Cardiovascular risk after orthotopic liver transplantation, a review of the literature and preliminary results of a prospective study

Improved surgical techniques and greater efficacy of new anti-rejection drugs have significantly improved the survival of patients undergoing orthotopic liver transplantation(OLT). This has led to an increased incidence of metabolic disorders as well as cardiovascular and cerebrovascular diseases as causes of morbidity and mortality in OLT patients. In the last decade, several studies have examined which predisposing factors lead to increased cardiovascular risk(i.e., age, ethnicity, diabetes, NASH, atrial fibrillation, and some echocardiographic parameters) as well as which factors after OLT(i.e., weight gain, metabolic syndrome, immunosuppressive therapy, and renal failure) are linked to increased cardiovascular mortality. However, currently, there are no available data that evaluate the development of atherosclerotic damage after OLT. The awareness of high cardiovascular risk after OLT has not only lead to the definition of new but generally not accepted screening of high risk patients before transplantation, but also to the need for careful patient follow up and treatment to control metabolic and cardiovascular pathologies after transplant. Prospective studies are needed to better define the predisposing factors for recurrence and de novo occurrence of metabolic alterations responsible for cardiovascular damage after OLT. Moreover, such studies will help to identify the timing of disease progression and damage,which in turn may help to prevent morbidity and mortality for cardiovascular diseases. Our preliminary results show early occurrence of atherosclerotic damage, which is already present a few weeks following OLT, suggesting that specific, patient-tailored therapies should be started immediately post OLT.

Hepatocellular carcinoma in nonalcoholic fatty liver: Role of environmental and genetic factors

Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.

Nonalcoholic fatty liver disease and vascular disease:State-of-the-art

Nonalcoholic fatty liver disease(NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis(NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis(increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific lifestyle modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.

A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia

AIM:To compare iron depletion to lifestyle changes alone in patients with severe nonalcoholic fatty liver disease(NAFLD)and hyperferritinemia,a frequent feature associated with more severe liver damage,despite at least 6 mo of lifestyle changes.METHODS:Eligible subjects had to be 18-75 years old who underwent liver biopsy for ultrasonographically detected liver steatosis and hyperferritinemia,ferritin levels≥250 ng/mL,and NAFLD activity score>1.Iron depletion had to be achieved by removing 350 cc of blood every 10-15 d according to baseline hemoglobin values and venesection tolerance,until ferritin<30 ng/mL and/or transferrin saturation(TS)<25%.Thirty-eight patients were randomized 1:1 to phlebotomy(n=21)or lifestyle changes alone(n=17).The main outcome of the study was improvement in liver damage according to the NAFLD activity score at 2 years,secondary outcomes were improvements in liver enzymes[alanine aminotransferases(ALT),aspartate aminotransferase(AST),and gamma-glutamyl-transferases(GGT)].RESULTS:Phlebotomy was associated with normalization of iron parameters without adverse events.In the21 patients compliant to the study protocol,the rate of histological improvement was higher in iron depleted vs control subjects(8/12,67%vs 2/9,22%,P=0.039).There was a better improvement in steatosis grade in iron depleted vs control patients(P=0.02).In patients followed-up at two years(n=35),ALT,AST,and GGT levels were lower in iron-depleted than in control patients(P<0.05).The prevalence of subjects with improvement in histological damage or,in the absence of liver biopsy,ALT decrease≥20%(associated with histological improvement in biopsied patients)was higher in the phlebotomy than in the control arm(P=0.022).The effect of iron depletion on liver damage improvement as assessed by histology or ALT decrease≥20%was independent of baseline AST/ALT ratio and insulin resistance(P=0.0001).CONCLUSION:Iron depletion by phlebotomy is likely associated with a higher rate of improvement of histological liver damage than lifestyle changes alone in patients with NAFLD and hyperferritinemia,and with amelioration of liver enzymes.

