Impact of the environment on the health: From theory to practice.

The Erice 56 Charter titled "Impact of the environment on the health: from theory to practice" was unanimously approved at the end of the 56th course of the "International School of Epidemiology and Preventive Medicine G. D'Alessandro" held from 3rd to November 7, 2019 in Erice - Sicily (Italy) and promoted by the Study Group of "Environment and Health" of the Italian Society of Hygiene, Preventive Medicine and Public Health. The course, that included lectures, open discussions and guided working groups, was aimed to provide a general training on epidemiological and toxicological aspects of the environmental health impact, to be used by public health professionals for risk assessment, without forgetting the risk communications. At the end of the course 12 key points were agreed among teachers and students: they underlined the need of specific training and research, in the perspective of "One Health" and "Global Health", also facing emerging scientific and methodological issues and focusing on communication towards stakeholders. This Discussion highlight the need to improve knowledge of Health and Environment topic in all sectors of health and environmental prevention and management.

[Surgical treatment of extraoesophageal symptoms of GERD. Critical points in the diagnostic-therapeutic pathway]. / Trattamento chirurgico dei sintomi extraesofagei da MRGE. Punti critici nel percorso diagnostico-terapeutico.

Patients with GERD and atypical symptoms represent a particular category with a less clear definition of the physiopatological mechanisms and thereby need a precise attention toward the indication to surgery. The less good response to surgery therefore requires a careful evaluation and selection of patients with atypical symptoms.

Kidney Transplantation in Elderly Recipients: A Single-Center Experience.

In this retrospective single-center study we evaluated the outcome after kidney transplant in recipients older than 65 years in terms of patient and graft survival and causes of death. PATIENTS AND METHODS: From 1993 to 2016, 109 consecutive first single kidney transplants in recipients older than 65 years were included. Furthermore, 2 age groups have also been identified (group A, 65-70 years old vs group B, 71-76 years old). Donor and recipient characteristics were analyzed. Other parameters were cold and warm ischemia times, delayed graft function, biopsy-proven acute rejection, and causes of death. Induction immunosuppressive therapy was performed with basiliximab or thymoglobulin. Baseline triple immunosuppression included calcineurin inhibitor, antimetabolite, and steroids. The results of preimplantation biopsies, which were performed in all expanded criteria donors were analyzed and graded according to Karpinski 2009 classification. RESULTS: Overall mortality was 39.4%: 23.2% women and 76.8% men. Causes of death were infections in 42%, tumors in 23%, cardiovascular disease in 14%, cerebrovascular disease in 7%, and unknown in 14%. The most common cause of death in men was infections (52%), and the most common cause in women was tumors (55%). At 1, 3, 5, and 10 years, overall patient survival was 89%, 84%, 72%, and 45%, and overall graft survival was 100%, 97%, 89%, and 84%, respectively. Patient and graft survival were statistically different between group A vs group B (P = .006 and P = .02, respectively). At univariate analysis significant risk factors for increased mortality were age, delayed graft function, and cold ischemia time. At multivariate analysis, delayed graft function maintained statistical significance. CONCLUSIONS: Kidney transplantation in patients older than 65 years is safe, feasible, and has good graft survival. Mortality is statistically significant in patients older than 71 years, despite a persistent low graft loss.

Tacrolimus Therapeutic Drug Monitoring in Stable Kidney Transplantation and Individuation of CYP3A5 Genotype.

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.

Graft vessel wall pathology in a case of hepatic artery pseudo-aneurysm in a liver transplant recipient.

Pseudo-aneurysms (PAs) of the hepatic artery are rare complications of liver transplantation, which are characterized by a high mortality rate. The majority occur within the first 2 months after orthotopic liver transplantation. They become clinically manifest with sudden hypotension, gastrointestinal bleeding, and abnormal liver function test results. Early diagnosis and treatment are essential to prevent life-threatening hemorrhage. Conventional treatment consists of surgical resection and vascular reconstruction, but a feasible treatment option involves an angiographic approach with the positioning of a stent or transarterial coil embolization followed by revascularization. We report a case of posttransplantation hepatic artery PA (HA-PA) with bleeding into the duodenum, diagnosed using abdominal computed tomography (CT). Arterial kinking prevented a covered stent graft from being inserted successfully using X-ray angiography, so the patient underwent emergency surgery in an attempt to exclude the PA and revascularize the organ via an aorto-hepatic bypass with an iliac vascular graft obtained from the donor. The surgical procedure failed due to progressive macroscopic dissection of the HA wall up to the bifurcation. The patient underwent retransplantation but died 25 days later due to multiple-organ failure. Histopathology of the first liver graft confirmed arterial graft dissection and pathological changes in the donor HA wall.

