNA profile,and cytokines,should be clarified in future investigations before clinical application.Therefore,the currently available serum biomarkers are insufficient for diagnosis,but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs.Surgical resection is still the only curative therapeutic option for localized pNETs.However,a debulking operation has also been proven to be effective for controlling the disease.As for drug therapy,steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor,while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs.Great progress has been achieved in the combination of systematic therapy with local control treatments.The optimal timing of local control intervention,planning of sequential therapies,and implementation of multidisciplinary care remain pending.

Minimally invasive vs open pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors

BACKGROUND The mainstay of treating nonfunctioning-pancreatic neuroendocrine tumors(NFPNETs)is surgical resection.However,minimally invasive approaches to pancreatic resection for treating NF-PNETs are not widely accepted,and the longterm oncological outcomes of such approaches remain unknown.AIM To determine the short-and long-term outcomes of minimally invasive pancreatic resection conducted in patients with NF-PNETs.METHODS Prospective databases from Severance Hospital were searched for 110 patients who underwent curative resection for NF-PNETs between January 2003 and August 2018.RESULTS The proportion of minimally invasive surgery(MIS)procedures performed for NF-PNET increased to more than 75%after 2013.There was no significant difference in post-operative complications(P=0.654),including pancreatic fistula(P=0.890)and delayed gastric emptying(P=0.652),between MIS and open approaches.No statistically significant difference was found in disease-free survival between the open approach group and the MIS group(median follow-up period,28.1 mo;P=0.428).In addition,the surgical approach(MIS vs open)was not found to be an independent prognostic factor in treating NF-PNET patients[Exp(β)=1.062;P=0.929].CONCLUSION Regardless of the type of surgery,a minimally invasive approach can be safe and feasible for select NF-PNET patients.

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.

Surgery for metastatic pancreatic neuroendocrine tumors: a narrative review

Background and Objective:Pancreatic neuroendocrine tumors(PanNETs)are derived from the islet cells of the pancreas and have been increasing in incidence.Most of these tumors are nonfunctional although some can secrete hormones and lead to hormone-specific clinical syndromes.Surgery is the mainstay of treatment for localized tumors,however,surgical resection is controversial in metastatic PanNETs.This narrative review seeks to summarize the current literature surrounding surgery,specifically in the controversial area of metastatic PanNETs,review current treatment paradigms,and understand the benefits of surgery in this group of patients.Methods:Authors searched PubMed using the terms“surgery pancreatic neuroendocrine tumor”,“metastatic neuroendocrine tumor”,and“liver debulking neuroendocrine tumor”from January 1990 to June 2022.Only English language publications were considered.Key Content and Findings:There is no consensus among the leading specialty organizations regarding surgery for metastatic PanNETs.When considering surgery for metastatic PanNETs,tumor grade and morphology,location of the primary tumor,extra-hepatic or extra-abdominal disease,as well as liver tumor burden and metastatic distribution should be considered.Because the liver is the most common site of metastasis and liver failure is the most common cause of death in patients with hepatic metastases,attention is centered here on debulking and other ablative techniques.Liver transplantation is rarely used for hepatic metastases but could be beneficial in a small subset of patients.Retrospective studies have demonstrated improvement in survival and symptoms after surgery for metastatic disease,but the lack of prospective randomized control trials significantly limits analysis of surgical benefits in patients with metastatic PanNETs.Conclusions:Surgery is the standard of care for localized PanNETs,while it remains controversial in metastatic disease.Many studies have shown a survival and symptomatic benefit to surgery and liver debulking in select groups of patients.However,most of the studies on which recommendations are based in this population are retrospective in nature and are subject to selection bias.This presents an opportunity for future investigation.

Molecular alterations and therapeutic targets in pancreatic neuroendocrine tumors

Human pancreatic neuroendocrine tumors(PanNETs)are a rare,deadly tumor type that is sporadic or arises in the background of a hereditary syndrome.A critical genetic event in sporadic tumors is inactivation of the gene menin 1(MEN1)on chromosome 11,and indeed,PanNETs occur in patients with the hereditary syndrome multiple endocrine neoplasia type 1(MEN1)due to germline mutations in the gene.Here,we review the recent progress in the field of molecular genetics and therapeutic targets of PanNETs.The key genomic alterations,including MEN1,ATRX/DAXX,mammalian target of rapamycin(mTOR),DNA damage and repair associated genes,vascular endothelial growth factor receptor(VEGFR)and SSTRs,and epigenetic aberrations in PanNETs are discussed.In addition,the commonly used preclinical models for PanNETs are enumerated.

