First-in-human liver transplantation from a centenarian deceased donor after brain death.

Liver transplantation from elderly donors is expanding due to demand for liver grafts, aging of recipients and donors, and introduction of machine perfusion. We report on a liver transplant from a 100-year-old deceased donor after brain death. The liver was transplanted after the use of hypothermic machine perfusion to a 60-year-old recipient with advanced hepatocellular carcinoma undergoing neoadjuvant immunotherapy. Nine months after the transplant, the patient is alive with a functioning graft and no evidence of acute rejection or tumor recurrence.

Mismatch Repair Deficiency in Biliary Tract Cancer: Prognostic Implications and Correlation with Histology.

INTRODUCTION: Mismatch repair (MMR) deficiency represents a biomarker and therapeutic target in various neoplasms, but its role in biliary tract cancers (BTCs) remains misunderstood. METHODS: MMR status was retrospectively assessed using immunohistochemistry in 163-BTCs patients. We identified MMR proficiency (pMMR)/deficiency (dMMR) according to the loss of MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary objective of the study was to assess the incidence of dMMR in BTCs; the secondary purpose was to explore its association with prognosis and clinical features. RESULTS: dMMR was recorded in 9 patients, and it was strongly associated with mucinous histology (p < 0.01). Regarding the prognostic effect, in 122-radically resected patients, disease-free survival (DFS) resulted significantly shorter in dMMR patients compared to pMMR patients (10.7 vs. 31.3 months, p = 0.025) and so did nodal status (48.2 vs. 15.3 months in N0 vs. N+) (p < 0.01). Moreover, dMMR confirmed its prognostic role in terms of DFS at multivariate analysis (p = 0.03), together with nodal status (p = 0.01), and resection margin (p = 0.03). In 103 M+ patients (encompassing 41 metastatic de novo and 62 recurred after surgery patients) there were not differences between dMMR and pMMR regarding survival analyses. CONCLUSIONS: dMMR status is strongly correlated with mucinous histology and represents an independent prognostic factor in terms of disease relapse in patients with resected BTC. IMPLICATIONS FOR PRACTICE: MMR may play an independent role in promoting an aggressive behaviour in patients with radically resected BTC. These results could be useful in improving the selection of patients after resection and, above all, should justify the evaluation of MMR status as a therapeutic target in BTC, especially in patients with atypical histology.

Response assessment of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: Is apparent diffusion coefficient useful on 3 T magnetic resonance imaging?

AIM: To assess the diagnostic value of apparent diffusion coefficient (ADC) on 3 T device for the prediction of tumoral response to neoadjuvant chemoradiotherapy (nCRT) and for the response assessment after nCRT in patients with locally advanced rectal cancer (LARC), using pathology as a reference. METHODS: Forty-one patients affected by LARC undergoing 3.0 T MRI before and after nCRT were retrospectively selected. After the conventional acquisition of high resolution T2-weighted sequences, diffusion-weighted MRI (DW-MRI) was performed using a spin-echo echo-planar sequence with multiple b values (150, 500, 1000, 1500 s/mm2 ). Fitted ADC values were calculated for each rectal lesion before and after nCRT by drawing a hand-made region of interest (ROI) around the tumour outline. All patients underwent surgery and pathological staging (classified according to tumour regression grading [TRG] and to tumour and node [TN]) represented the reference standard. Pretreatment ADC value (pre-ADC), ADC value obtained after nCRT (post-ADC) and the difference between post-ADC and pre-ADC (ΔADC) were correlated with both the TRG classes and the TN staging system in each patient. RESULTS: The ADC values obtained in the post nCRT examination and the ΔADC were statistically related both to TRG (p = 0.0004; p = 0.0126, respectively) and TN (p = 0.0484; p = 0.0673, respectively) stages at histopathology. On the contrary, the pre-ADC was not related either to the TRG classes or to the lesion TN staging system (p > 0.05). CONCLUSIONS: 3 T DW-MRI using ADC value can be useful to assess the efficacy of nCRT in LARC; in fact, post-ADC and ΔADC values improve MR capability to evaluate tumour response.

Live enteroviruses, but not other viruses, detected in human pancreas at the onset of type 1 diabetes in the DiViD study.