Technical solutions for venous outflow reconstruction in damaged liver grafts during procurement: case reports.

The incidence and clinical consequences of hepatic injuries (parenchymal, vascular, and biliary) due to surgical handling during multiorgan procurement are still underestimated. Surgical damage to liver grafts may lead to an increased mortality and graft dysfunction rate; therefore, multiorgan procurements require a high level of expertise and training. We report our experience in two cases of accidental venous outflow damage during liver procurement focusing on our repair strategies. In one case, a short suprahepatic inferior vena cava (IVC) was extended by a venous cuff obtained from a long infrahepatic IVC from the same liver graft. In the second case, we observed a complete transection of the middle hepatic vein during in situ splitting procedure. The damage was reconstructed by cadaveric iliac vein interposition. In both cases, liver transplantation was successfully performed without venous complication. An adequate surgical technique in liver procurement and venous reconstruction during living donor and domino liver transplantation are formidable tools to achieve successful liver transplantation with a damaged graft.

Indigo Thrombectomy System for Hepatic Artery Thrombosis After Liver Transplantation: A Case Report.

INTRODUCTION: Hepatic artery thrombosis still represents a major complication after liver transplantation responsible for graft failure, possibly resulting in the need for retransplantation. CASE REPORT: We describe a case of a patient undergoing liver transplant complicated by hepatic artery thrombosis, successfully treated with an endovascular approach using the Indigo System. This new system allows mechanical fragmentation and aspiration of the thrombus, with no injection of any thrombolytic agents, thereby reducing the risk of bleeding. Hepatic artery flow was immediately restored, with no complications for the patient and the graft. DISCUSSION: The Indigo System appears to be a safe, affordable, and manageable technique for endovascular management of late hepatic artery thrombosis after liver transplant.

Laparoscopic cholecystectomy in patients with mild cirrhosis and symptomatic cholelithiasis.

BACKGROUND: Our goal was to support the emerging opinion that laparoscopic cholecystectomy is safe and well tolerated in selected cirrhotic patients with indications for surgery. We present our experience with 50 laparoscopic cholecystectomies performed on patients with mild cirrhosis. METHODS: We retrospectively reviewed and analyzed the outcomes of 50 laparoscopic cholecystectomies performed between January 1995 and May 2006 in patients with Child-Pugh A and B cirrhosis. RESULTS: Laparoscopic cholecystectomy was uneventful for 35 cirrhotic patients. Conversion to an open procedure was necessary in two Child-Pugh B patients with chronic cholelcystitis. One Child-Pugh B cirrhotic patient required blood transfusion. Postoperative complications occurred in 12 patients, including hemorrhage, wound infection, intra-abdominal collection, and cardiopulmonary complications. The mean postoperative stay was 5 days (range, 3 to 13). No deaths occurred. CONCLUSIONS: Laparoscopic cholecystectomy is a safe procedure in well-selected Child-Pugh A and B cirrhotic patients and should be the gold standard for patients with mild cirrhosis and symptomatic cholelithiasis.

Selective bilirubin removal by plasma treatment with Plasorba BR-350 for early cholestatic graft dysfunction.

Early cholestatic graft dysfunction is a frequent cause of morbidity after orthotopic liver transplantation (OLT). We analyze the role of selective bilirubin plasma absorption (PAP) using Plasorba BR-350 in 4 OLT patients who had experienced early severe cholestatic graft dysfunction within 15 days after transplantation. Patients were treated with 3 consecutive cycles of PAP with Plasorba BR-350. The median amount of plasma treated was 7500 mL. Median treatment duration was 231 minutes. The average plasma bilirubin level was 37 +/- 1 mg/dL before PAP and decreased to 15 +/- 0.2 mg/dL at the end of the third cycle of PAP; 3 of 4 cases had progressive bilirubin normalization after PAP. The average amount of bilirubin removed from the plasma of the patients during each PAP treatment was 143 +/- 24 mg. At the beginning of each cycle of PAP, the Plasorba BR-350 was able to remove >90% of the total plasma bilirubin, a percentage that decreased to 60%, 50%, and 40% after 2 L, 4 L, and 7 L of plasma were treated, respectively. Liver biopsies performed after the third treatment showed reduced cholestasis when compared with the pretreatment biopsy specimen. The preliminary data suggested that PAP selective for bilirubin removal may not only reduce the bilirubin level, but may also improve the histological pattern of the graft in terms of reduced cholestatic signs.

Redox proteomics and immunohistology to study molecular events during ischemia-reperfusion in human liver.

