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.

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.

Limitations and suggestions for type 2 diabetes mellitus and pancreatic neuroendocrine tumors based on meta-analysis

We read with great interest the systematic review and meta-analysis by Cigrovski Berkovic et al published recently,which evaluated the association between type 2 diabetes mellitus(T2DM)and pancreatic neuroendocrine tumors(pNETs).The study identified T2DM as a risk factor for the development of pNETs and linked it to poor tumor-free survival.However,due to the limited number of studies and high heterogeneity,the role of metformin in the diagnosis and prognosis of pNETs remained inconclusive.We believe the study has some limitations regarding literature search,risk of bias assessment,and analysis of heterogeneity and publication bias.Expanding the search to more databases,applying more appropriate bias assessment tools,and using better statistical methods to evaluate heterogeneity and publication bias would strengthen the study’s conclusions.Addressing these concerns could provide more robust evidence for understanding the diagnostic and prognostic impact of T2DM in pNETs.

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.

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: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.

Laparoscopic resection of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors(PNETs)are a rare heterogeneous group of endocrine neoplasms.Surgery remains the best curative option for this type of tumor.Over the past two decades,with the development of laparoscopic pancreatic surgery,an increasingly larger number of PNET resections are being performed by these minimally-invasive techniques.In this review article,the various laparoscopic surgical options for the excision of PNETs are discussed.In addition,a summary of the literature describing the outcome of these treatment modalities is presented.

Non-functioning pancreatic neuroendocrine tumors: Surgery or observation?

Incidentally detected, sporadic, nonfunctional pancreatic neuroendocrine tumors are increasingly diagnosed on imaging studies performed for unrelated purposes. Although their resection is usually recommended, controversy still exists regarding their optimal management, due to their highly variable and difficult to predict biologic behavior. Recently, several studies and guidelines advocated an expectant management approach in small size, low grade, incidentally diagnosed nonfunctional pancreatic neuroendocrine tumors. The aim of this study is to review and summarize the available literature addressing nonfunctional pancreatic neuroendocrine tumors, with an emphasis on surgical management controversies.

Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases

A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography （PET）/computed tomography （CT） demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor （pNET）. According to the latest World Health Organization （WHO, 2013） classification, the tumor was classified as stage IV fimctional G1 pNET. After referral to the multidisciplinary treatment board （MDT）, the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α （IFNα） and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 （1251） seeds implantation therapy, radiofrequency ablation therapy （RFA） or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization （TACE）, RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission （RECIST criteria） with a good quality of life.

Prognostic factors and survival after surgical resection of pancreatic neuroendocrine tumor with validation of established and modified staging systems

Background: Pancreatic neuroendocrine tumors(PNETs) display wide heterogeneity with highly variable prognosis. This study aimed to identify variables related to survival after surgical resection of PNET.Methods: A total of 143 patients were identified from a prospectively maintained database. Patient characteristics were analyzed and prognostic factors for overall survival and progression-free survival were evaluated. The WHO, ENETS and AJCC scoring systems were applied to the cohort, and their ability to predict patient outcomes were compared.Results: Multivariate analysis found that female gender, lymph node metastases and increasing WHO2010 grade to be independently associated with reduced overall survival(P < 0.05). Patients requiring multi-visceral resection or debulking surgery found to be associated with shortest survival. ROC analysis found the ENETS and AJCC scoring systems to be similarly predictive of 5-year overall survival. Modified Ki67 significantly improved its accuracy in predicting 5-year overall survival(AUROC: 0.699 vs 0.605;P < 0.01).Conclusions: Multi-visceral or debulking surgery is associated with poor outcomes. There seems to be no significant difference between enucleation and anatomical segmental resection. Available scoring systems have reasonable accuracy in stratifying disease severity, with no system identified as being superior.Prognostic stratification with modified grading systems needs further validation before applied in clinical practice.

Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors

AIM: To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs).

Genomic landscape of pancreatic neuroendocrine tumors

AIM: To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs).

Using a Nomogram to Preoperatively Predict Distant Metastasis of Pancreatic Neuroendocrine Tumor in Elderly Patients

