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.

Challenges and opportunities in the application of artificial intelligence in gastroenterology and hepatology

Artificial intelligence(AI)is an umbrella term used to describe a cluster of interrelated fields.Machine learning(ML)refers to a model that learns from past data to predict future data.Medicine and particularly gastroenterology and hepatology,are data-rich fields with extensive data repositories,and therefore fruitful ground for AI/ML-based software applications.In this study,we comprehensively review the current applications of AI/ML-based models in these fields and the opportunities that arise from their application.Specifically,we refer to the applications of AI/ML-based models in prevention,diagnosis,management,and prognosis of gastrointestinal bleeding,inflammatory bowel diseases,gastrointestinal premalignant and malignant lesions,other nonmalignant gastrointestinal lesions and diseases,hepatitis B and C infection,chronic liver diseases,hepatocellular carcinoma,cholangiocarcinoma,and primary sclerosing cholangitis.At the same time,we identify the major challenges that restrain the widespread use of these models in healthcare in an effort to explore ways to overcome them.Notably,we elaborate on the concerns regarding intrinsic biases,data protection,cybersecurity,intellectual property,liability,ethical challenges,and transparency.Even at a slower pace than anticipated,AI is infiltrating the healthcare industry.AI in healthcare will become a reality,and every physician will have to engage with it by necessity.

Liver transplantation:Fifty years of experience

Since 1963,when the first human liver transplantation(LT)was performed by Thomas Starzl,the world has witnessed 50 years of development in surgical techniques,immunosuppression,organ allocation,donor selection,and the indications and contraindications for LT.This has led to the mainstream,wellestablished procedure that has saved innumerable lives worldwide.Today,there are hundreds of liver transplant centres in over 80 countries.This review aims to describe the main aspects of LT regarding the progressive changes that have occurred over the years.We herein review historical aspects since the first experimental studies and the first attempts at human transplantation.We also provide an overview of immunosuppressive agents and their potential side effects,the evolution of the indications and contraindications of LT,the evolution of survival according to different time periods,and the evolution of methods of organ allocation.

Gastrointestinal complications after kidney transplantation

Gastrointestinal complications are common after renal transplantation,and they have a wide clinical spectrum,varying from diarrhoea to post-transplant inflammatory bowel disease(IBD).Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for IBD in kidney transplant re-cipients despite immunosuppression.Differentiating the various forms of post-transplant colitis is challenging,since most have similar clinical and histological features.Drug-related colitis are the most frequently encountered colitis after kidney transplantation,particularly those related to the chronic use of mycophenolate mofetil,while de novo IBDs are quite rare.This review will explore colitis after kidney transplantation,with a particular focus on different clinical and histological features,attempting to clearly identify the right treatment,thereby improving the final outcome of patients.

Kidney transplantation from donors with hepatitis C infection

The increasing demand for organ donors to supply the increasing number of patients on kidney waiting lists has led to most transplant centers developing protocols that allow safe utilization from donors with special clini cal situations which previously were regarded as contra indications.Deceased donors with previous hepatitis C infection may represent a safe resource to expand the donor pool.When allocated to serology-matched recipi ents,kidney transplantation from donors with hepatitis C may result in an excellent short-term outcome and a significant reduction of time on the waiting list.Specia care must be dedicated to the pre-transplant evaluation of potential candidates,particularly with regard to live functionality and evidence of liver histological damage such as cirrhosis,that could be a contraindication to transplantation.Pre-transplant antiviral therapy could be useful to reduce the viral load and to improve the long-term results,which may be affected by the progression of liver disease in the recipients.An accurate selection of both donor and recipient is mandatory to achieve a satisfactory long-term outcome.

Psychopathological aspects of kidney transplantation: Efficacy of a multidisciplinary team

Renal transplantation is a well established treatment for end-stage renal disease, allowing most patients to return to a satisfactory quality of life. Studies have identified many problems that may affect adaptation to the transplanted condition and postoperative compliance. The psychological implications of transplantation have important consequences even on strictly physical aspects. Organ transplantation is very challenging for the patient and acts as an intense stressor stimulus to which the patient reacts with neurotransmitter and endocrine-metabolic changes. Transplantation can result in a psychosomatic crisis that requires the patient to mobilize all bio-psychosocial resources during the process of adaptation to the new foreign organ which may result in an alteration in self-representation and identity, with possible psychopathologic repercussions. These reactions are feasible in mental disorders, e.g., post-traumatic stress disorder, adjustment disorder, and psychosomatic disorders. In organ transplantation, the fruitful collaboration between professionals with diverse scientific expertise, calls for both a guarantee for mental health and greater effectiveness in challenging treatments for a viable association between patients, family members and doctors. Integrated and multidisciplinary care should include uniform criteria and procedures for standard assessments, for patient autonomy, adherence to therapy, new coping strategies and the adoption of more appropriate lifestyles.