Oxidative stress is a condition occurring in liver disorders and causing liver damage due to ischemia-reperfusion (I/R) during liver transplantation. Several markers of chronic oxidative stress are well known; however, early protein targets of oxidative injury are not well defined. To identify them, we used a differential proteomics approach to HepG2 human liver cells that has been treated for 10 minutes with 500 micromol/L H(2)O(2). By differential proteomic analysis, using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified four proteins sensitive to H(2)O(2) treatment that underwent posttranslational modification of native polypeptides. Three of the proteins belong to the Peroxiredoxin family of hydroperoxide scavengers, PrxI, PrxII, and Prx VI, that showed changes in their pI as result of hyperoxidation. Mass mapping experiments demonstrated specific modification of the peroxiredoxins active site thiol into sulphinic and/or sulphonic acid, thus explaining an increased negative charge. The oxidation kinetics of all peroxiredoxins were extremely rapid and sensitive, occurring at H(2)O(2) doses unable to affect common markers of cellular oxidative stress. A differential proteomics approach was also applied to liver needle biopsies after cold (T(1)) and warm (T(2)) ischemia. Proteomic analysis of this material was related to histological changes and immunophenotypic expression of APE1/Ref-1. Hyperoxidation of PrxI occurring during I/R upon liver transplantation is dependent on the time of warm ischemia. Histological changes and APE1/Ref-1 expression parallel Peroxiredoxin changes. Our present data may be relevant to better graft preservation and evaluation for transplantation.

Intraperitoneal Tenckhoff catheter for the treatment of recurrent lymphoceles after kidney transplantation: our early experience.

Lymphoceles may occur as frequently as 16% of the time after kidney transplantation, becoming clinically evident between 18 and 180 days after surgery. The management of lymphoceles is unclear. Percutaneous needle aspiration and external drainage are associated with high recurrence and complications. Surgical intraperitoneal marsupialization of lymphocele is considered the treatment of choice, but requires hospital admission, general anesthesia, and sometimes extensive surgical dissection. We discuss our experience in the treatment of recurrent symptomatic lymphocele intraperitoneally drained using a Tenckhoff catheter in 7 consecutive patients. Clinical manifestations became evident between 26 and 90 days after transplantation. The diagnosis was obtained with abdominal ultrasound in all cases; mean lymphocele diameter was 14 +/- 6 cm. After percutaneous drainage, performed to differentiate urinoma/lymphocele and to rule out infections, the lymphocele recurred within 1 month. Thereafter, we decided to treat recurrent lymphatic collection using a Tenckhoff catheter. The lymphocele was located during the operative procedure using a sterile 3.5-MHz ultrasound probe. With the patient under local anesthesia, we performed 2 vertical 1-cm incisions to the lymphocele and peritoneum, respectively. The Tenckoff catheter was first positioned into the lymphocele and the tunneled inside the peritoneal cavity. One cuff of the Tenckhoff was fixed to the fascia to avoid possible delocalization. The patients were discharged the same day. The catheter was removed 6 months later with no evidence of lymphocele recurrence.

Comparison of two techniques of arterial anastomosis during adult cadaveric liver transplantation.

Arterial complications are a major source of morbidity and mortality after orthotopic liver transplantation (OLT). The incidence of hepatic artery thrombosis (HAT) ranges from 1.6% to 8%, with a mortality rate that ranges from 11% to 35%. We have described herein a technique of arterial anastomosis aiming to perform the anastomosis as straight as possible to avoid any kinking, redundancy, or malposition of the artery when the liver is released in its final position. We compared this technique with the traditional technique of arterial anastomosis using an aortic Carrel patch, namely, 198 OLT (group A) with the traditional technique and 117 OLT (group B) with the modified technique. An aorto-hepatic bypass was necessary in 25% of the cases in group A and in 21% of the cases in group B (P = .33). Vascular anomalies were present in 20% of cases in group A and in 27.5% in group B (P = .14). Fourteen cases (7%) of HAT developed in group A versus 0 cases in group B (P = .003). In group B, we experienced 2 (1.7%) late arterial stenoses that were successfully treated using percutaneous transluminal angioplasty. The 14 cases of HAT occurring in group A were successfully managed using immediate surgical revascularization with graft salvage in 6 cases (43%), whereas the remaining 8 cases needed urgent retransplantation. We suggest that a technique of arterial anastomosis aimed at avoiding kinking, redundancy, or malposition of the artery may be a viable option to reduce the risk of HAT after OLT.

Superiority of transplantation versus resection for the treatment of small hepatocellular carcinoma.