Practical review for diagnosis and clinical management of perihilar cholangiocarcinoma

Cholangiocarcinoma(CCC)is the most aggressive malignant tumor of the biliary tract.Perihilar CCC(pCCC)is the most common CCC and is burdened by a complicated diagnostic iter and its anatomical location makes surgical approach burden by poor results.Besides its clinical presentation,a multimodal diagnostic approach should be carried on by a tertiary specialized center to avoid missdiagnosis.Preoperative staging must consider the extent of liver resection to avoid post-surgical hepatic failure.During staging iter,magnetic resonance can obtain satisfactory cholangiographic images,while invasive techniques should be used if bile duct samples are needed.Consistently,to improve diagnostic potential,bile duct drainage is not necessary in jaundice,while it is indicated in refractory cholangitis or when liver hypertrophy is needed.Once resecability criteria are identified,the extent of liver resection is secondary to the longitudinal spread of CCC.While in the past type IV pCCC was not considered resectable,some authors reported good results after their treatment.Conversely,in selected unresectable cases,liver transplantation could be a valuable option.Adjuvant chemotherapy is the standard of care for resected patients,while neoadjuvant approach has growing evidences.If curative resection is not achieved,radiotherapy can be added to chemotherapy.This multistep curative iter must be carried on in specialized centers.Hence,the aim of this review is to highlight the main steps and pitfalls of the diagnostic and therapeutic approach to pCCC with a peculiar attention to type IV pCCC.

Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity

Cereal crops and cereal consumption have had a vital role in Mankind's history. In the recent years gluten ingestion has been linked with a range of clinical disorders. Gluten-related disorders have gradually emerged as an epidemiologically relevant phenomenon with an estimated global prevalence around 5%. Celiac disease, wheat allergy and non-celiac gluten sensitivity represent different gluten-related disorders. Similar clinical manifestations can be observed in these disorders, yet there are peculiar pathogenetic pathways involved in their development. Celiac disease and wheat allergy have been extensively studied, while non-celiac gluten sensitivity is a relatively novel clinical entity, believed to be closely related to other gastrointestinal functional syndromes. The diagnosis of celiac disease and wheat allergy is based on a combination of findings from the patient's clinical history and specific tests, including serology and duodenal biopsies in case of celiac disease, or laboratory and functional assays for wheat allergy. On the other hand, non-celiac gluten sensitivity is still mainly a diagnosis of exclusion, in the absence of clear-cut diagnostic criteria. A multimodal pragmatic approach combining findings from the clinical history, symptoms, serological and histological tests is required in order to reach an accurate diagnosis. A thorough knowledge of the differences and overlap in clinical presentation among gluten-related disorders, and between them and other gastrointestinal disorders, will help clinicians in the process of differential diagnosis.

Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease?

The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines,resulting in the upregulation of the iron hormone hepcidin,also increased by iron therapy and reduced glomerular filtration,with consequent reduction in iron absorption,recycling,and availability to the erythron.This response proves advantageous in the short-term to restrain iron availability to pathogens,but ultimately leads to severe anemia,and impairs the response to erythropoietin(Epo)and iron.Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores,thereby resulting in inadequate inhibition of the activity of Ferroportin-1,inappropriately high iron absorption and recycling,and iron overload.However,in hemodialysis patients,carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation,thereby improving iron availability to erythropoiesis,anemia control,the response to Epo,and possibly survival.Therefore,anti-hepcidin therapies may improve anemia management in hemodialysis.However,HFE mutations directly favor hemoglobinization independently of hepcidin,and reduce macrophages activation in response to inflammation,whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis,so that direct inhibition of HFEmediated regulation of iron metabolism may represent a valuable alternative therapeutic target.Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies.

Efficacy and tolerability of high and low-volume bowel preparation compared:A real-life single-blinded large-population study

