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.

Primary hyperparathyroidism-induced acute pancreatitis in pregnancy:A systematic review with a diagnostic-treatment algorithm

BACKGROUND Primary hyperparathyroidism(PHPT)-induced acute pancreatitis(AP)during pregnancy has rarely been described.Due to this rarity,there are no diagnostic or treatment algorithms for pregnant patients.AIM To determine appropriate diagnostic methods,therapeutic options,and factors related to maternal and fetal outcomes for PHPT-induced AP in pregnancy.METHODS A literature search of articles in English,Japanese,German,Spanish,and Italian was performed using PubMed(1946-2023),PubMed Central(1900-2023),and Google Scholar.The Preferred Reporting Items for Systematic reviews and Meta-Analyses(PRISMA)protocol was followed.The search terms included“pancreatite acuta,”“iperparatiroidismo primario,”“gravidanza,”“travaglio,”“puerperio,”“postpartum,”“akute pankreatitis,”“primärer hyperparathyreoidismus,”“Schwangerschaft,”“Wehen,”“Wochenbett,”“pancreatitis aguda,”“hiperparatiroidismo primario,”“embarazo,”“parto,”“puerperio,”“posparto,”“acute pancreatitis,”“primary hyperparathyroidism,”“pregnancy,”“labor,”“puerperium,”and“postpartum.”Additional studies were identified by reviewing the reference lists of retrieved studies.Demographic,imaging,surgical,obstetric,and outcome data were obtained.RESULTS Fifty-four cases were collected from the 51 studies.The median maternal age was 29 years.PHPT-induced AP starts at the 20th gestational week;higher gestational weeks were seen in mothers who died(mean gestational week 28).Median values of amylase(1399,Q1-Q3=519-2072),lipase(2072,Q1-Q3=893-2804),serum calcium(3.5,Q1-Q3=3.1-3.9),and parathormone(PTH)(384,Q1-Q3=123-910)were reported.In 46 cases,adenoma was the cause of PHPT,followed by 2 cases of carcinoma and 1 case of hyperplasia.In the remaining 5 cases,the diagnosis was not reported.Neck ultrasound was positive in 34 cases,whereas sestamibi was performed in 3 cases,and neck computed tomography or magnetic resonance imaging was performed in 9 cases(the enlarged parathyroid gland was not localized in 3 cases).Surgery was the preferred treatment during pregnancy in 33 cases(median week of gestation 25,Q1-Q3=20-30)and postpartum in 12 cases.The timing was not reported in the remaining 9 cases,or surgery was not performed.AP was managed surgically in 11 cases and conservatively in 43(79.6%)cases.Maternal and fetal mortality was 9.3%(5 cases).Surgery was more common in deceased mothers(60.0%vs 16.3%;P=0.052),and PTH values tended to be higher in this group(910 pg/mL vs 302 pg/mL;P=0.059).Maternal mortality was higher with higher serum lipase levels and earlier delivery week.Higher calcium(4.1 mmol/L vs 3.3 mmol/L;P=0.009)and PTH(1914 pg/mL vs 302 pg/mL;P=0.003)values increased fetal/child mortality,as well as abortions(40.0%vs 0.0%;P=0.007)and complex deliveries(60.0%vs 8.2%;P=0.01).CONCLUSION If serum calcium is not tested during admission,definitive diagnosis of PHPT-induced AP in pregnancy is delayed,while early diagnosis and immediate intervention lead to excellent maternal and fetal outcomes.