The best therapy for hepatocellular carcinoma (HCC) is still debated. Hepatic resection (HR) is the treatment of choice for single HCC in Child A patients, whereas liver transplantation (OLT) is usually reserved for Child B and C patients with multiple nodules. The aim of this study was to compare HR and OLT for HCC within the Milan criteria on an intention-to-treat basis. Forty-eight patients were treated by OLT and 38 by HR. Three- and 5-year patient survival rates were significantly higher (P = .0057) in the OLT group (79% and 74%) than after HR (61% and 26%). The 3- and 5-year disease-free survival rate was better (P = .0005) for OLT (74% and 74%) versus HR (41% and 11%). The probability of HCC recurrences after resection was greater (P = .0002) than after transplantation, achieving 31% and 76% for HR and 2% and 2% for OLT at 3 and 5 years after surgery. The median waiting list time was 118 days; two patients dropped out for HCC progression. We concluded that OLT is superior to HR for small HCC in cirrhotic patients assuming that OLT can be performed within 6 to 10 months after listing to reduce dropouts due to tumor progression.

Peritoneal leiomyosarcoma in a kidney transplant patient: a case report.

Sarcomas are rare neoplasms, accounting for a 1.7% incidence among all transplanted patients presenting with de novo malignancies. Our present report focused on a 46-year-old woman who received immunosuppressive therapy based on cyclosporine and steroids for renal transplantation. Eight years after transplantations, she suffered lower abdominal pain and a mass involving peritoneal soft tissues was located near the right iliac vessels. Upon radical tumor excision, the histological examination revealed a high-grade leiomyosarcoma. Immunosuppression was reduced and cyclosporine switched to rapamycin. After 30 days, a computed tomography scan revealed two small pulmonary metastases, so the patient received adriamycin. Six months after the diagnosis, there was no intra-abdominal relapse and the pulmonary metastasis remain stable. The function of the transplanted kidney was normal and the patient was listed for laparoscopic pulmonary resection. Sarcomas in solid organ transplant patients appear to have aggressive features with 62% being high grade and 40% metastatic at the time of primary diagnosis with a recurrence rate of 30% and a 5-year survival rate of 25%. Patients diagnosed with sarcoma should be treated with multimodality therapy. After aggressive surgery whenever possible, a combination of a traditional cytotoxic drug and a "signal" blocking agent like rapamycin may increase selectivity toward tumor cells.

[Uretero-vescical anastomosis during kidney transplantation. Preliminary results of two surgical techniques]. / L'anastomosi uretero-vescicale nel trapianto di rene. Risultati preliminari di due tecniche a confronto.

AIM: The most frequent urologic complications after renal transplantation involve the uretero-vescical anastomosis (leakage, stenosis, and reflux), with a frequency of 1% to 30% in different series. METHODS: We present our results in a prospective randomized trial performed from October 2004 to September 2005, in a cohort of 36 patients, who underwent renal transplantation from cadaveric donor at our institution. A uretero-vescical anastomosis according to Lich-Gregoir was used in 18 cases (group A), whereas an anastomosis according to Knechtle was performed in other 18 patients (group B), respectively. The groups were comparable for donors and recipients characteristics. The mean donor age was 46.3 years vs 44.9 years, and the mean duration of cold ischemia was 1 086+/-296 min vs 1 100+/-381 min for group A and for group B respectively. The mean recipient age was 47.5 years vs 46.1 for group A and group B, respectively. RESULTS: No differences were evidenced between the two uretero-vescical anastomosis in term of surgical complications, infections or patient and graft survival at one year of follow-up. Stenosis and leakage involved 2 patients for each group respectively. Numbers of infections, days of antibiotic therapy were similar between the two groups. CONCLUSION: Our early experience does not evidence differences between the two types of uretero-vescical anastomosis.

Transient ischemic attack after rizatriptan administration in a liver transplant recipient: a case report.

We report the case of a male liver transplant recipient who developed de novo migraine while on tacrolimus therapy. Considering the inadequate control of pain using nonsteroidal antiinflammatory drugs, rizatriptan benzoate (10 mg orally) was administered (double administration). After both administrations a clinically transient ischemic attack (TIA) occurred. Rizatriptan was discontinued, the patient recovered without sequelae from both episodes of TIA. Remission of migraine occurred after discontinuation of tacrolimus and substitution with cyclosporine. We suggest that the association of rizatriptan and tacrolimus could potentially lead to an excessive risk of cerebral vasospasm and should be used with caution. A change in immunosuppressive therapy (from tacrolimus to cyclosporine or sirolimus) may improve migraine and should be the first choice. Further prospective comparative randomized trials are needed to establish the best therapeutic option in this particular subset of patients.