Values of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumors:a comparative study

Background and objective:The value of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumor(m-PNET)remains poorly defined.This study aimed to evaluate the outcomes of m-PNET following debulking surgery in our institute.Methods:Patients with well-differentiated m-PNET in our hospital between February 2014 and March 2022 were collected.Clinicopathological and long-term outcomes of patients treated with radical resection,debulking surgery,and conservative therapy were compared retrospectively.Results:Fifty-three patients with well-differentiated m-PNET were reviewed,including 47 patients with unresectable m-PNET(debulking surgery,25;conservative therapy,22)and 6 patients with resectable m-PNET(radical resection).Patients undergoing debulking surgery had a post-operative Clavien–DindoIII complication rate of 16.0%without mortality.The 5-year overall survival(OS)rate of patients treated with debulking surgery was significantly higher than that of those treated with conservative therapy alone(87.5%vs 37.8%,log-rank P=0.022).Besides,the 5-year OS rate of patients treated with debulking surgery was comparable to that of patients with resectable m-PNET undergoing radical resection(87.5%vs 100%,log-rank P=0.724).Conclusions:Patients with unresectable well-differentiated m-PNET who underwent resection had better long-term outcomes than those who received conservative therapy alone.The 5-year OS of patients undergoing debulking surgery and radical resection were comparable.Debulking surgery could be considered for patients with unresectable well-differentiated m-PNET if no contraindication exists.

Perspective of molecular imaging and peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors:where do we stand?

The clinical use of nuclear medicine imaging and therapy in pancreatic neuroendocrine tumors has been greatly strengthened since the approval of ^(68)Ga-DOTATATE and ^(177)Lu-DOTATATE.However,many aspects are still under discussion.In this 2-part article,we aim to collect and discuss current evidence of molecular imaging and peptide receptor radionuclide therapy(PRRT)in pancreatic neuroendocrine tumor.In the first part,we will address some critical aspects of ^(68)Ga-SSAs imaging,including diagnostic efficacy,recurrence detection and follow-up,patient selection for PRRT,and pitfalls in image interpretation.Besides,we will also briefly discuss the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography,special imaging strategy in regard to insulinoma,and the status of radiolabeled somatostatin receptor antagonist.In the second part,we aim to review the current evidence of PRRT in pancreatic neuroendocrine tumor,focusing on efficacy and safety in particular.We will also introduce the recent development of PRRT,including PRRT in high-grade neuroendocrine neoplasms,retreatment PRRT,upfront PRRT,PRRT in the setting of neoadjuvant therapy and conversion therapy,combination therapies with PRRT,PRRT withαradionuclides,and PRRT with antagonists.

Targeted deep sequencing reveals the genetic heterogeneity in well-differentiated pancreatic neuroendocrine tumors with liver metastasis

Background:Pancreatic neuroendocrine tumor is a rare and heterogeneous entity,and approximately half of the patients harbored liver metastasis when initially diagnosed,whose prognosis is dismal.High-throughput sequencing has largely uncovered the genomic features of pancreatic neuroendocrine tumor,but the genetic alterations in the metastatic cases remain relatively unclear,which we aimed to study.Methods:Pathologically confirmed well-differentiated pancreatic neuroendocrine tumor samples resected in our hospital from 2000 to 2019 were collected.We performed deep sequencing on the exome of 341 tumor-related genes,and compared the differences of genetic alterations between the metastatic and the non-metastatic cases,as well as between the primary and the paired liver metastatic tumors.Results:Sequencing data of 79 samples from 29 pancreatic neuroendocrine tumor patients were included into analysis.A total of 2,471 somatic variants were identified,75.5%of which were considered as low-abundance.NOTCH1 was the most frequently mutated gene,altered in 26(53.1%)pancreatic neuroendocrine tumor samples from 18(62.1%)patients.Compared with the non-metastatic pancreatic neuroendocrine tumors,the metastatic cases were discovered with more single nucleotide variants and copy number variations,indicating the increased genomic instability.In addition,among the paired metastatic cases,the primary and the metastatic lesions shared limited mutated genes.Conclusions:Through the targeted deep sequencing,we identified the intratumor,intraindividual,and interindividual heterogeneity in the pancreatic neuroendocrine tumor patients,particularly in the metastatic cases,bringing potential challenges for the current biopsy strategies in guiding clinical treatments.