Key challenges of post-liver transplant weight management

Liver transplantation serves as a life-saving intervention for patients with endstage liver disease,yet long-term survival remains a challenge.Post-liver transplant obesity seems to have a significant contribution to this challenge and it emerges as a significant risk factor for graft steatosis,metabolic syndrome and denovo malignancy development.This review synthesizes current literature on prevalence,risk factors and management strategies for post-liver transplant obesity,emphasizing its impact on graft and patient survival.Literature review consultation was conducted in Medline/PubMed,SciELO and EMBASE,with the combination of the following keywords:Weight management,liver transplantation,immunosuppressive therapy,lifestyle interventions,bariatric surgery.Immunosuppressive therapy has a significant influence on long-term survival of liver transplant patients,yet it seems to have lesser effect on post-transplant obesity development than previously thought.However,it significantly contributes to the development of other components of metabolic syndrome.Key predisposing factors for post-transplant obesity development encompass elevated recipient and donor body mass index,a history of alcoholic liver disease,hepatocellular carcinoma,male gender,the absence of cellular rejection and the marital status of the recipient.Tailored immunosuppressive regimens,pharmacotherapy,lifestyle interventions and bariatric surgery represent key components in mitigating post-transplant obesity and improving long-term survival and quality of life in this group of patients.Timely identification and intervention thus hold paramount importance.Further research is warranted to refine optimal management strategies and enhance outcomes in this patient population.

Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma:A systematic review and meta-analysis

BACKGROUND Hepatocellular carcinoma(HCC)is among the commonest malignancies associated with significant cancer-related death.The identification of chemopreventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing.Metformin,a first-line agent used in the treatment of type 2 diabetes mellitus(T2DM),has been associated with inhibition of HCC growth.AIM To determine whether metformin can prevent adverse events(i.e.,death,tumor progression,and recurrence)after any HCC treatment in T2DM patients.METHODS A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy.A search of the PubMed and Cochrane Central Register of Controlled Trials Databases was conducted.RESULTS A total of 13 studies(n=14886 patients)were included in this review.With regard to the risk of death,a decreased risk was reported in cases receiving metformin,although this decrease was not statistically significant[odds ratio(OR)=0.89,P=0.42].When only patients treated with curative strategies were considered,a more marked correlation between metformin and favorable cases was reported(OR=0.70,P=0.068).When analyzing palliative treatment,there was no statistical significance in terms of the correlation between metformin and favorable cases(OR=0.74,P=0.66).As for the risks of progressive disease and recurrence,no obvious correlation between metformin use and reduced risk was reported.When sub-analyses were performed for patients from different regions,the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin(OR=0.69,P=0.17),but the same was not seen in patients from Western countries(OR=1.19,P=0.31).CONCLUSION Metformin failed to show a marked impact in preventing adverse effects after HCC treatment.A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death,especially in patients from Eastern regions.Great heterogeneity was reported among the different studies.Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.

Interventional treatment options for management of delayed arterial hemorrhage after major hepato-pancreatic-biliary surgery

Hilar cholangiocarcinoma is a biliary malignancy arising from the perihilar biliary tree,which is associated with poor oncological outcomes due to its aggressive biology,chemo-resistance and insidious onset[1].As stated by Di Martino et al.,the standard of care is radical resection,and during the last decades,there have been great efforts to improve survival of potentially resectable hilar cholangiocarcinoma,with surgery being the treatment associated with longer survival[2].However,radical resection still represents a challenging operation with high risk of intraoperative and postoperative complications.

Hypothermic oxygenated perfusion for a steatotic liver graft

To the Editor:Donor steatosis represents a well-known risk factor for primary non-function,early allograft dysfunction,and biliary complications after liver transplantation(LT)[1,2].Recently,machine perfusion(MP)technology has been implemented in the clinical practice,with the primary intent to assess the graft quality and to optimize the organ selection process[3].A limited number of articles has been published specifically investigated the role of MP in steatotic livers[4–10],with few of them looking at the role of hypothermic MP.

Platelet-to-lymphocyte ratio in the setting of liver transplantation for hepatocellular cancer: A systematic review and meta-analysis