BACKGROUND Low-volume preparations for colonoscopy have shown similar efficacy compared to high-volume ones in randomized controlled trials(RCT).However,most RCTs do not provide data about clinical outcomes including lesions detection rate.Moreover,real-life comparisons are lacking.AIM To compare efficacy(both in terms of adequate bowel preparation and detection of colorectal lesions)and tolerability of a high-volume(HV:4 L polyethylene glycol,PEG)and a low-volume(LV:2 L PEG plus bisacodyl)bowel preparation in a real-life setting.METHODS Consecutive outpatients referred for colonoscopy were prospectively enrolled between 1 December 2014 and 31 December 2016.Patients could choose either LV or HV preparation,with a day-before schedule for morning colonoscopies and a split-dose for afternoon procedures.Adequate bowel preparation according to Boston Bowel Preparation Scale(BBPS),clinical outcomes including polyp detection rate(PDR),adenoma detection rate(ADR),advanced adenoma detection rate(AADR),sessile/serrated lesion detection rate(SDR)and cancer detection rate and self-reported tolerability of HV and LV were blindly assessed.RESULTS Total 2040 patients were enrolled and 1815(mean age 60.6 years,50.2%men)finally included.LV was chosen by 52%of patients(50.8%of men,54.9%of women).Split-dose schedule was more common with HV(44.7%vs 38.2%,P=0.005).High-definition scopes were used in 33.4%of patients,without difference in the two groups(P=0.605).HV and LV preparations showed similar adequate bowel preparation rates(89.2%vs 86.6%,P=0.098),also considering the two different schedules(HV split-dose 93.8%vs LV split-dose 93.6%,P=1;HV daybefore 85.5%vs LV day-before 82.3%,P=0.182).Mean global BBPS score was higher for HV preparations(7.1±1.7 vs 6.8±1.6,P<0.001).After adjustment for sex,age and indications for colonoscopy,HV preparation resulted higher in PDR[Odds ratio(OR)1.32,95%CI:1.07-1.63,P=0.011]and ADR(OR 1.29,95%CI 1.02–1.63,P=0.038)and comparable to LV in AADR(OR 1.51,95%CI 0.97-2.35,P=0.069),SDR and cancer detection rate.The use of standard-definition colonoscopes was associated to lower PDR(adjusted OR 1.59,95%CI:1.22-2.08,P<0.001),ADR(adjusted OR 1.71,95%CI:1.26–2.30,P<0.001)and AADR(adjusted OR 1.97,95%CI:1.09-3.56,P=0.025)in patients receiving LV preparation.Mean Visual Analogue Scale tolerability scored equally(7,P=0.627)but a≥75%dose intake was more frequent with LV(94.6%vs 92.1%,P=0.003).CONCLUSION In a real-life setting,PEG-based low-volume preparation with bisacodyl showed similar efficacy and tolerability compared to standard HV preparation.However,with higher PDR and ADR,HV should still be considered as the reference standard for clinical trials and the preferred option in screening colonoscopy,especially when colonoscopy is performed with standard resolution imaging.

Digital liver biopsy:Bio-imaging of fatty liver for translational and clinical research

The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines(Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver.

PNPLA3 I148M polymorphism and progressive liver disease

The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.

Rectal neuroendocrine tumors:Current advances in management,treatment,and surveillance

Rectal neuroendocrine neoplasms(r-NENs)are considered among the most frequent digestive NENs,together with small bowel NENs.Their incidence has increased over the past few years,and this is probably due to the widespread use of endoscopic screening for colorectal cancer and the advanced endoscopic procedures available nowadays.According to the current European Neuroendocrine Tumor Society(ENETS)guidelines,well-differentiated r-NENs smaller than 10 mm should be endoscopically removed in view of their low risk of local and distant invasion.R-NENs larger than 20 mm are candidates for surgical resection because of their high risk of distant spreading and the involvement of the muscularis propria.There is an area of uncertainty regarding tumors between 10 and 20 mm,in which the metastatic risk is intermediate and the endoscopic treatment can be challenging.Once removed,the indications for surveillance are scarce and poorly codified by international guidelines,therefore in this paper,a possible algorithm is proposed.

Gastrinoma and Zollinger Ellison syndrome:A roadmap for the management between new and old therapies

Zollinger-Ellison syndrome(ZES)associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion,which typically leads to gastroesophageal reflux disease,recurrent peptic ulcers,and chronic diarrhea.As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders,the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years.The critical step for the diagnosis of ZES is represented by the initial clinical suspicion.Hypergastrinemia is the hallmark of ZES;however,hypergastrinemia might recognize several causes,which should be ruled out in order to make a final diagnosis.Gastrin levels>1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma;some specific tests,including esophageal pH-recording and secretin test,might be useful in selected cases,although they are not widely available.Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES,particularly in the setting of multiple endocrine neoplasia type 1.Some controversies about the management of these tumors also exist.For the localized stage,the combination of proton pump inhibitory therapy,which usually resolves symptoms,and surgery,whenever feasible,with curative intent represents the hallmark of gastrinoma treatment.The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs,supporting their use as anti-proliferative agents in patients not amenable to surgical cure.Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms,and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series.The multidisciplinary approach remains the cornerstone for the proper management of this composite disease.Herein,we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis,providing potential diagnostic and therapeutic algorithms.

Celiac disease: From pathophysiology to treatment

Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.