AIMS/HYPOTHESIS: Enterovirus (EV) infection of pancreatic islet cells is one possible factor contributing to type 1 diabetes development. We have reported the presence of EV genome by PCR and of EV proteins by immunohistochemistry in pancreatic sections. Here we explore multiple human virus species in the Diabetes Virus Detection (DiViD) study cases using innovative methods, including virus passage in cell cultures. METHODS: Six recent-onset type 1 diabetes patients (age 24-35) were included in the DiViD study. Minimal pancreatic tail resection was performed under sterile conditions. Eleven live cases (age 43-83) of pancreatic carcinoma without diabetes served as control cases. In the present study, we used EV detection methods that combine virus growth in cell culture, gene amplification and detection of virus-coded proteins by immunofluorescence. Pancreas homogenates in cell culture medium were incubated with EV-susceptible cell lines for 3 days. Two to three blind passages were performed. DNA and RNA were extracted from both pancreas tissue and cell cultures. Real-time PCR was used for detecting 20 different viral agents other than EVs (six herpesviruses, human polyomavirus [BK virus and JC virus], parvovirus B19, hepatitis B virus, hepatitis C virus, hepatitis A virus, mumps, rubella, influenza A/B, parainfluenza 1-4, respiratory syncytial virus, astrovirus, norovirus, rotavirus). EV genomes were detected by endpoint PCR using five primer pairs targeting the partially conserved 5' untranslated region genome region of the A, B, C and D species. Amplicons were sequenced. The expression of EV capsid proteins was evaluated in cultured cells using a panel of EV antibodies. RESULTS: Samples from six of six individuals with type 1 diabetes (cases) and two of 11 individuals without diabetes (control cases) contained EV genomes (p<0.05). In contrast, genomes of 20 human viruses other than EVs could be detected only once in an individual with diabetes (Epstein-Barr virus) and once in an individual without diabetes (parvovirus B19). EV detection was confirmed by immunofluorescence of cultured cells incubated with pancreatic extracts: viral antigens were expressed in the cytoplasm of approximately 1% of cells. Notably, infection could be transmitted from EV-positive cell cultures to uninfected cell cultures using supernatants filtered through 100 nm membranes, indicating that infectious agents of less than 100 nm were present in pancreases. Due to the slow progression of infection in EV-carrying cell cultures, cytopathic effects were not observed by standard microscopy but were recognised by measuring cell viability. Sequences of 5' untranslated region amplicons were compatible with EVs of the B, A and C species. Compared with control cell cultures exposed to EV-negative pancreatic extracts, EV-carrying cell cultures produced significantly higher levels of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP1). CONCLUSIONS/INTERPRETATION: Sensitive assays confirm that the pancreases of all DiViD cases contain EVs but no other viruses. Analogous EV strains have been found in pancreases of two of 11 individuals without diabetes. The detected EV strains can be passaged in series from one cell culture to another in the form of poorly replicating live viruses encoding antigenic proteins recognised by multiple EV-specific antibodies. Thus, the early phase of type 1 diabetes is associated with a low-grade infection by EVs, but not by other viral agents.

Leptin resistance before and after obesity: evidence that tissue glucose uptake underlies adipocyte enlargement and liver steatosis/steatohepatitis in Zucker rats from early-life stages.

BACKGROUND: Leptin resistance occurs in obese patients, but its independent contribution to adiposity and the accompanying metabolic diseases, i.e., diabetes, liver steatosis, and steatohepatitis, remains to be established. This study was conducted in an extreme model of leptin resistance to investigate mechanisms initiating diabetes, fat expansion, liver steatosis, and inflammatory disease, focusing on the involvement of glucose intolerance and organ-specific glucose uptake in brown and subcutaneous adipose tissues (BAT, SAT) and in the liver. METHODS: We studied preobese and adult Zucker rats (fa/fa, fa/+ ) during fasting or glucose loading to assess glucose tolerance. Relevant pancreatic and intestinal hormonal levels were measured by Milliplex. Imaging of 18F-fluorodeoxyglucose by positron emission tomography was used to quantify glucose uptake in SAT, BAT, and liver, and evaluate its relationship with adipocyte size and biopsy-proven nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). RESULTS: Preobese fa/fa pups showed impaired glucose tolerance, adipocyte enlargement, hepatic microsteatosis, and lobular inflammation, with elevated hepatic post-glucose load glucose uptake and production. Adult fa/fa rats had more severe glucose intolerance, fasting hyperglycemia, hormonal abnormalities, elevated glucose uptake in SAT and BAT, and more markedly in the liver, together with macrosteatosis, and highly prevalent hepatic inflammation. Organ glucose uptake was proportional to the degree of fat accumulation and tissue inflammation and was able to dissect healthy from NAFLD and NAFLD/NASH livers. Most severe NASH livers showed a decline in glucose uptake and liver enzymes. CONCLUSIONS: In fa/fa Zucker rats, leptin resistance leads to glucose intolerance, mainly due to hepatic glucose overproduction, preceding obesity, and explaining pancreatic and intestinal hormonal changes and fat accumulation in adipocytes and hepatocytes. Our data support the involvement of liver glucose uptake in the pathogenesis of liver inflammatory disease. Its potential as more generalized biomarker or diagnostic approach remains to be established outside of our leptin-receptor-deficient rat model.