AIM To perform a systematic review and meta-analysis on platelet-to-lymphocyte ratio(PLR) as a risk factor for post-transplant hepatocellular cancer(HCC) recurrence. METHODS A systematic literature search was performed using PubM ed. Participants of any age and sex, who underwent liver transplantation for HCC were considered following these criteria:(1) studies comparing pre-transplant low vs high PLR values;(2) studies reporting post-transplant recurrence rates; and(3) if more than one study was reported by the same institute, only the most recent was included. The primary outcome measure was set for HCC recurrence after transplantation. RESULTS A total of 5 articles, published between 2014 and 2017, fulfilled the selection criteria. As for the quality of the reported studies, all the investigated articles presented an overall high quality. A total of 899 cases were investigated: 718 cases(80.0%) were males. Three studies coming from European countries and one from Japan presented HCV as the main cause of cirrhosis. On the opposite, one Chinese study presented a greater incidence of HBV-related cirrhotic cases. In all the studies apart one, the PLR cut-off value of 150 was reported. At meta-analysis, high PLR value was associated with a significant increase in recurrence after transplantation(OR = 3.33; 95%CI: 1.78-6.25; P < 0.001). A moderate heterogeneity was observed among the identified studies according to the Higgins I^2 statistic value.CONCLUSION Pre-transplant high PLR values are connected with an increased risk of post-operative recurrence of hepatocellular cancer. More studies are needed for better clarify the biological mechanisms of this results.

Selection tool alpha-fetoprotein for patients waiting for liver transplantation: How to easily manage a fractal algorithm

Alpha-fetoprotein(AFP) behavior in patients with hepatocellular carcinoma(HCC) waiting for liver transplant(LT) represents a perfect biological example of a fractal model in which its progressive modification and possible future prediction of its values are very hard to capture. As a consequence, AFP represents a useful but poorly manageable tool to increase the ability to better select HCC patients waiting for LT. Trying to find a "filrouge" in the recent literature, no definitive answers can be done to several open questions:(1) the best AFP value to adopt;(2) the best cut-off measurement; and(3) the best way to comfortably capture the effective, time-related, fluctuations of this biological marker. More, structured and prospective, studies using serial determination of AFP values within and without the context of locoregional therapies are needed in order to find the "ideal"(static and dynamic) cut-off values allowing to respond to all the still open questions in this field of transplant oncology.

From portal to splanchnic venous thrombosis:What surgeons should bear in mind

The present study aims to review the evolution of surgical management of portal(PVT) and splanch-nic venous thrombosis(SVT) in the context of liver transplantation over the last 5 decades. PVT is more commonly managed by endovenous thrombectomy, while SVT requires more complex technical expedients. Several surgical techniques have been proposed, such as extensive eversion thrombectomy, anastomosis to collateral veins, reno-portal anastomosis, cavo-portal hemi-transposition, portal arterialization and combined liver-intestinal transplantation. In order to achieve satisfactory outcomes, careful planning of the surgical strategy is mandatory. The excellent results that are ob-tained nowadays confirm that, even extended, splanch-nic thrombosis is no longer an absolute contraindication for liver transplantation. Patients with advanced portal thrombosis may preferentially be referred to specialized centres, in which complex vascular approaches and even multivisceral transplantation are performed.

Hepatocellular carcinoma recurrence after acute liver allograft rejection treatment: A multicenter European experience

Background:During the last decades,several risk factors for the recurrence of hepatocellular carcinoma(HCC)after liver transplantation(LT)have been investigated.However,the impact of two important drivers of oncogenesis,namely the immunosuppression and the treatment of acute cellular rejection(ACR)have been marginally addressed.This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population.Methods:Seven hundred and eighty-one adult patients transplanted between February 1,1985 and June 30,2016 were retrospectively analyzed.After propensity score match,116 patients treated for ACR using steroid boluses were compared with 115 patients who did not present any ACR or a histologic but clinical irrelevant ACR.Results:Steroid boluses treated patients had a 18-fold higher overall incidence of HCC recurrence than those non-treated patients(16.4%vs.0.9%;P<0.0001).At multivariate Cox regression analysis,steroid boluses used to treat ACR were an independent risk factor for HCC recurrence(HR=14.2;95%CI:1.8–110.4;P=0.010).Conclusions:The decision to treat ACR as well as to reinforce immunosuppression load should be cautiously taken in view of the presented results.Prospective studies are needed to further elucidate the clinical impact of immunosuppression on HCC recurrence after transplantation.