Non-invasive evaluation of intestinal disorders: The role of elastographic techniques

Over the recent years the non-invasive techniques for the evaluation of the small bowel have been playing a major role in the management of chronic intestinal diseases, such as inflammatory bowel diseases(IBD). The diagnostic performances of magnetic resonance imaging, computed tomography and ultrasound in the field of small bowel disorders, have been assessed and established for more than two decades. Newer sonographic techniques, such as strain elastography and shear wave elastography, have been put forward for the assessment of disease activity and characterization of IBD-related damage in the setting of Crohn's disease and other gastrointestinal disorders. The data from the preliminary research and clinical studies have shown promising results as regards the ability of elastographic techniques to differentiate inflammatory from fibrotic tissue. The distinction between IBD activity(inflammation) and IBD-related damage(fibrosis) is currently considered crucial for the assessment and management of patients. Moreover, all the elastographic techniques are currently being considered in the setting of other intestinal disorders(e.g., rectal tumors, appendicitis). The aim of this paper is to offer both a comprehensive narrative review of the non-invasive techniques available for the assessment of small-bowel disorders, with particular emphasis on inflammatory bowel diseases, and a summary of the current evidence on the use of elastographic techniques in this setting.

Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies?

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs) frequently present with distant metastases at the time of diagnosis and the liver is the most frequent site of spreading. The early identification of metastatic disease represents a major prognostic factor for GEP-NENs patients. Radical surgical resection, which is feasible for a minority of patients, is considered the only curative option, while the best management for patients with unresectable liver metastases is still being debated. In the last few years, a number of locoregional and systemic treatments has become available for GEP-NEN patients metastatic to the liver. However, to date only a few prospective studies have compared those therapies and the optimal management option is based on clinical judgement. Additionally, locoregional treatments appear feasible and safe for disease control for patients with limited liver involvement and effective in symptoms control for patients with diffuse liver metastases. Considering the lack of randomized controlled trials comparing the locoregional treatments of liver metastatic NEN patients, clinical judgment remains key to set the most appropriate therapeutic pathway. Prospective data may ultimately lead to more personalized and optimized treatments. The present review analyzes all the locoregional therapy modalities(i.e., surgery, ablative treatments and transarterial approach) and aims to provide clinicians with a useful algorithm to best treat GEP-NEN patients metastatic to the liver.

Dilation assisted stone extraction for complex biliary lithiasis:Technical aspects and practical principles

Common bile duct stones are frequently diagnosed worldwide and are one of the main indications for endoscopic retrograde cholangio-pancreatography.Endoscopic sphincterotomy(EST)has been used for the removal of bile duct stones for the past 40 years,providing a wide opening to allow extraction.Up to 15%of patients present with complicated choledocholithiasis.In this context,additional therapeutic approaches have been proposed such as endoscopic mechanical lithotripsy,intraductal or extracorporeal lithotripsy,or endoscopic papillary large balloon dilation(EPLBD).EPLBD combined with EST was introduced in 2003 to facilitate the passage of large or multiple bile duct stones using a balloon greater than 12 mm in diameter.EPLBD without EST was introduced as a simplified technique in 2009.Dilation-assisted stone extraction(DASE)is the combination of two techniques:EPLBD and sub-maximal EST.Several studies have reported this technique as safe and effective in patients with large bile duct stones,without any increased risk of adverse events such as pancreatitis,bleeding,or perforation.Nevertheless,it is difficult to analyze the outcomes of DASE because there are no standard techniques and definitions between studies.The purpose of this paper is to provide technical guidance and specific information about the main issues regarding DASE,based on current literature and daily clinical experience in biliary referral centers.

Intestinal ischemic manifestations of SARS-CoV-2:Results from the ABDOCOVID multicentre study

BACKGROUND Intestinal ischemia has been described in case reports of patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)disease(coronavirus disease 19,COVID-19).AIM To define the clinical and histological,characteristics,as well as the outcome of ischemic gastrointestinal manifestations of SARS-CoV-2 infection.METHODS A structured retrospective collection was promoted among three tertiary referral centres during the first wave of the pandemic in northern Italy.Clinical,radiological,endoscopic and histological data of patients hospitalized for COVID-19 between March 1st and May 30th were reviewed.The diagnosis was established by consecutive analysis of all abdominal computed tomography(CT)scans performed.RESULTS Among 2929 patients,21(0.7%)showed gastrointestinal ischemic manifestations either as presenting symptom or during hospitalization.Abdominal CT showed bowel distention in 6 patients while signs of colitis/enteritis in 12.Three patients presented thrombosis of main abdominal veins.Endoscopy,when feasible,confirmed the diagnosis(6 patients).Surgical resection was necessary in 4/21 patients.Histological tissue examination showed distinctive features of endothelial inflammation in the small bowel and colon.Median hospital stay was 9 d with a mortality rate of 39%.CONCLUSION Gastrointestinal ischemia represents a rare manifestation of COVID-19.A high index of suspicion should lead to investigate this complication by CT scan,in the attempt to reduce its high mortality rate.Histology shows atypical feature of ischemia with important endotheliitis,probably linked to thrombotic microangiopathies.