Octogenarian liver grafts:Is their use for transplant currently justified?

AIM To analyse the impact of octogenarian donors in liver transplantation.METHODS We present a retrospective single-center study, performed between November 1996 and March 2015, that comprises a sample of 153 liver transplants. Recipients were divided into two groups according to liver donor age: recipients of donors ≤ 65 years(group A; n = 102), and recipients of donors ≥ 80 years(group B; n = 51). A comparative analysis between the groups was performed. Quantitative variables were expressed as mean values and SD, and qualitative variables as percentages. Differences in properties between qualitative variables were assessed by χ2 test. Comparison of quantitative variables was made by t-test. Graft and patient survivals were estimated using the Kaplan-Meier method.RESULTS One, 3 and 5-year overall patient survival was 87.3%, 84% and 75.2%, respectively, in recipients of younger grafts vs 88.2%, 84.1% and 66.4%, respectively, in recipients of octogenarian grafts(P = 0.748). One, 3 and 5-year overall graft survival was 84.3%, 83.1% and 74.2%, respectively, in recipients of younger grafts vs 84.3%, 79.4% and 64.2%, respectively, in recipients of octogenarian grafts(P = 0.524). After excluding the patients with hepatitis C virus cirrhosis(16 in group A and 10 in group B), the 1, 3 and 5-year patient(P = 0.657) and graft(P = 0.419) survivals were practically the same in both groups. Multivariate Cox regression analysis demonstrated that overall patient survival was adversely affected by cerebrovascular donor death, hepatocarcinoma, and recipient preoperative bilirubin, and overall graft survival was adversely influenced by cerebrovascular donor death, and recipient preoperative bilirubin.CONCLUSION The standard criteria for utilization of octogenarian liver grafts are: normal gross appearance and consistency, normal or almost normal liver tests, hemodynamic stability with use of < 10 μg/kg per minute of vasopressors before procurement, intensive care unit stay < 3 d, CIT < 9 h, absence of atherosclerosis in the hepatic and gastroduodenal arteries, and no relevant histological alterations in the pre-transplant biopsy, such as fibrosis, hepatitis, cholestasis or macrosteatosis > 30%.

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.

Obesity and bariatric surgery in kidney transplantation:A clinical review

Obesity is increasing worldwide,and this has major implications in the setting of kidney transplantation.Patients with obesity may have limited access to transplantation and increased posttransplant morbidity and mortality.Most transplant centers incorporate interventions aiming to target obesity in kidney transplant candidates,including dietary education and lifestyle modifications.For those failing nutritional restriction and medical therapy,the use of bariatric surgery may increase the transplant candidacy of patients with obesity and endstage renal disease(ESRD)and may potentially improve the immediate and late outcomes.Bariatric surgery in ESRD patients is associated with weight loss ranging from 29.8% to 72.8% excess weight loss,with reported mortality and morbidity rates of 2% and 7%,respectively.The most commonly performed bariatric surgical procedures in patients with ESRD and in transplant patients are laparoscopic sleeve gastrectomy(LSG)and laparoscopic Roux-en-Y gastric bypass.However,the correct timing of bariatric surgery and the ideal type of surgery have yet to be determined,although pretransplant LSG seems to be associated with an acceptable risk-benefit profile.We review the impact of obesity on kidney transplant candidates and recipients and in potential living kidney donors,exploring the potential impact of bariatric surgery in addressing obesity in these populations,thereby potentially improving posttransplant outcomes.

Psychological perspective of medication adherence in transplantation

AIM To identify the risk factors and the post-transplant psychological symptoms that affect adherence to therapy in a population of kidney transplant recipients. METHODS The study examined the psychological variables likely responsible for the non-adherent behavior using a psychological-psychiatric assessment, evaluation of the perception of patients' health status, and an interview regarding the anti-rejection drug therapy assumption. The study included 74 kidney transplant recipients. RESULTS Individuals with a higher level of education and more years since transplantation showed better mental balance. Regarding gender, women appeared to be less adherent to therapy. Further, the years since transplantation adversely affected the proper pharmacological assumption. Adherence to therapy did not significantly change with the mental health index. CONCLUSION The biopsychosocial illness model provides a conceptualframe of reference in which biological, psychological, and social aspects take on the same importance in the adherence to treatment protocols. For effective management, it is necessary to understand the patients' personal experiences, their assumptions about the disease, health status perception, and mood, and to identify any "barriers" that could cause them to become noncompliant.