Objective To establish a nomogram for predicting the distant metastasis risk of pancreatic neuroendocrine tumors(pNETs)in elderly patients.Methods We extracted data of patients with diagnosis of pNETs at age≥65 years old between 1973 and 2015 from the Surveillance,Epidemiology,and End Results(SEER)database.All eligible patients were divided randomly into a training cohort and validation cohort.Uni-and multivariate logistic regression analyses were performed on the training cohort to identify independent factors for distant metastasis.A nomogram was developed based on the independent risk factors using rms packages of R software,and was validated internally by the training cohort and externally by the validation cohort using C-index and calibration curves.Results A total of 411 elderly patients were identified,of which 260 were assigned to training cohort and 151 to validation cohort.Univariate and multivariate logistic regression analyses indicated the tumor site(body/tail of pancreas:odds ratio[OR]=2.282;95%confidence interval[CI]:1.174–4.436,P<0.05),histological grade(poorly differentiated/undifferentiated:OR=2.600,95%CI:1.266–5.339,P<0.05),T stage(T2:OR=8.913,95%CI:1.985–40.010,P<0.05;T3:OR=11.830,95%CI:2.530–55.350,P<0.05;T4:OR=68.650,95%CI:8.020–587.600,P<0.05),and N stage(N1:OR=3.480,95%CI:1.807–6.703,P<0.05)were identified as independent risk factors for distant metastasis of pNETs in elderly.The nomogram exhibited good predicting accuracy,with a C-index of 0.809(95%CI:0.757–0.861)in internal validation and 0.795(95%CI:0.723–0.867)in external validation,respectively.The predicted distant metastasis rates were in satisfactory agreement with the observed values by the calibration curves.Conclusion The nomogram we established showed high discriminative ability and accuracy in evaluation of distant metastasis risk in elderly pNETs patients,and could provide a reference for individualized tumor evaluation and treatment decision in elderly pNETs patients.

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.

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.

Does Prior Cancer Have an Influence on the Survival Outcomes of Patients with Localized Pancreatic Neuroendocrine Tumors?

Objective To investigate the impact of prior non-pancreatic cancer on the survival outcomes of patients with localized pancreatic neuroendocrine tumors(Pan NETs).Methods We reviewed the Surveillance,Epidemiology,and End Results database and selected patients with localized Pan NETs diagnosed between 1973 and 2015.We divided the patients into two groups according to the presence or absence of prior non-pancreatic malignancy.Before and after propensity score matching,we compared the clinicopathological characteristics and studied the overall survival and cancer-specific survival.Results A total of 357(12.9%)of 2778 patients with localized Pan NETs had prior cancer.A total of 1211 cases with only a localized Pan NET and 133 cases with a localized Pan NET and prior cancer had complete data and met the inclusion criteria of the current study.Patients with prior cancer were associated with advanced age(>65 years,57.9%prior cancer vs.31.0%no prior cancer,P<0.001),later year of diagnosis(87.2%vs.80.2%,P=0.049),a higher proportion of poorly differentiated/undifferentiated grade tumors(4.5%vs.1.5%,P=0.025),and a higher proportion of no primary site surgery(19.5%vs.10.4%,P=0.003).Prostate(29.32%),breast(18.05%),other genitourinary and retroperitoneal(16.54%),and gastrointestinal(12.78%)cancers were the most common prior cancer types.Most of the prior cancers(95.49%)were localized and regional,and only 4.51%of the prior cancers were distant.Patients with interval periods between the prior cancer and Pan NET of≤36 months,36-60 months,60-120 months,and>120 months accounted for 33.08%,13.53%,24.06%,and 29.32%of all cases with prior cancers,respectively.Univariate and multivariate Cox proportional hazards analyses were performed.The presence/absence of prior cancers did not impact survival outcomes of patients with localized Pan NETs before and after propensity score matching(PSM).Further subgroups analysis showed that,patients with localized Pan NETs and prior distant cancer had worse cancer-specific survival than patients with prior local/regional cancer or patients without prior cancer(P<0.001).No significant differences in cancerspecific survival were observed in terms of the different sites of the prior cancers and the different interval periods of prior cancers and Pan NETs(P<0.05).Conclusions Patients with localized Pan NETs and a history of prior cancer had survival outcomes that were comparable to those of patients with no history of prior cancer.Patients with localized Pan NETs and prior cancer could be candidates for clinical trials if they satisfy all other conditions;aggressive and potentially curative therapies should be offered to these patients.

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.

Consensus on the clinical diagnosis and treatment of grade 3 pancreatic neuroendocrine tumors

The World Health Organization(WHO)2017 classifications for neuroendocrine neoplasms(NENs)subdivided grade 3 pancreatic neuroendocrine neoplasms(pNENs)into G3 well-differentiated pancreatic neuroendocrine tumors(G3 pNETs)and poorly differentiated pancreatic neuroendocrine carcinomas(pNECs),according to the mitotic count,Ki-67 index,and cell differentiation.As a new category,G3 pNETs remain a challenging group of tumors to manage by lacking large randomized trials and consensus to support its clinical practice.Therefore,the Chinese Pancreatic Surgery Association,Chinese Society of Surgery,Chinese Medical Association gathered experts in this field to formulate this consensus for the diagnosis and treatment of G3 pNETs.

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.