Analysis of risk factors affecting the prognosis of pancreatic neuroendocrine tumors

Background Pancreatic neuroendocrine tumors （pNETs） are a type of tumors with the characteristics of easy metastasis and recurrence.Till date,the risk factors affecting the prognosis are still in the debate.In this study,several risk factors will be discussed combined with our cases and experience.Methods Thirty-three patients diagnosed as pNETs were enrolled and the clinical features,blood tests,pathological features,surgical treatment,and follow-up data of these patients were collected and analyzed.Results In this study,operation time of G3 cases was longer than G1/G2 cases （P=0.017）.The elevated level of tumor markers such as AFP,CEA,Ca125,and Ca19-9 may predict easier metastasis,earlier recurrence,and poor prognosis （P=0.007）.The presence of cancer embolus and nerve invasion increases along with the TNM stage （P=0.037 and P=0.040）,and the incidence of positive surgical margin increased （P=0.007）.When the presence of nerve invasion occurs,the chance of cancer embolus and lymph node metastasis also increases （P=0.016 and P=0.026）.Conclusions pNETs were tumors with the features of easy recurrence and metastasis and many risk factors could affect its prognosis such as the elevated levels of tumor markers and the presence of nerve invasion,except some recognized risk factors.If one or more of these factors existed,postoperative treatments may be needed to improve prognosis.

The effect of using long-acting octreotide as adjuvant therapy for patients with grade 2 pancreatic neuroendocrine tumors after radical resection

Objective:To investigate the effect of long-acting octreotide as adjuvant therapy in the prevention of tumor recurrence in patients with grade 2 pancreatic neuroendocrine tumors(pNETs)after radical resection.Methods:The postoperative follow-up data of 130 patients with resectable G2 pNET treated in the Changhai Hospital from 2008 to 2018 were retrospectively analyzed:59 patients received long-acting octreotide as adjuvant therapy for 6 to 12 months(Oct group)and 71 patients received active follow-up(control group),both of which began after the radical resection,with the primary observation endpoint of disease-free survival(DFS)and the secondary study endpoint of overall survival.Results:The median age of the patients in the Oct group and control group was 52 and 54 years,respectively.There were 28 male cases(47.5%)and 33 male cases(46.5%)in the 2 groups.The median maximum tumor diameter was 3.5 and 3.0 cm,respectively;lymph node metastasis was positive in 13 cases(22.0%)and 9 cases(12.7%);there was peripancreatic nerve invasion in 11 cases(18.6%)and 6 cases(8.5%).Survival analysis revealed that there were significant differences in 2-year DFS%(98.3%vs 88.7%,P=.0371)and 3-year DFS%(96.6%vs 85.9%,P=.0498)between the Oct group and control group.Long-acting octreotide treatment was found to reduce the risk of 3-year recurrence of G2 pNET after radical resection(HR=0.2,P=.044)with the application of inverse-probability-of-treatment weighted to balance the limited data bias.Conclusion:Using long-acting octreotide as adjuvant therapy for G2 pNET patients after radical surgery may improve the rate of 3y-DFS,but the benefit needs to be confirmed in a well-designed random control clinical trial.

Concomitant pancreatic neuroendocrine tumors in hereditary tumor syndromes: who, when and how to operate?

Pancreatic neuroendocrine tumors(pNETs)might present as part of a complex of hereditary(familial)syndromes caused by germline mutations such as multiple endocrine neoplasia type 1(MEN1),von Hippel-Lindau syndrome(VHL),tuberous sclerosis,and neurofibromatosis syndromes.Hereditary pNETs are frequently misdiagnosed because their presentation may mimic other more common diseases,resulting in diagnostic delays.Although non-operative(conservative)management could be advocated in select cases in most patients,hereby avoiding surgery without loss of oncological safety,some cases still need operative intervention before malignancy develops.The objective of this review is to address the most recent literature and the evidence it provides for the indications,timing and options of operative treatment for concomitant pNETs in hereditary tumor syndromes.Complete sequencing of the whole gene is recommended for suspected hereditary pNETs.Proven functional pNETs with hereditary tumor syndromes is a good indication for surgical treatment.Conservative management for MEN1 patients with a non-functional pNET of 2cm or smaller is associated with a low risk of malignant transformation and metastasis development.VHL-related pNETs patients with tumor size>1.5cm or a missense mutation or any mutation type in exon 3 may benefit from surgical intervention.The parenchyma-sparing surgical strategy should be preferentially performed whenever possible in all hereditary syndromes.The decision to recommend surgery to prevent malignant transformation and tumor spread,which is based on multidisciplinary expertise and the patient’s preference,should be balanced with operative mortality and morbidity.