Cerium oxide nanoparticles administration during machine perfusion of discarded human livers: A pilot study.

The combined approach of ex situ normothermic machine perfusion (NMP) and nanotechnology represents a strategy to mitigate ischemia/reperfusion injury in liver transplantation (LT). We evaluated the uptake, distribution, and efficacy of antioxidant cerium oxide nanoparticles (nanoceria) during normothermic perfusion of discarded human livers. A total of 9 discarded human liver grafts were randomized in 2 groups and underwent 4 h of NMP: 5 grafts were treated with nanoceria conjugated with albumin (Alb-NC; 50 µg/ml) and compared with 4 untreated grafts. The intracellular uptake of nanoceria was analyzed by electron microscopy (EM) and inductively coupled plasma-mass spectrometry (ICP-MS). The antioxidant activity of Alb-NC was assayed in liver biopsies by glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) assay, telomere length, and 4977-bp common mitochondrial DNA deletion (mtDNA4977 deletion). The cytokine profile was evaluated in perfusate samples. EM and ICP-MS confirmed Alb-NC internalization, rescue of mitochondrial phenotype, decrease of lipid droplet peroxidation, and lipofuscin granules in the treated grafts. Alb-NC exerted an antioxidant activity by increasing GSH levels (percentage change: +94% ± 25%; p = 0.01), SOD (+17% ± 4%; p = 0.02), and CAT activity (51% ± 23%; p = 0.03), reducing the occurrence of mtDNA4977 deletion (-67.2% ± 11%; p = 0.03), but did not affect cytokine release. Alb-NC during ex situ perfusion decreased oxidative stress, upregulating graft antioxidant defense. They could be a tool to improve quality grafts during NMP and represent an antioxidant strategy aimed at protecting the graft against reperfusion injury during LT.

Ex-vivo human pancreatic specimen evaluation by 7 Tesla MRI: a prospective radiological-pathological correlation study.

PURPOSE: To compare the characteristics detected by 7Tesla (7 T) MR and the histological composition of ex-vivo specimens from lesions diagnosed at preoperative CT scan as Pancreatic Ductal Adenocarcinoma (PDAC). MATERIALS AND METHODS: Ten pancreatic specimens were examined. The 7 T imaging protocol included both morphologic and quantitative sequences; the latter was acquired by conventional methods and a novel multiparametric method, the magnetic resonance fingerprinting (MRF) sequence. Two radiologists reviewed the images to: (1) evaluate the quality of the morphological and quantitative sequences by assigning an "image consistency score" on a 4-point scale; (2) identify the lesion, recording its characteristics; (3) perform the quantitative analysis on "target lesion" and "non target tissue". Finally, the specimen was analysed by two pathologists. RESULTS: Seven out of 10 lesions were PDAC, 2/10 were biliary carcinomas, whereas one lesion was an ampullary adenocarcinoma. The quality of the morphological sequences was judged "excellent". The "image consistency score" for the conventional quantitative sequences and MRF were 2.8 ± 0.42 and 2.9 ± 0.57; the "overall MR examination score" was 3.5 ± 0.53. A statistical correlation was found between the relaxation time values of conventional and MRF T1-weighted sequences (p < 0.0001), as well as between conventional and MRF fat- and water-fraction maps (p < 0.05). The "target lesion" and "non target tissue" relaxation time values were statistically different according to conventional T1-, T2-weighted, and MRF T1-weighted sequences. CONCLUSIONS: Conventional T1-, T2-weighted sequences and MRF derived relaxometries may be useful in differentiating between tumour and non-target pancreatic tissue. Moreover, the MRF sequence can be used to obtain reliable relaxation time data.

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut-Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice.