Prognostic role of artificial intelligence among patients with hepatocellular cancer:A systematic review

BACKGROUND Prediction of survival after the treatment of hepatocellular carcinoma(HCC)has been widely investigated,yet remains inadequate.The application of artificial intelligence(AI)is emerging as a valid adjunct to traditional statistics due to the ability to process vast amounts of data and find hidden interconnections between variables.AI and deep learning are increasingly employed in several topics of liver cancer research,including diagnosis,pathology,and prognosis.AIM To assess the role of AI in the prediction of survival following HCC treatment.METHODS A web-based literature search was performed according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis guidelines using the keywords“artificial intelligence”,“deep learning”and“hepatocellular carcinoma”(and synonyms).The specific research question was formulated following the patient(patients with HCC),intervention(evaluation of HCC treatment using AI),comparison(evaluation without using AI),and outcome(patient death and/or tumor recurrence)structure.English language articles were retrieved,screened,and reviewed by the authors.The quality of the papers was assessed using the Risk of Bias In Non-randomized Studies of Interventions tool.Data were extracted and collected in a database.RESULTS Among the 598 articles screened,nine papers met the inclusion criteria,six of which had low-risk rates of bias.Eight articles were published in the last decade;all came from eastern countries.Patient sample size was extremely heterogenous(n=11-22926).AI methodologies employed included artificial neural networks(ANN)in six studies,as well as support vector machine,artificial plant optimization,and peritumoral radiomics in the remaining three studies.All the studies testing the role of ANN compared the performance of ANN with traditional statistics.Training cohorts were used to train the neural networks that were then applied to validation cohorts.In all cases,the AI models demonstrated superior predictive performance compared with traditional statistics with significantly improved areas under the curve.CONCLUSION AI applied to survival prediction after HCC treatment provided enhanced accuracy compared with conventional linear systems of analysis.Improved transferability and reproducibility will facilitate the widespread use of AI methodologies.

Complex hepatic outflow reconstruction in domino liver transplantation

Domino liver transplantation has been accepted as a safe procedure to further expand the organ donor pool. The most important technical challenge of the procedure resides in restoring a proper hepatic venous allograft outflow in the familial amyloidotic polyneuropathy-liver recipient. To overcome this issue, combined techniques were used to perform an innovative outflow reconstruction. A domino liver transplantation was successfully performed with reconstruction of complex venous outflow. The inferior vena cava sparing hepatectomy technique in the familial amyloidotic polyneuropathy-donor was used to cut the hepatic vein to the liver parenchyma. To overcome this issue the venous outflow tract was reconstructed using a longitudinally opened iliac vein graft from a post-mortem donor to create a new outflow tract using a diamond patch between the right and middle/left hepatic veins.

BCLC staging system and liver transplantation:From a stage to a therapeutic hierarchy

The Barcelona Clinic Liver Cancer(BCLC)system was proposed in 1999 with the intent to improve a therapeutic algorithm for the management of patients with hepatocellular carcinoma(HCC)[1].Both the European and the American Guidelines on the Treatment of HCC have endorsed the BCLC as the standard staging algorithm with prognostic and therapeutic implications[2,3].The BCLC staging system stratifies HCC patients into five stages(0,A,B,C and D).According to the algorithm,liver transplantation(LT)is indicated only in patients in the stages BCLC 0 and A,special situations provided.

Locoregional therapy response in patients with hepatocellular cancer waiting for liver transplantation:Only selection or biological effect?

Locoregional treatments(LRT) represent a broad strategy used for reducing the risk of drop-off and contextually improving the survivals in patients with hepatocellular cancer receiving a liver transplantation(LT). However, it is not sufficiently clear if LRT are only a surrogate of tumor aggressiveness or if they consent a real benefit in terms of tumor stabilization. A recent study by Pommergaard et al reported the results from the European Liver Transplant Registry. Patients receiving LRT before LT had better 5-year survival rates respect to no-LRT cases(69.7% vs 65.8%; P < 0.001). When the number of LRT was tested, one-to-two treatments were connected with improved survivals respect to no treatment [hazard ratio(HR) = 0.85 and 0.71, respectively]. The efficacy of LRT was also reported in the presence of larger tumors(HR = 0.78) and micro-macrovascular invasion(HR = 0.71). The results observed in the present study are partially in discordance with other analyses showing a detrimental effect of LRT. The main problem in the interpretation of these results is connected with the possible initial selection biases present in the studies. The most recent guidelines suggest to perform LRT before the transplant, but the level of evidence is typically low due to the absence of prospectively designed studies.