Rapamycin increased development of CD4^+ CD25~h ighFoxp3^+ T cells of peripheral blood in liver transplant recipients

Objective To investigate the possible influence of immunosuppressive therapy,including sirolimus ( SRL) and calcineurin inhibitors ( CNI,tacrolimus) ,on level of Treg in liver allo - graft recipients. Methods Forty - seven liver transplant recipients with stable liver function were assessed for at least 2 years,and divided into

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.

Downstaging disease in patients with hepatocellular carcinoma outside up-to-seven criteria: Strategies using degradable starch microspheres transcatheter arterial chemo-embolization

AIM: To evaluate the downstaging rates in hepatitis C virus-patients with hepatocellular carcinoma(HCC), treated with degradable starch microspheres transcatheter arterial chemoembolization(DSM-TACE), to reach new-Milan-criteria(nM C) for transplantation. METHODS: This study was approved by the Ethics Committee of our institution. From September 2013 to March 2014 eight patients(5 men and 3 women) with liver cirrhosis and multinodular HCC, that did not meet n MC at baseline, were enrolled in this study. Patients who received any other type of treatment such as termal ablation or percutaneous ethanol injection were excluded. DSM-TACE was performed in all patients using Embo Cept? S and doxorubicin. Baseline and follow-up computed tomography or magnetic resonance imaging was assessed measuring the longest enhancing axial dimension of each tumor according to the modified Response Evaluation Criteria In Solid Tumors measure-ments, and medical records were reviewed.RESULTS: DSM-TACE was successfully performed in all patients without major complication. We treated 35 lesions(mean 4.3 per patient). Six of eight patients(75%) had their HCC downstaged to meet nM C. Every patient whose disease was downstaged eventually underwent transplantation. The six patients who received transplant were still living at the time of this writing, without recurrence of HCC. Baseline age(P = 0.25), Model for End-stage Liver Disease score(P = 0. 77), and α-fetoprotein level(P = 1.00) were similar between patients with and without downstaged HCC. CONCLUSION: DSM-TACE represents a safely and effective treatment option with similar safety and efficacy of conventional chemoembolization and could be successfully performed also for downstaging disease in patients without n MC, allowing them to reach liver transplantation.

A case of successful management with splenectomy of intractable ascites due to congenital dyserythropoietic anemia type II-induced cirrhosis

The congenital dyserythropoietic anemias comprise agroup of rare hereditary disorders of erythropoiesis,characterized by ineffective erythropoiesis as thepredominant mechanism of anemia and by characteristicmorphological aberrations of the majority of erythroblastsin the bone marrow.Congenital dyserythropoieticanemia type II is the most frequent type.All types ofcongenital dyserythropoietic anemias distinctly share ahigh incidence of iron loading.Iron accumulation occurseven in untransfused patients and can result in heartfailure and liver cirrhosis.We have reported about apatient who presented with liver cirrhosis and intractableascites caused by congenital dyserythropoietic anemiatype Ⅱ.Her clinical course was further complicatedby the development of autoimmune hemolyticanemia.Splenectomy was eventually performed whichachieved complete resolution of ascites,increase ofhemoglobin concentration and abrogation of transfusionrequirements.

Elevation of vascular endothelial growth factor production and its effect on revascularization and function of graft islets in diabetic rats

AIM: To determine whether the elevated vascular endothelial growth factor (VEGF) expression produced by the transfected vascular endothelial cells (VECs) could stimulate angiogenesis of the graft islets and exert its effect on the graft function. METHODS: Thirty diabetic recipient rats were divided into three groups (n = 10 per group). In the control group,300 IEQ islets were transplanted in each rat under the capsule of the right kidney,which were considered as marginal grafts. In the VEC group,VEC together with the islets were transplanted in each rat. In the VEGF group,VEC transfected by pIRES2-EGFP/ VEGF165 plasmid and the islets were transplanted in each rat. Blood glucose and insulin levels were evaluated every other day after operation. Intravenous glucose tolerance test (IVGTT) was performed 10 d after the transplantation. Hematoxylin and eosin (HE) staining was used to evaluate the histological features of the graft islets. Immunohistochemical staining was used to detect insulin-6,VEGF and CD34 (MVD) expression in the graft islets. RESULTS: Blood glucose and insulin levels in the VEGF group restored to normal 3 d after transplantation. In contrast,diabetic rats receiving the same islets with or without normal VECs displayed moderate hyperglycemia and insulin,without a significant difference between these two groups. IVGTT showed that both the amplitude of blood glucose induction and the kinetics of blood glucose in the VEGF group restored to normal after transplantation. H&E and immunohistochemical staining showed the presence of a large amount of graft islets under the capsule of the kidney,which were positively stained with insulin-6 and VEGF antibodies in the VEGF group. In the cell masses,CD34-stained VECs were observed. The similar masses were also seen in the other two groups,but with a fewer positive cells stained with insulin-6 and CD34 antibodies. No VEGF-positive cells appeared in these groups. Microvessel density (MVD) was significantly higher in the VEGF group compared to the other two groups. CONCLUSION: Elevated VEGF production by trans-fected vascular endothelial cells in the site of islet transplantation stimulates angiogenesis of the islet grafts. The accelerated islet revascularization in early stage could improve the outcome of islet transplantation,and enhance the graft survival.