Interventions affecting gastrointestinal (GI) physiology suggest that the GI tract plays an important role in modulating the uptake of ingested glucose by body tissues. We aimed at validating the use of positron emission tomography (PET) with oral 18FDG administration in mice, and to examine GI effects on glucose metabolism in adipose tissues, brain, heart, muscle, and liver, and interfering actions of oral lipid co-administration. We performed sequential whole-body PET studies in 3 groups of 10 mice, receiving i.p. glucose and 18FDG or oral glucose and 18FDG ± lipids, to measure tissue glucose uptake (GU) and GI transit, and compute the absorption lumped constant (LCa) as ratio of oral 18FDG-to-glucose incremental blood levels. GI and liver histology and circulating hormones were tested to generate explanatory hypothesis. Median LCa was 1.18, constant over time and not significantly affected by lipid co-ingestion. Compared to the i.p. route, the oral route (GI effect) resulted in lower GU rates in adipose tissues and brain, and a greater steatohepatitis score (+17%, p = 0.03). Lipid co-administration accelerated GI transit, in relation to the suppression in GIP, GLP1, glucagon, PP, and PYY (GI motility regulators), abolishing GI effects on subcutaneous fat GU. Duodenal crypt size, gastric wall 18FDG uptake, and macro-vesicular steatosis were inversely related to adipose tissue GU, and positively associated with liver GU. We conclude that 18FDG-PET is a suitable tool to examine the role of the GI tract on glucose transit, absorption, and bio-distribution. The GI effect consists in the suppression of glucose metabolism selectively in organs responsible for energy intake and storage, and is blunted by lipid ingestion. Modulation of gut and liver inflammation, as reflected by high GU, may be involved in the acute signalling of the energy status.

The P2X7R-NLRP3 and AIM2 Inflammasome Platforms Mark the Complexity/Severity of Viral or Metabolic Liver Damage.

P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD/NASH associated with chronic HCV infection than those with metabolic damage only (p ≤ 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.

HER2 Overexpression as a Poor Prognostic Determinant in Resected Biliary Tract Cancer.

BACKGROUND: HER2 overexpression has been investigated as a potential biomarker and therapeutic target in biliary tract cancer (BTC), but a prognostic role of such alteration has not been demonstrated yet. MATERIALS AND METHODS: We retrospectively evaluated HER2 protein expression by immunohistochemistry (IHC) in 100 patients with radically resected BTC. HER2 gene amplification was assessed by fluorescence in situ hybridization (FISH) in 2+ and 3+ cases at IHC. High HER2 protein expression was defined as either IHC 3+ or 2+ associated with FISH positivity. The primary objective of the study was to evaluate the prognostic role of HER2 overexpression in terms of disease-free survival (DFS) and overall survival (OS). Secondary endpoints were the prevalence of HER2 overexpression and the possible correlation with other clinicopathological features. RESULTS: HER2 overexpression was identified in 11 patients and was not related to other clinicopathological factors. DFS was significantly shorter in HER2-positive compared with HER2-negative patients (10.6 vs. 20.9 months, log-rank p = .017). HER2 confirmed its prognostic value for DFS at multivariate analysis (hazard ratio 2.512; 95% confidence interval, 1.232-5.125; p = .011) together with nodal stage (p < .001), resection margin (p = .027), and tumor site (p = .030). There was no difference in OS between HER2-positive and -negative patients (p = .068). CONCLUSION: HER2 overexpression represents an independent prognostic factor for disease recurrence in patients with BTC treated with potentially curative surgery. IMPLICATIONS FOR PRACTICE: HER2 overexpression may play an independent role in promoting an aggressive behavior in resectable biliary tract cancer. This evidence could be helpful in improving prognostic stratification after resection and, primarily, should endorse the rationale to investigate HER2 as a therapeutic target in biliary tract cancer.

Pilot, Open, Randomized, Prospective Trial for Normothermic Machine Perfusion Evaluation in Liver Transplantation From Older Donors.

Ex situ normothermic machine perfusion (NMP) might minimize ischemia/reperfusion injury (IRI) of liver grafts. In this study, 20 primary liver transplantation recipients of older grafts (≥70 years) were randomized 1:1 to NMP or cold storage (CS) groups. The primary study endpoint was to evaluate graft and patient survival at 6 months posttransplantation. The secondary endpoint was to evaluate liver and bile duct biopsies; IRI by means of peak transaminases within 7 days after surgery; and incidence of biliary complications at month 6. Liver and bile duct biopsies were collected at bench surgery, end of ex situ NMP, and end of transplant surgery. Interleukin (IL) 6, IL10, and tumor necrosis factor α (TNF-α) perfusate concentrations were tested during NMP. All grafts were successfully transplanted. Median (interquartile range) posttransplant aspartate aminotransferase peak was 709 (371-1575) IU/L for NMP and 574 (377-1162) IU/L for CS (P = 0.597). There was 1 hepatic artery thrombosis in the NMP group and 1 death in the CS group. In NMP, we observed high TNF-α perfusate levels, and these were inversely correlated with lactate (P < 0.001). Electron microscopy showed decreased mitochondrial volume density and steatosis and an increased volume density of autophagic vacuoles at the end of transplantation in NMP versus CS patients (P < 0.001). Use of NMP with older liver grafts is associated with histological evidence of reduced IRI, although the clinical benefit remains to be demonstrated.