Perspective of neo-adjuvant/conversion and adjuvant therapy for pancreatic neuroendocrine tumors

The incidence rate of pancreatic neuroendocrine tumors(panNET)is increasing continuously.Curative resection was the primary treatment choice for panNET.However,till now,there were few studies concerning neo-adjuvant/conversion and adjuvant therapy for panNET.In this article,we reviewed the currently widely used medical treatments for advanced panNET.It seemed that peptide receptor radionuclide therapy(PRRT),chemotherapy(temozolomide-based or streptozocin-based)and sunitinib might be more effective to induce tumor shrinkage in panNET and therefore,these treatments could be tried in panNET when neo-adjuvant/conversion therapy was considered.As for adjuvant therapy,it was of great importance to identify patients with high risks of recurrence after curative surgery and previous studies found that high ki-67 index,large tumor size,lymphatic metastasis and perineural/vascular invasion,and so on,were correlated with early recurrence of panNET.Since PRRT and chemotherapy were more cytotoxic,these two kinds of therapies might be worth trying as adjuvant therapies in patients with high risks of recurrence after curative resection of panNET.Admittedly,no studies discussed in this review directly investigated neo-adjuvant/conversion and adjuvant therapy for panNET.Therefore,more prospective studies were still warranted.

Lymph node involvement in pancreatic neuroendocrine tumors: significance as a predictor of survival

Whether regional lymph node involvement exerts significant effect on the prognosis still remains obscure for pancreatic neuroendocrine tumors.To clarify this association and identify predictors for lymph node involvement,we studied the data of patients aged>18 years with regional lymph node involvement histologically confirmed pancreatic neuroendocrine tumors from 2004 to 2014 in the Surveillance,Epidemiology,and End Results database(http://seer.cancer.gov/about).We evaluated Lymph node involvement as a prognostic factor by Cox regression.We reduced 9 variables of demographic and tumor characteristics to 5 potential predictors using least absolute shrinkage and selection operator(LASSO)regression model.We further constructed a lymph node involvement model by logistic regression.The model was verified by the verification set,and the visual expression of the model was realized by a nomogram.A total of 1545 cases of pancreatic neuroendocrine tumors were included in our study.Lymph node positivity was significantly associated with disease-specific survival(P<0.001).Younger patients(P<0.05),patients with tumors in the pancreatic head(P<0.05),patients at high American Joint Committee on Cancer T stage(P<0.001),and patients of an undifferentiated status(P<0.05)showed a significantly higher possibility of developing lymph node involvement.The reliability of this model was verified by cross-validation between the training and testing set,and we obtained good discrimination and calibration power.This model also showed great performance in C-index and area under receiver operating characteristic curve.Lymph node positivity was an important negative prognostic predictor for pancreatic neuroendocrine tumor.We developed a lymph node involvement model based on the predictors including age,marital status,primary site,T status,and tumor grade.

Values of spleen-preserving distal pancreatectomy in well-differentiated non-functioning pancreatic neuroendocrine tumors:a comparative study

Background The feasibility of spleen-preserving distal pancreatectomy(SPDP)to treat well-differentiated non-functioning pancreatic neuroendocrine tumors(NF-pNETs)located at the body and/or tail of the pancreas remains controversial.Distal pancreatectomy with splenectomy(DPS)has been widely applied in the treatment of NF-pNETs;however,it may increase the post-operative morbidities.This study aimed to evaluate whether SPDP is inferior to DPS in post-operative outcomes and survivals when being used to treat patients with NF-pNETs in our institute.Methods Clinicopathological features of patients with NF-pNETs who underwent curative SPDP or DPS at the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between January 2010 and January 2022 were collected.Short-term outcomes and 5-year survivals were compared between patients undergoing SPDP and those undergoing DPS.Results Sixty-three patients(SPDP,27;DPS,36)with well-differentiated NF-pNETs were enrolled.All patients had grade 1/2 tumors.After identifying patients with T1–T2 NF-pNETs(SPDP,27;DPS,15),there was no disparity between the SPDP and DPS groups except for tumor size(median,1.4 vs 2.6 cm,P=0.001).There were no differences in operation time(median,250 vs 295 min,P=0.478),intraoperative blood loss(median,50 vs 100 mL,P=0.145),post-operative major complications(3.7%vs 13.3%,P=0.287),clinically relevant post-operative pancreatic fistula(22.2%vs 6.7%,P=0.390),or post-operative hospital stays(median,9 vs 9 days,P=0.750)between the SPDP and DPS groups.Kaplan–Meier curve showed no significant differences in the 5-year overall survival rate(100%vs 100%,log-rank P>0.999)or recurrence-free survival(100%vs 100%,log-rank P>0.999)between patients with T1–T2 NF-pNETs undergoing SPDP and those undergoing DPS.Conclusions In patients with T1–T2 well-differentiated NF-pNETs,SPDP could achieve comparable post-operative outcomes and prognosis compared with DPS.