Donor-to-recipient gender match in liver transplantation: A systematic review and meta-analysis

AIM To perform a systematic review and meta-analysis on donor-to-recipient gender mismatch as a risk factor for post-transplant graft loss. METHODS A systematic literature search was performed using PubM ed, Cochrane Library database and EMBASE. The primary outcome was graft loss after liver transplantation. Odds ratios and 95% confidence intervals were calculated to compare the pooled data between groups with different donor-to-recipient gender matches. Three analyses were done considering(1) gender mismatches(F-M and M-F) vs matches(M-M and F-F);(2) Femaleto-Male mismatch vs other matches; and(3) Male-toFemale mismatch vs other matches.RESULTS A total of 7 articles were analysed. Gender mismatch(M-F and F-M) was associated with a significant increase of graft loss respect to match(M-M and F-F)(OR: 1.30; 95%CI: 1.13-1.50; P < 0.001). When F-M mismatch was specifically investigated, it confirmed its detrimental role in terms of graft survival(OR: 1.83; 95%CI: 1.20-2.80; P = 0.005). M-F mismatch failed to present a significant role(OR: 1.09; 95%CI: 0.73-1.62; P = 0.68).CONCLUSION Gender mismatch is a risk factor for poor graft survival after liver transplantation. Female-to-male mismatch represents the worst combination. More studies are needed with the intent to better clarify the reasons for these results.

New insights in the management of the middle hepatic vein dilemma

When the first series of adult-to-adult living donor liver transplantation(A2A-LDLT)were performed in Hong Kong[1],it was immediately clear that great technical challenges existed,mainly concerning the middle hepatic vein(MHV)tributaries management.

Morphology does not tell us the entire story: biological behavior improves our ability to select patients with hepatocellular carcinoma waiting for liver transplantation

The Milan criteria （solitary lesion 〈5 cm or twothree lesions 〈3 cm）, published in 1996 in relation to the selection of patients harboring hepatocel-lular carcinoma （HCC） in a diseased liver are still dominating the allocation of liver allografts in all international organ allocation organisms, this despite the fact that excellent results have been reported after liver transplantation （LT） done for patients presenting HCC outside these criteria,

Survivals after liver transplantation for hepatocellular carcinoma:Granular data for a better allocation process?

To the Editor:A large international study has been recently published focusing on the combination of morphological aspects and alpha-fetoprotein(AFP)as predictors of survival in patients with hepatocellular cancer(HCC)treated with liver transplantation(LT)[1].As a matter of fact,morphology and biology represent the two sides of the same

Composite hepatocellular and hemangiosarcomatous tumor: The prognosis is determined by the sarcomatous component

Nowadays, mixed liver tumors are more frequently diagnosed due to better imaging, advanced immunohistochemistry (IHC) staining techniques and better knowledge of hepatic tumorigene- sis [1–3] . Such tumors represent a mosaic of components with dis- tinct histogenesis and carcinogenic pathways. As their occurrence in the liver is very rare, their behavior and natural history are difficult to determine, and their management remains empirical. An uncommon case of a composite tumor harboring hepatocellular carcinoma (HCC) and hepatic hemangiosarcoma (HHS) components in a liver transplant (LT) recipient is reported herein.

Development and validation of an artificial intelligence model for predicting post-transplant hepatocellular cancer recurrence

Dear Editor,In recent years,criteria based on the combinationof morphology and biology have been proposed forimproving the selection of hepatocellular cancer(HCC)patients waiting for liver transplantation(LT)[1,2].Since all the proposed models showed suboptimalresults in predicting the risk of postLT recurrence,aprediction model constructed using artificial intelligence(Al)could be an attractive way to surpass this limit[3,4].Therefore,the Time_Radiological-response_Alpha-fetoproteIN_Artificial-Intelligence(TRAIN-AI)modelwas developed,combining morphology and biology tumorvariables.