A propensity score-matched analysis of robotic versus open pancreatoduodenectomy for pancreatic cancer based on margin status.

BACKGROUND: No study has shown the oncologic non-inferiority of robotic pancreatoduodenectomy (RPD) versus open pancreatoduodenectomy (OPD) for pancreatic cancer (PC). METHODS: This is a single institution propensity score matched study comparing RPD and ODP for resectable PC, based on factors predictive of R1 resection (≤ 1 mm). Only patients operated on after completion of the learning curve in both procedures and for whom circumferential margins were assessed according to the Leeds pathology protocol were included. The primary study endpoint was the rate of R1 resection. Secondary study endpoints were as follows: number of examined lymph nodes (N), rate of perioperative transfusions, percentage of patients receiving adjuvant therapies, occurrence of local recurrence, overall survival, disease-free survival, and sample size calculation for randomized controlled trials (RCT). RESULTS: Factors associated with R1 resection were tumor diameter, number of positive N, N ratio, logarithm odds of positive N, and duodenal infiltration. The matching process identified 20 RPDs and 24 OPDs. All RPDs were completed robotically. R1 resection was identified in 11 RPDs (55.0%) and in 10 OPDs (41.7%) (p = 0.38). There was no difference in the rate of R1 at each margin as well as in the proportion of patients with multiple R1 margins. RPD and OPD were also equivalent with respect to all secondary study endpoints, with a trend towards lower rate of blood transfusions in RPD. Based on the figures presented herein, a non-inferiority RCT comparing RPD and OPD having the rate of R1 resection as the primary study endpoint requires 3355 pairs. CONCLUSIONS: RPD and OPD achieved the same rate of R1 resections in resectable PC. RPD was also non-inferior to OPD with respect to all secondary study endpoints. Because of the high number of patients required to run a RCT, further assessment of RPD for PC would require the implementation of an international registry.

The Role of Prep1 in the Regulation of Mesenchymal Stromal Cells.

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of Prep1 downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of Prep1 are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells. Furthermore, our data suggest that in vivo decreased Prep1 gene dosage favors a pro-adipogenic phenotype and induces a "browning" effect in all fat tissues.

Incidence and reasons of pancreatic resection in patients with asymptomatic serous cystadenoma.

BACKGROUND/OBJECTIVES: Despite diagnostic refinements, pancreatic resection (PR) is eventually performed in some patients with asymptomatic serous cystadenoma (A-SCA). The aim of this study was to define incidence and reasons of PR in A-SCA. METHODS: A retrospective analysis of a prospectively maintained database was performed for all the patients referred for pancreatic cystic lesions (PCL) between January 2005 and March 2016. RESULTS: Overall, there were 1488 patients with PCL, including 1271 (85.4%) with incidental PCL (I-PCL). During the study period referral of I-PCL increased 8.5-fold. Surgery was immediately advised in 94 I-PCL (7.3%) and became necessary later on in 11 additional patients (0.9%), because of the development of symptoms. Overall, PR was performed in 105/1271 patients presenting with I-PCL (8.2%), including 27 with A-SCA (2.1%). All patients with A-SCA underwent ultrasonography and contrast-enhanced computed tomography. Magnetic resonance imaging was performed in 21 patients (77.8%), 18 F-FDG positron emission tomography in 8 (29.6%), endoscopic ultrasonography (EUS) in 2 (7.4%), and EUS-guided fine needle aspiration (EUS-FNA) in 1 (3.7%). These studies demonstrated a combination of atypical features such as solid tumor (3; 11.1%), oligo-/macrocystic tumor (24; 88.8%), mural nodules (14; 51.8%), enhancing cyst walls (17; 62.9%), dilation of the main pancreatic duct (3; 11.1%), and upstream pancreatic atrophy (1; 3.7%). Additionally, 14/27 patients (51.8%) were females with oligo-/macrocystic tumors located in the body-tail of the pancreas. CONCLUSIONS: Management of patients with A-SCA entails a small risk of PR especially when these tumors demonstrate atypical radiologic features associated with confounding anatomic and demographic characteristics.