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.

Rare cause of odynophagia: Giant esophageal ulcer

Gastrointestinal complications are a frequent cause of morbidity after transplantation and may affect up to 40% of kidney transplant recipients. Here we report a rare case of idiopathic giant esophageal ulcer in a kidney transplant recipient. A 37-year-old female presented with a one-week history of odynophagia and weight loss. Upon admission, the patient presented cold sores, and a quantitative cytomegalovirus polymerase chain reaction was positive(105 copies/ml). An upper endoscopy demonstrated the presence of a giant ulcer. Serological test and tissue biopsies were unable to demonstrate an infectious origin of the ulcer. Immunosuppression was reduced and everolimus was introduced. An empirical i.v. therapy with acyclovir was started, resulting in a dramatic improvement in symptoms and complete healing of the ulcer. Only two cases of idiopathic giant esophageal ulcer in kidney transplant recipients have been reported in the literature; in both cases, steroid therapy was successful without recurrence of symptoms or endoscopic findings. However, this report suggests that correction of immune imbalance is mandatory to treat such a rare complication.

EVOLUTION OF THE BLOOD INTERFACE USING AN AUTOLOGOUS VENOUS PATCH TO CORRECT AN AORTIC DEFECT IN RATS

In order to investigate the evolution of the venous patch blood inter face after implantation, an experimental model utilizing an autologous venous patch to repair an infrarenal abdominal aortic defect in rats was developed. A small piece of both the jugular vein and the aorta were first excised. After implantation and reestablishment of blood flow, the animals were subsequently sacrificed in groups of 3 at the following intervals: 10 seconds, 1, 10, 30 minutes, 1, 6, 12, 24 hours, 7, 30 and 90 days. All the patches and adjacent aortae were collected and studied using scanning electron microscopy. The results of our present show that: 1) the extensive endothelial lesion of both the autologous vein patch and the adjacent aorta is presented before implantation due to operative manipulation; 2) after blood flow reestablishment, the patch and the adjacent aortic interface are reactive to platelets and other blood cells; 3) the new cellular lining begins to appear from the 7th day after implantation, but it is not complete at 3 months; 4)from the model, the endothelial repair of autologous venous patch and its adjacent aorta is a very slow process.

Psychiatric Variables in <i>Cytomegalovirus</i>or <i>Toxoplasma gondii</i>—Infected Pregnants: Prospects for Cure with a Program of “Counseling about Behavioral Change”

TORCH complex, one of the potential infections that may occur during pregnancy, may contribute also to prenatal pregnant women’s anxiety and depression. The aim of this study was to explore the presence of psychiatric symptoms, in relation with infection of TORCH agents, specifically the Toxoplasma gondii (T. gondii) and Cytomegalovirus (CMV). The study was conducted on 58 pregnant women recruited from the Clinical Virology Unit, A.O.U. Policlinico-Vittorio Emanuele, P.O. “Gaspare Rodolico”, from September 2012 to March 2014. Psychiatric symptoms were evaluated through the Symptom Checklist-90 Revised (SCL-90 R) in pregnant women with CMV or T. gondii infection. Moreover, pregnant women were invited to participate in a program of “Counseling about behavioral change”, an effective psychotherapeutic training for the development of new motivational strategies to the infection acceptance, the greater self-confidence and greater adherence to treatment. The age of the subjects was positively correlated with Depression (r = 0.119, p ? 0.178, p ? 0.231, r = ? 0.320, p ? 0.208, p ? 0.105, p ? 0.236, p < 0.05). Finally, we can notice an improvement of the variables Anxiety and Somatization in the whole sample after the attendance at the counseling psychotherapic program. Our study suggests the presence of anxiety and somatization in pregnant women with infection, expression of a phase of emotional fragility with the concern of transmitting a serious disease in the unborn child. The program “Counseling about behavioral change” allowed us to create an atmosphere of trust and to understand the usefulness of “empathic listening”. Giving correct and accurate information about the disease reassures the patient and prevents the realization of negative thoughts and further concern and discomfort.

Prehospital difficult airway management:old things still work

To the Editor:Airway management is a crucial skill for emergency physician,who's often called to deal with difficult airways and requests for quick,simple and effective responses,as the many factors responsible for difficulties might be enhanced by emergency setting.[1]We now have many rescue devices as the LMA,I-gel,but they do