Comparison of clinical and pathological staging and long-term results of liver transplantation for hepatocellular carcinoma in a single transplant center.

Liver transplantation (OLT) is a treatment for hepatocellular carcinoma (HCC) superimposed on cirrhosis provided that the disease meets defined criteria. The aim of the study was to evaluate our experience with respect to clinical and pathological staging and long-term results. From 1996 to 2005, 50 patients underwent OLT for HCC including 43 men (86%) and seven women (14%) of median age 57 years (range 37 to 67). All patients fulfilled the Milan criteria. The HCC diagnosis was based on preoperative imaging and alpha-fetoprotein levels; no tumor biopsy was performed. Upon histological examination of the resected specimens, we discovered 6 (12%) incidentalomas and 8 (16%) cases of no HCC. Finally we had 42 "true" HCC. Twenty-six patients (52%) have been downstaged and 10 (20%) upstaged by preoperative imaging; 15% were pT1, 45% were pT2, 27% pT3, and 13% pT4a. Twenty-six percent of cases exceeded the Milan criteria. One patient (pT4a) with microvascular invasion died of pulmonary metastases at 14 months after transplantation. No HCC recurrences within the liver have been encountered at a median follow-up of 20 months (range 0 to 80 months). Overall the estimated 1-, 3-, and 5-year survival rates were 83%, 77%, and 72%, respectively. One-, 3-, and 5-year estimated survival rates were 87%, 75%, and 75% for pT1, and pT2, and 75%, 67%, and 67% for pT3 and pT4a, respectively (P = .99). Based on our experience OLT for HCC has long-term results comparable to those without HCC despite the presence of a significant number of cases exceeding the Milan criteria upon pathological staging.

The role of hepatic biopsy to detect macrovacuolar steatosis during liver procurement.

The ability to predict graft function before transplantation has proven to be a difficult task, especially for macrovacuolar steatosis that is considered a major cause of posttransplant dysfunction. It is well known that macrovacuolar steatosis greater than 25% influences the short- and long-term outcomes of liver transplantation. We retrospectively analyzed frozen sections from 43 donor livers comparing preoperative laboratory/clinical values, and liver ultrasound of a cohort of donors without (group A, n=21) versus with steatosis of 25% to 35% (group B, n=22) upon liver biopsy performed during harvesting. We analyzed the possible correlations between preoperative donor data and the degree of macrovacuolar steatosis. None of the biochemical and clinical parameters were related to the degree of hepatic steatosis. The only difference between the two groups was the echographic pattern, with evidence of 27% fatty liver by ultrasound in group B and 5% in group A (p=.04). The specificity of hepatic ultrasound for macrovacuolar steatosis was 95% and the sensitivity was only 27%, while the positive and negative predictive value were 86% and 55%, respectively. In conclusion, liver biopsy during donor harvesting remains the gold standard to identify macrovacuolar steatosis greater than 25%. Hepatic ultrasound has a role to exclude the presence of steatosis in normal livers due to its high specificity, but it is not useful to make the diagnosis of a fatty liver since it has a low sensitivity and negative predictive value. Thereafter a liver ultrasound positive for hepatic steatosis alone should not be considered a valuable tool to discard an organ from transplantation.

De novo malignancies after kidney and liver transplantations: experience on 582 consecutive cases.

De novo malignancies after transplantation are a growing problem of solid organ transplant recipients, due to longer survival follow-up under chronic immunosuppression. The aim of this study was to analyze a population of 582 consecutive kidney (n = 382) and liver (n = 202) transplant recipients, who survived at least 12 months after transplantation, at a single transplant center for the development of de novo cancers. The incidence of de novo malignancies was 7% after both renal and liver transplantation. The median elapsed time from transplant to the diagnosis of de novo malignancy was 45 months (range 3 to 220) months for kidney and 37 months (range 12 to 101 months) for liver transplants. Skin cancers were the most common within renal recipients, while gastroenteric cancers were more frequently encountered in liver transplants. Oropharyngeal and upper digestive tract tumors were always associated with a history of chronic alcohol consumption in liver recipients. Liver transplant recipients treated for acute rejection had a worse cancer prognosis than patients without rejection 1- and 2-year survivals 83% and 63% versus 36% and 17% (P = .026). The estimated 1- and 2-year survival rates for all types of de novo malignancies were 79% and 66%, including 64% and 51% for solid organ tumors versus 89% and 89% for skin cancers and posttransplant lymphoproliferative disorder (PTLD) (P = .17) in renal transplants and 70% and 42%, including 57% and 28% for solid organ tumors versus 85% and 64% for skin cancers and PTLD (P = .43) in liver transplants respectively.