Multiple small bowel perforations due to invasive aspergillosis in a patient with acute myeloid leukemia: case report and a systematic review of the literature.

PURPOSE: Invasive aspergillosis (IA) represents a major cause of morbidity and mortality in immunocompromised patients. Involvement of the gastrointestinal tract by Aspergillus is mostly reported as part of a disseminated infection from a primary pulmonary site and only rarely as an isolated organ infection. METHODS: We report a case of small bowel perforation due to IA in a patient with acute leukemia under chemotherapy and pulmonary aspergillosis. We performed a systematic review of the literature as well. RESULTS: A 43-year-old man with acute myeloid leukemia under chemotherapy developed severe neutropenia and pulmonary aspergillosis due to Aspergillus flavus. He developed melena and hemodynamic failure and a contrast-enhanced ultrasound scan suggested active intestinal bleeding. During emergency laparotomy we found multiple intestinal abscesses, several perforations of intestinal loop and Aspergillus flavus was isolated from the abscesses. Resection of the jejunum was performed. The patient received voriconazole and finally recovered. The patient is now alive and in complete disease remission. From literature review we found 35 intestinal IA previously published in single case reports or small case series as well. CONCLUSION: Clinical manifestations of gastrointestinal aspergillosis are nonspecific, such as abdominal pain, and only occasionally it presents as an acute abdomen. Antemortem detection of bowel involvement is rarely achieved and, only in cases of complicated gastrointestinal aspergillosis, the diagnosis is achieved thanks to the findings during surgery. Gastrointestinal aspergillosis should be suspected in patients with severe and prolonged neutropenia with or without pulmonary involvement in order to consider the right therapy and prompt surgery.

Conformal coating by multilayer nano-encapsulation for the protection of human pancreatic islets: In-vitro and in-vivo studies.

To improve the efficiency of pancreatic islet transplantation, we performed in-vitro and in-vivo experiments with isolated human pancreatic islets coated by multi-layer nano-encapsulation using differently charged polymers [chitosan and poly(sodium styrene sulfonate)] to obtain up to 9 layers. The islet coating (thickness: 104.2 ±â€¯4.2 nm) was uniform, with ≥ 90% cell viability and well preserved beta- and alpha-cell ultrastructure. Nano-encapsulated islets maintained physiological glucose-stimulated insulin secretion by both static incubation and perifusion studies. Notably, palmitate- or cytokine-induced toxicity was significantly reduced in nano-coated islets. Xenotransplantation of nano-encapsulated islets under the kidney capsule of streptozotocin-induced C57Bl/6J diabetic mice allowed long term normal or near normal glycemia, associated with minimal infiltration of immune cell into the grafts, well preserved islet morphology and signs of re-vascularization. In summary, the multi-layer nano-encapsulation approach described in the present study provides a promising tool to effectively protect human islets both in-vitro andin-vivo conditions.

Risk analysis of ischemic-type biliary lesions after liver transplant using octogenarian donors.

The use of octogenarian donors to increase the donor pool in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk of ischemic-type biliary lesions (ITBL). The aim of this study was to investigate retrospectively the role of a number of different pre-LT risk factors for ITBL in a selected population of recipients of octogenarian donor grafts. Between January 2003 and December 2013, 123 patients underwent transplantation at our institution with deceased donor grafts from donors of age ≥80 years. Patients were divided into 2 groups based on the presence of ITBL in the posttransplant course. Exclusion criteria were retransplantations, presence of vascular complications, and no availability of procurement liver biopsy. A total of 88 primary LTs were included, 73 (83.0%) with no posttransplant ITBLs and 15 (17.0%) with ITBLs. The median follow-up after LT was 2.1 years (range, 0.7-5.4 years). At multivariate analysis, donor hemodynamic instability (hazard ratio [HR], 7.6; P = 0.005), donor diabetes mellitus (HR, 9.5; P = 0.009), and donor age-Model for End-Stage Liver Disease (HR, 1.0; P = 0.04) were risk factors for ITBL. Transplantation of liver grafts from donors of age ≥80 years is associated with a higher risk for ITBL. However, favorable results can be achieved with accurate donor selection. Donor hemodynamic instability, a donor history of diabetes mellitus, and allocation to higher Model for End-Stage Liver Disease score recipient all increase the risk of ITBL and are associated with worse graft survival when octogenarian donors are used. Liver Transplantation 22 588-598 2016 AASLD.