Pneumothorax Complicating Port-a-Cath and Groshong Catheter Positioning in Children: Our Experience before Routine Ultrasound-Guided Puncture

Objective: To study incidence and management of long term central venous catheter (CVC) placement related pneumothorax (PNX) in children. Aim: To construct a baseline value before the introduction of systematic use of ultrasound guidance, which requires specific training and equipment. Background: Anesthesia Service and Pediatric Oncology of the Italian National Cancer Center;patients were children (age ≤ 18 years) with solid tumors, needing long-term central venous catheters (Groshong or Port-a-Cath). Materials/Methods: Catheter placement was performed, mostly under general anesthesia, utilizing a micropuncture 5-7 Fr needle and fluoroscopy. In the study period ultrasound was used only in case of previously failed attempts. Relevant data were collected retrospectively. Results: From August 2008 to December 2011, 452 catheters were implanted to our patients. The prevalent approach was from subclavian vein (left 85.7%, right 9.7%);in few cases internal jugular vein was chosen (right 2.4%, left 2.2%). Pneumothorax occurred in 14 patients (3.1%;95%CI 1.9-5.1). In 4/14 children the PNX was considered minimal and not treated. In 10 patients the PNX was drained. In 7 cases a traditional, surgical thoracostomy was performed, while in 3 children a 14-Ga polyurethane catheter (Arrow International&#174) was inserted over a wire guide in the pleural space by anaesthetists. Conclusions: In our centre rates of PNX are the same as those described in literature and are expected to lower when ultrasound guidance of the puncture will be routinely applied. Percutaneous drainage of PNX seems as effective as surgically placed thoracostomy catheter, but less invasive.

Polymorphism AGT2(rs4762)is involved in the development of dermatologic events:Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib

BACKGROUND Dermatologic adverse events(DAEs)are associated with a better outcome in patients with hepatocellular carcinoma(HCC)irrespective of the therapeutic agent received.The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors(TKIs)to the skin or an immune-mediated reaction triggered by the oncologic treatment.As is the case in other conditions,individual genetic variants may partially explain a higher risk of DAEs.AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.METHODS We first analyzed 27 single-nucleotide polymorphisms(SNPs)from 12 genes selected as potential predictors of adverse event(AE)development in HCC patients treated with sorafenib[Barcelona Clinic Liver Cancer 1(BCLC1)cohort].Three additional cohorts were analyzed for AGT1(rs699)and AGT2(rs4762)polymorphisms-initially identified as predictors of DAEs:BCLC2(n=79),Northern Italy(n=221)and Naples(n=69)cohorts,respectively.The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models,and presented with hazard ratios and their 95%confidence intervals(95%CI).RESULTS The BCLC1 cohort showed that patients with arterial hypertension(AHT)(HR=1.61;P value=0.007)and/or AGT SNPs had an increased risk of DAEs.Thereafter,AGT2(rs4762)AA genotype was found to be linked to a statistically significant increased probability of DAEs(HR=5.97;P value=0.0201,AA vs GG)in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage,ECOG-PS,diabetes and AHT.The value of this genetic marker was externally validated in the cohort combining the BCLC1,BCLC2 and Naples cohorts[HR=3.12(95%CI:1.2-8.14),P value=0.0199,AGT2(rs4762)AA vs AG genotype and HR=2.73(95%CI:1.18-6.32)P value=0.0188,AGT2(rs4762)AA vs GG genotype].None of the other gene variants tested were found to be associated with the risk of DAE development.CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2(rs4762)gene variant.If validated in other anti-oncogenic treatments,it might be considered a good prognosis marker.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease

Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 2020,the more inclusive term metabolic dysfunction-associated fatty liver disease(MAFLD)was proposed to replace the term non-alcoholic fatty liver disease(NAFLD).The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD.However,to date,there is no appropriate guidance on CKD in individuals with MAFLD.Furthermore,there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.Methods and Results:Using a Delphi-based approach,a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.Conclusions:This Delphi-based consensus statement provided guidance on the epidemiology,mechanisms,management and treatment of MAFLD and CKD,as well as the relationship between the severity of MAFLD and risk of CKD,which establish a framework for the early prevention and management of these two common and interconnected diseases.